genetics reflection essay

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Personal Reflections on the Origins and Emergence of Recombinant DNA Technology

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Paul Berg, Janet E Mertz, Personal Reflections on the Origins and Emergence of Recombinant DNA Technology, Genetics , Volume 184, Issue 1, 1 January 2010, Pages 9–17, https://doi.org/10.1534/genetics.109.112144

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The emergence of recombinant DNA technology occurred via the appropriation of known tools and procedures in novel ways that had broad applications for analyzing and modifying gene structure and organization of complex genomes. Although revolutionary in their impact, the tools and procedures per se were not revolutionary. Rather, the novel ways in which they were applied was what transformed biology.

Anecdotal, Historical and Critical Commentaries on Genetics

FREEMAN Dyson contrasts what he called the “Kuhnian” and “Galisonian” views of the origins of scientific revolutions in a review of Peter Galison's book, Einstein's Clocks, Poincare's Maps: Empires of Time ( Dyson 2003 ). In The Structure of Scientific Revolutions , Thomas Kuhn proposes that revolutionary breakthroughs in science are triggered primarily by ideas that, by their novelty, transform or replace the prevailing paradigm ( Kuhn 1962 ). By contrast, Galison (2003) attributes such breakthroughs to new tools that, by their nature, make possible new approaches to formerly intractable problems. Galison also acknowledges that the application of existing tools in novel ways often provides the means to explore what was previously impossible. As Alfred Hershey has been quoted saying, “There is nothing more satisfying to me than developing a method. Ideas come and go, but a method lasts” ( Stahl 1998 ).

The Galison view is exemplified by the genetic revolution in biotechnology, which relied on both the discovery of new tools and the use of existing tools in new ways. The key methodological advances were: (i) the discovery of enzymes that modify DNA molecules in ways that enable them to be joined together in new combinations; (ii) the demonstration that DNA molecules can be cloned, propagated, and expressed in bacteria; (iii) the development of methods for chemically synthesizing and sequencing DNA molecules; and (iv) the development of the polymerase chain reaction method for amplifying DNA in vitro .

Although the emergence of recombinant DNA technology was transformational in its impact, the tools and procedures that were the keys to its development largely emerged as enhancements and extensions of existing knowledge, i.e. , they were evolutionary, not revolutionary, in nature. What was novel was the numerous ways in which many investigators applied these technologies for analyzing and modifying gene structure and the organization of complex genomes. Especially striking was the rapidity with which the new technologies took hold and dominated research into many different biological problems. Today, recombinant DNA technology has altered the ways both questions are formulated and solutions are sought. Scientists now routinely isolate genes from any organism on our planet, alive or dead. The construction of new variants of genes, chromosomes, and viruses has become standard practice in research laboratories. Only science fiction one-half century ago, the introduction of new genes into microbes, plants, and animals, including humans, is a common occurrence. The tools of recombinant DNA greatly expedite sequencing of the genomes of humans and numerous other species. Along with these advances have come astonishing improvements in medical diagnoses, prognoses, and therapies. In addition, many commercial opportunities have been realized, with the United States being the world leader in the biotechnology industry. Equally profound is the influence these developments have had on many related fields. Even a cursory look at journals in such diverse fields as chemistry, evolutionary biology, paleontology, anthropology, linguistics, psychology, medicine, plant science, and, even, forensics, information theory, and computer science shows the pervasive influence of this new technology. This essay traces the conceptual and experimental origins of the recombinant DNA technology.

Background:

During the 1960s, enormous progress was made in understanding the structure of genes and the mechanisms of their replication, expression, and regulation in prokaryotes and the viruses that infect them. However, largely unknown at the end of that decade was whether these findings were applicable to eukaryotes, i.e ., organisms with an authentic nucleus, and, in particular, mammalian cells. The reason was that the experimental tools available at that time for exploring the molecular and genetic properties of mammalian organisms were woefully inadequate for the task.

One method that had been very powerful in investigations of the molecular biology of the most widely studied microbe, Escherichia coli , was the property of bacteriophage (commonly abbreviated “phage”) to transfer genes from one strain to another, a process referred to as transduction. For example, in the case of “generalized transduction” by phage P1, E. coli cells are infected with phage P1, the viral proteins are synthesized, the viral genome is replicated, and new infectious virus particles are assembled. However, concomitant with virus multiplication, random segments of the infected cell's DNA are also incorporated into newly formed virus particles in place of viral DNA. When such a pseudo-P1 phage “infects” a bacterium, neither virus replication nor cell death occurs. Instead, the bacterial DNA contained within the pseudo-P1 phage enters the bacterium and recombines at low frequency with the cell's chromosome to become a permanent part of that cell's genetic makeup. If the newly acquired bacterial DNA confers a measurable or selectable property, the rare recombinant can be recovered using an appropriate selection condition. In this way, any part of the genome of one E. coli strain can be transferred to the genome of another E. coli strain. Zinder's recollections of his and Lederberg's discovery of bacteriophage-mediated gene transfer in bacteria has been described in an earlier Perspectives article ( Zinder 1992 ).

An alternate way of transferring genes from one E. coli cell to another is exemplified by phage λ-mediated “specialized transduction.” In this system, transduction occurs when the phage DNA integrates into the infected cell's chromosome, and bacterial DNA adjacent to the site of integration is excised and packaged into phage particles along with the viral DNA. The cellular DNA acquired by the phage can then be transferred to new hosts during subsequent rounds of infection. These two modes of virus-mediated transduction are distinctive in that phage P1 can transfer DNA from any region of the bacterial chromosome while phage λ transfers only regions of the bacterial chromosome adjacent to sequence-specific phage λ integration sites ( Campbell 2007 ).

It seemed reasonable to consider whether a comparable virus-mediated gene-transfer system exists for mammalian cells. The small DNA viruses, polyoma and SV40, were deemed to be good candidates. It was already known that infection of cultured mouse cells with polyoma virus results in the production of infectious polyoma progeny and virus particles containing exclusively mouse DNA. Importantly, the mouse DNA contained in these polyoma “pseudovirions” is representative of the entire mouse genome. A similar finding was made with the related primate virus, SV40. However, in this case, some virus particles are produced in which host cellular DNA is covalently joined to the viral DNA. Might it be possible, we mused, that polyoma or SV40 could be used to transfer genes from one mammalian cell to another in much the same way that phage transfer genes among bacteria? On the face of it, that seemed unlikely for the following reasons. The amount of bacterial DNA that can be accommodated in a phage P1 particle is ∼2% of the E. coli genome; somewhat less cellular DNA can be transferred by phage λ. By contrast, polyoma and SV40 virions can accommodate only 5–6 kbp of DNA, i.e. , roughly one-millionth of a mammalian genome. Thus, the probability of acquiring a specific mammalian gene in a polyoma or SV40 virion particle is at least four orders of magnitude lower than is the probability that a P1 or λ phage particle will contain one or more specific E. coli genes. In addition, the difficulty of picking out a specific, unique segment of mammalian DNA without having on hand a very strong method of selection or detection made the whole notion rather infeasible.

An alternative that seemed worth exploring was whether specific segments of mammalian, or any DNA for that matter, could be recombined with SV40 DNA in vitro . That would bypass the need for the recombinant product to be incorporated into a virus particle. This idea was attractive because mammalian cells have the capacity to take up “naked” DNA such as the SV40 genome, integrating it into the host cell's genome. Thus, any DNA covalently linked to SV40 DNA could become integrated into the chromosomes of a mammalian cell along with the viral DNA. In theory, such cells could be screened or selected for the presence and expression of both the SV40 and foreign DNAs. Thus, the first step toward achieving this game plan involved devising a method for introducing foreign DNA into the SV40 genome.

In early 1971, the American Cancer Society approved a grant application in which Berg proposed to develop the means for transducing foreign DNA into mammalian cells ( Berg 1970 ). In the proposal, he identified SV40 DNA as the vector because it can be taken up by rodent and primate cells, including human ones, where it can replicate to high copy number as an autonomous plasmid or integrate into the host cell's genome. For the recombinant partner, the DNA would, ideally, be one (i) whose integration and possible expression in mammalian cells could be assayed, (ii) that could replicate as an autonomous plasmid in E. coli , and (iii) that has a gene whose expression could provide a way to screen or select E. coli cells containing the DNA.

But first, a method for joining together two DNAs in vitro needed to be developed. The plan was based on the knowledge that the bacteriophage λ genome exists as a linear DNA molecule within its virus particle, yet becomes a circular molecule following infection of its host, E. coli . That property stems from the existence of complementary, single-stranded extensions on the 5′-ends of the linear phage λ DNA enabling the ends to be joined ( Hershey et al . 1963 ). At low DNA concentration, intramolecular base pairing of these complementary single-stranded ends leads primarily to the formation of monomeric circular DNA molecules; at high DNA concentration, intermolecular end-to-end joining leads primarily to the formation of oligomeric DNA molecules. Such complementary ends are referred to as being “cohesive” or “sticky.” Furthermore, these hydrogen-bonded rings can be sealed in vitro by incubation with DNA ligase to create covalently closed circular DNA molecules ( Gellert et al . 1968 ; Wu and Kaiser 1968 ). Thus, it seemed attractive to consider constructing “artificial” cohesive ends as the strategy for joining together two different DNAs.

Following that strategy required a procedure for constructing short stretches of complementary nucleotides onto the ends of the two molecules to be recombined and to rely on their capacity to base pair in vitro to effect the joining. The enzyme terminal deoxynucleotidyl transferase (TdT) seemed admirably suited for this purpose since it was known to synthesize chains of a single nucleotide onto the 3′-ends of duplex DNA when a single nucleoside triphosphate is provided as the nucleotidyl donor ( Kato et al. 1967 ). Synthesizing short polynucleotide chains of adenylates onto the 3′-ends of one DNA and approximately the same length polynucleotide chains of thymidylates onto the 3′-ends of the other DNA would create the necessary cohesive ends for joining together two DNA molecules. David Jackson 4 and Robert Symons 5 undertook the task of exploring this approach.

Peter Lobban 6 independently conceived the idea of using a series of enzymes to covalently join DNAs together in vitro while fulfilling the Stanford Biochemistry Department's requirement for Ph.D. students to write and defend an original research proposal ( Lobban 1969 ).

Lobban's stated goal was to create a λ phage-based transduction system by replacing nonessential DNA in the middle of the phage λ genome with “foreign” DNA ( Figure 1 ). He proposed to isolate DNA segments derived from the left and right “arms” of λ phage DNA and then to join the foreign DNA to the two internal ends of these arms. The cohesive ends present on the left and right arms would be left intact to permit the recombinant genome to circularize and replicate. The formation of the recombinant was to be achieved by using TdT to add short polymeric tails to the 3′-ends of the foreign DNA and complementary polymeric tails to the internal 3′-ends of the left and right arms of the λ DNA.

“Steps in the creation of transducing genomes (digestion with λ exonuclease not shown),” the procedure originally proposed by Lobban for inserting “foreign DNA” into the left and right arms of phage λ DNA in vitro . Reproduced from Figure 3 of Lobban (1969) .

In his proposal and Ph.D. thesis ( Lobban 1972 , Lobban ) foresaw the prospect of inserting any foreign DNA, including from mammalian cells, into the phage DNA. He suggested that such an approach might enable specific mammalian genes to be identified and their mRNA and protein products to be detected and recovered in E. coli . He speculated that there would be many uses for such transducing phage, including “genetic engineering” ( Lobban 1969 , 1972 ). However, rather than directly pursuing the construction of a λ phage transducing virus as proposed, Lobban decided it would be better to focus initially on developing an in vitro DNA joining protocol to form circular dimers of phage P22 DNA from P22 DNA monomers ( Lobban 1972 ; Lobban and Kaiser 1973 ). His reasoning was that the latter was a better model system for working out the detail methodology since P22 phage DNA naturally has blunt ends and is circularly permuted and, therefore, would be unable to dimerize without the addition of (dA) n and (dT) n tails.

During this period, Lobban and Jackson were in close communication, freely sharing enzymes and their findings while they worked on their respective projects. Unbeknownst to them, Jensen et al. (1971) were also attempting to join together two DNAs in vitro by synthesizing complementary tails with TdT followed by incubation with DNA ligase in the presence of DNA polymerase I; in this case, they used phage T7 DNA as the two templates. Clearly, the idea of joining together DNAs by generating cohesive ends with TdT was a logical extension of facts already known to many biochemists at this time.

A suitable DNA for linking to SV40 DNA was developed during the winter of 1971 through the collaborative efforts of D. Berg 7 et al .(1974). This DNA, called λ dvgal 120, contains both the genes from phage λ necessary for replication as an autonomous plasmid in E. coli and an intact gal operon, i.e ., the three genes from E. coli needed for metabolizing galactose. At the time, Mertz also showed that purified λ dvgal 120 DNA could be reestablished as an autonomously replicating plasmid in E. coli using a procedure originally developed by Mandel and Higa (1970) for transformation of linear phage DNAs. Thus, both the mammalian and bacterial cloning DNAs were in hand, along with methods for reintroducing them into their host cells.

Several kinds of experiments could potentially be explored with an SV40-λ dvgal 120 recombinant DNA. One was to determine whether the E. coli gal operon is expressed in mammalian cells and, if so, to study its expression and regulation in that environment. The other objective was to determine whether the SV40-λ dvgal 120 plasmid DNA could replicate autonomously in E. coli . The latter would provide a way (i) to produce large quantities of SV40 DNA and, possibly, its encoded proteins, and (ii) to generate mutants of SV40 in vitro or in vivo that could be propagated in E. coli and their phenotypes assessed by introduction into mammalian cells.

Creating recombinant DNA in vitro :

Both SV40 and λ dvgal 120 exist naturally as circular DNA molecules. Thus, as a first step, methods were needed to cleave each of them once to produce full-length linear molecules. This task was achieved in two ways. One procedure relied on the fact that circular DNAs can be cleaved to linear molecules by incubation with pancreatic DNase I in the presence of the divalent cation Mn 2+ , a condition that limits the reaction to one or two double-stranded cleavages per molecule ( Melgar and Goldthwait 1968 ). The second procedure grew out of the seminal findings of Kelly and Smith (1970) and Danna and Nathans (1971) that some restriction endonucleases can be used to quantitatively cleave DNAs at unique sites. By testing several DNA restriction enzymes, John Morrow 8 found one, Eco RI endonuclease, an enzyme from E. coli discovered by Herbert Boyer, 9 that cleaved both SV40 ( Morrow and Berg 1972 ) and λ dvgal 120 (D. Berg et al. 1974 ) DNA once at unique sites. The latter method was chosen for our studies because it generated much higher yields of linear DNAs that were both unit length and devoid of single-strand nicks.

On the basis of a finding by Lobban, Jackson and Symons pared back the 5′-ends of the duplex linear DNAs with a λ phage-encoded 5′-exonuclease to improve the TdT-catalyzed addition of nucleotides at the 3′-ends. Accordingly, they digested Eco RI-cleaved SV40 and λ dvgal 120 DNAs with λ 5′-exonuclease to create 3′-extensions and then added 50–100 adenylate nucleotides to the 3′-ends of the SV40 DNA and 50–100 thymidylate nucleotides to the 3′-ends of the λ dvgal 120 DNA ( Figure 2 ). Specific annealing conditions led to the formation of noncovalently associated chimeric circular DNA molecules. Because the (dA) n and (dT) n tails had only approximately similar lengths, there were gaps at the (dA) n :(dT) n joints. These gaps were filled in using E. coli DNA polymerase I in the presence of the four deoxynucleoside triphosphates and exonuclease III, and the joints were covalently sealed using E. coli DNA ligase I. Exo III was included in the final reaction mixture because Lobban had found that the enzyme's presence greatly increased his yield of covalently closed circular P22 dimers. Jackson proved he had succeeded in constructing covalently closed SV40-λ dvgal 120 chimeric DNA molecules in vitro by separating them from the unreacted linear DNAs by CsCl-ethidium bromide equilibrium centrifugation and documenting their existence and size by electron microscopy ( Jackson et al. 1972 ).

Method used by Jackson et al. (1972) for constructing SV40-λ dvgal 120 recombinant DNA in vitro.

Thus, by the spring of 1972, the first chimeric recombinant DNA had been produced by sequentially using six enzymes with previously known properties: Eco RI endonuclease provided by Boyer and the others provided by colleagues in the Stanford Biochemistry Department. Undoubtedly, the ready availability of all of the above-mentioned enzymes and the expertise in their use was a very important contributor to the venture's success. Noteworthy is the fact that none of the individual procedures, manipulations, and reagents used to construct this recombinant DNA was novel; the novelty lay in the specific way in which they were used in combination. The procedure outlined above worked well with two relatively pure DNAs. However, the complexity of the products is problematic with mixtures of DNAs. Indeed, when David Hogness 10 and his colleagues used the (dA) n :(dT) n joining procedure to recombine random-sized fragments of Drosophila DNA with a bacterial plasmid, they ended up with a complex mixture of inseparable recombinants ( Wensink et al. 1974 ). To overcome that problem, a method was needed to enrich or, preferably, completely separate recombinants one from another.

The plan to construct SV40-λ dvgal 120 recombinant DNAs and to propagate them in E. coli became public in July, 1971, while Mertz was taking a course on animal cells and viruses at the Cold Spring Harbor Laboratory. Upon hearing her description of this project, Robert Pollack, the course's instructor, expressed concern about it. His anxiety, soon repeated by others, centered on the facts that: (i) SV40 can promote oncogenic transformation of human cells in culture and produce tumors in rodents; and (ii) E. coli , the presumptive carrier of the recombinant plasmid, is a natural inhabitant of the human intestinal tract. Most of the scenarios imagined the inadvertent or intentional release of E. coli carrying the SV40 DNA, with the attendant potential to spread a cancer-causing gene within the human population. Our initial reaction was that those fears were overblown and that procedures could be designed to mitigate against those risks. While some experienced tumor virologists and bacteriologists were also dismissive of the fears of the potential hazards, others thought the likelihood of something amiss happening were quite small, but not absolutely zero. Although there was little reason to believe that the SV40-λ dvgal 120 recombinant DNA itself posed a risk to human health, we, nevertheless, agreed after considerable hesitation to defer the introduction of this chimeric DNA into E. coli until better assessments regarding its safety were developed.

Prompted by concerns relating to the possible oncogenic potential of SV40 in humans, Berg and other prominent scientists convened a meeting to assess the risks of working with tumor viruses and recombinant DNAs that contain them. That meeting, sponsored by the National Institutes of Health and the National Science Foundation, was held in January, 1973 at the Asilomar Conference Center in Pacific Grove, California. Although no well-documented problems arising from working with these agents were uncovered, several recommendations were made for scientists working with them ( Hellman et al. 1973 ). These recommendations included to periodically monitor researchers who work with tumor viruses for infection, to prohibit pipetting by mouth, and to use laminar flow hoods during all manipulations involving potentially infectious material.

Shortly thereafter, another important breakthrough occurred. In the spring of 1972, Mertz discovered an unexpected property of the Eco RI endonuclease. She had repeatedly observed that Eco RI-cleaved linear SV40 DNA is approximately one-tenth as infectious as circular SV40 DNA in monkey cells; the recovered replicated viral DNA is circular and contains an intact Eco RI site. Although Kelly and Smith (1970) had shown that the restriction endonuclease they had characterized from Haemophilus influenza cleaves DNA leaving blunt ends, Mertz hypothesized that Eco RI-cut SV40 DNA contained cohesive ends and that it could form circles by annealing of these ends in the same way that linear phage λ DNA forms circles. Using electron microscopy, she showed that incubation of Eco RI-cut linear SV40 DNA with E. coli DNA ligase I at 15° results in the efficient reformation of covalently closed circular DNA molecules. Then, working in collaboration with Ronald Davis, 11 Mertz determined that, although less than 1% of Eco RI-cut SV40 DNA molecules are circular when spread in 50% formamide at room temperature, more than half of them are circular when incubated and spread at 3°. Thus, the ends created by cleavage with Eco RI endonuclease are cohesive. The T m for the circular-to-linear molecule transition is 6°. Mertz and Davis (1972) also found that at least 18 of the 19 fragments of various lengths produced by Eco RI cleavage of an ∼74-kbp plasmid, F8 (P17), can form intramolecular circles when incubated and spread for electron microscopy at 3°. Thus, they concluded that all ends created by Eco RI cleavage are probably identical, cohesive, and can be joined together with DNA ligase.

To demonstrate directly that the cohesive ends created by Eco RI cleavage could be used to create chimeric DNAs, they also incubated Eco RI-cleaved SV40 DNA and Eco RI-cleaved λ dvgal 120 DNA together in equimolar amounts at high DNA concentration with E. coli DNA ligase I at 15°. While the linear DNAs ligated separately had distinctive buoyant densities in CsCl, most of the molecules produced when the two DNAs were ligated in the same reaction mixture had an intermediate buoyant density. Taken together, these experiments definitively established that any two DNA molecules whose ends are created by cleavage with Eco RI endonuclease can be readily joined together by ligation in vitro . Electron microscopic analysis of the lengths of these chimeric DNA molecules indicated that most consisted of circular DNAs containing a mixture of three or more copies of the input DNAs. Thus, the products of this reaction probably included some containing two or more tandem copies of λ dvgal 120 DNA covalently linked to one or more copies of SV40 DNA. These chimeric molecules would have been able to replicate in E. coli. However, that supposition was not tested because of our self-imposed moratorium on producing E. coli containing SV40 oncogenes.

Boyer was promptly informed about the discovery that cleavage of DNA with Eco RI endonuclease generates cohesive ends. Together with Joe Hedgpeth 12 and Howard Goodman, 13 Boyer used this knowledge to determine that the nucleotide sequence of the 5′-extensions generated by cleavage with Eco RI endonuclease is 5′-AATT-3′ ( Hedgpeth et al. 1972 ). This finding agreed well with the Mertz and Davis (1972) estimate of 4 or 6 bases obtained by measuring the T m for annealing of the ends.

Cloning in bacteria:

Prior to 1972, Stanley Cohen 14 had been studying the structure and replication of DNA plasmids such as pSC101 that bear antibiotic resistance genes in bacteria. Aware of the not-yet-published findings of Mertz and Davis (1972) and D. Berg et al . (1974) , Cohen realized that these techniques could be quite helpful for his research. In collaboration with Annie Chang 15 and Leslie Hsu, 15 Cohen showed that Eco RI endonuclease-cleaved pSC101 DNA can be taken up by E. coli where it recircularizes and replicates as an autonomously replicating plasmid ( Cohen et al. 1972 ). Next, Cohen, Chang, Boyer, and Robert Helling 16 (1973) relied on the cohesive property of Eco RI endonuclease-generated ends to recombine pSC101 with a segment of DNA from an E. coli plasmid that contained a different antibiotic resistance gene; the new plasmid could be propagated in E. coli where it expressed both antibiotic resistance properties. Chang and Cohen (1974) then constructed a wholly novel interspecies recombinant plasmid by joining together pSC101 and a plasmid DNA originating from the gram-positive bacterium, Staphylococcus aureus. This chimeric plasmid propagated efficiently in gram-negative E. coli , exhibiting the unique antibiotic resistance characteristics of both parental plasmids. Thus, Cohen and his collaborators demonstrated that novel recombinant DNAs created in vitro , including even interspecies ones, can be cloned, propagated, and expressed in E. coli .

The finding that DNAs of different microbial origins can be propagated in E. coli still left unanswered the provocative, key question of whether eukaryotic or, for that matter, any DNA can be cloned in a bacterial host. John Morrow, who was finishing his Ph.D. thesis research in 1973 in Berg's laboratory and was aware of the Mertz and Davis (1972) and Cohen et al. (1972 , 1973 ) discoveries, undertook to answer that question. Knowing about the concerns of introducing potentially biohazardous genes into bacteria, Morrow proposed to Boyer at the June 1973 Gordon Conference on Nucleic Acids that they attempt to propagate Xenopus laevis ribosomal DNA in E. coli . Morrow had already determined that a sample of purified X. laevis ribosomal DNA obtained from Donald Brown, Morrow's prospective postdoctoral mentor, was cleaved by Eco RI endonuclease. With Cohen joining the collaborative effort, pSC101 was chosen as the cloning vector because it contained a readily selectable marker. After ligating the mixture of Eco RI-cleaved pSC101 and X. laevis ribosomal DNAs, they selected and characterized clones expressing the pSC101-encoded antibiotic resistance gene. The outcome was quite clear: ∼20% of the bacterial clones containing pSC101 DNA also contained 18S or 28S X. laevis ribosomal DNA ( Morrow et al. 1974 ). In some instances, RNA complementary to the X. laevis ribosomal DNA could be detected in the cells containing the chimeric plasmid DNAs, although these RNAs probably arose from transcripts initiated within pSC101 sequences. Thus, the Morrow et al. experiment demonstrated that genes from a eukaryotic organism can be cloned and replicated in E. coli .

The profound implication of this experiment was that DNA from any organism on the planet could probably be cloned and propagated in E. coli . This experiment also provided a prototype for many subsequent ones aimed at cloning specific genes. By 1976, Davis and his colleagues demonstrated functional expression of a protein-coding gene from yeast ( Struhl 2008 ). Eventually, cloning served as the archetypical approach used to sequence entire genomes. It also paved the way toward creating E. coli containing recombinant plasmids in which genes encoding proteins or RNAs are linked to regulatory sequences, thereby enabling the expression of their products.

Patenting and start of biotechnology industry:

None of the members of the Berg, Kaiser, or Davis groups ever considered patenting the reagents or procedures that were used for recombining DNA in vitro . Neither had the scientists who discovered TdT, DNA polymerases, DNA ligases, exonucleases, and restriction enzymes ever sought patents for their efforts. Indeed, few, if any, of the discoveries, reagents, and methods that constitute the foundations of molecular biology were ever patented. While some academic institutions such as the University of Wisconsin–Madison had a long history of patenting inventions in the biological and biochemical sciences ( e.g. , vitamins, antibiotics), the sociology among most U. S. life scientists prior to the 1970s was to eschew patents, believing that they would restrict the free flow of information and reagents and impede the pace of discovery. However, that reticence disappeared in November, 1974 when Stanford University and the University of California at San Francisco jointly filed a United States patent application citing their respective faculty members, Stanley Cohen and Herbert Boyer, as the sole inventors of the recombinant DNA technology. Their claims to commercial ownership of the techniques for cloning all possible DNAs, in all possible vectors, joined in all possible ways, in all possible organisms were dubious, presumptuous, and hubristic. Nevertheless, these claims, only slightly modified, were eventually approved in 1980 by the U. S. Patent Office ( Cohen and Boyer 1980 ). By employing what proved to be very wise terms regarding licensing and royalties, the two universities collectively garnered nearly $300 million in revenues during the life of this and two other related patents. Following university practices, Cohen, Boyer, and their respective university departments each received shares of the income from the “Cohen-Boyer patents,” while the institutions' shares were used to support universitywide research and education. In retrospect, Stanford's and UCSF's action set in motion an escalating cascade of patent claims by universities covering their faculties' respective discoveries that continues to this day. The emergence of the biotechnology industry followed naturally from the encouragement of academic scientists to patent their research discoveries and to explore their newly discovered entrepreneurial instincts. The early successes of Genentech, Biogen, and Amgen owe much to those encouragements. The events leading to the approval of the Cohen-Boyer patents and the founding of the biotechnology industry are described in detail by Hughes (2001) and Yi (2008) .

Development of regulatory guidelines:

Boyer's presentation of the Cohen et al. (1973) experiments, resulting in the creation of plasmids with novel combinations of antibiotic resistance genes, triggered concerns about the safety of such recombinants among the participants attending the June 1973 Gordon Conference on Nucleic Acids ( Singer and Söll 1973 ). In response to those concerns, the U. S. National Academy of Sciences (NAS) asked Berg to convene a committee of scientists who were familiar with and likely to use the new tools in their own research. That committee was asked to examine the scientific prospects and potential risks of what came to be known as recombinant DNA. Just before the committee met, news of the Morrow et al. (1974) experiment became known. Even though this experiment involved the cloning of a DNA segment generally accepted as being quite innocuous, its success was viewed as having “opened the door” to cloning DNAs from any biological source, including viruses, toxin-coding genes, and mammalian oncogenes. At the spring 1974 meeting of the NAS committee, the participants acknowledged that recombinant DNA technology had great promise for advancing basic and applied biology, but agreed there was insufficient information and data to determine the magnitude, if any, of the risks (P. Berg et al. 1974 ). In light of the uncertainty, the committee recommended that certain types of DNA cloning experiments be deferred until a conference of experts could be convened to assess the nature of the benefits and risks associated with such research.

The International Conference on Recombinant DNA was convened in February of 1975 at the Asilomar Conference Center in Pacific Grove, California. After considerable debate, the conference recommended that the moratorium on the previously deferred experiments be lifted and replaced with guidelines governing such research ( Berg et al. 1975 ). In the summer of 1976, the National Institutes of Health issued its first set of Guidelines for Research Involving Recombinant DNA . These guidelines and analogous ones from other international jurisdictions along with their updates have been adhered to throughout the world. In the over three decades since adoption of these various regulations for conducting recombinant DNA research, many millions of experiments have been performed without reported incident. No documented hazard to public health has ever been attributable to the applications of recombinant DNA technology. Moreover, the concern that moving DNA among species would breach customary breeding barriers with profound effects on natural evolutionary processes has substantially diminished as research has revealed such exchanges occur in nature as well. Table 1 summarizes the chronology as we know it of the events described in this essay.

Chronology of main events relating to development of methods for constructing and cloning recombinant DNAs

Year(s) in which event occurred.

Impacts of recombinant DNA technology:

The most far-reaching consequence of the emergence of the recombinant DNA technology has been the great strides made in understanding fundamental life processes and the ability to investigate problems that had previously been unapproachable. Emerging from myriad investigations has been the appreciation that nothing in the man-made world rivals the complexity and diversity of this earth's organisms. No man-made information system invented to date comes anywhere close to containing the amount of information encoded in their genomes or encompassing the complexity of the intricate machinery for their functioning. We have learned enough to reveal how much we do not know and to acknowledge that nature's secrets are not beyond our capabilities of discovery.

The advances made possible by recombinant DNA technology have profound implications for the future of medicine for they have placed us at the threshold of new methods of diagnosis, prevention, and treatment of numerous human diseases. Hormones, vaccines, therapeutic agents, and diagnostic tools developed using recombinant DNA methods are already greatly enhancing medical practice. Although the production and consumption of genetically engineered food are realities, the benefits have yet to be fully realized. Nevertheless, recombinant DNA technologies will, undoubtedly, play roles in the future in increasing the supply of both food and energy needed by the world's growing human population.

This article is dedicated to Arthur Kornberg, who fostered a group of colleagues that made this work possible.

Paul Berg was professor and chair of the Biochemistry Department at Stanford University Medical Center at the time of the events described here.

Janet Mertz was a graduate student in P. Berg's laboratory from 1970 to 1975.

David Jackson was a postdoctoral fellow in P. Berg's laboratory.

Robert Symons was a visiting professor in P. Berg's laboratory.

Peter Lobban was a graduate student in A. D. Kaiser's laboratory in the Biochemistry Department at Stanford University.

Douglas Berg was a postdoctoral fellow in A. D. Kaiser's laboratory.

John Morrow was a graduate student in P. Berg's laboratory.

Herbert Boyer was an associate professor in the Department of Microbiology at University of California, San Francisco (UCSF).

David Hogness was a professor in the Biochemistry Department at Stanford University.

Ronald Davis was an assistant professor in the Biochemistry Department at Stanford University.

Joe Hedgpeth was a postdoctoral fellow in Boyer's laboratory.

Howard Goodman was an associate professor in the Department of Biochemistry and Biophysics at UCSF.

Stanley Cohen was an assistant professor in the Department of Medicine at Stanford University.

Annie Chang and Leslie Hsu were technician and graduate student, respectively, in Cohen's laboratory.

Robert Helling was a postdoctoral fellow in Boyer's laboratory.

We thank Douglas Berg, William Dove, David Jackson, A. Dale Kaiser, Peter Lobban, John Morrow, Maxine Singer, and Adam Wilkins for their suggestions for improving this article and Peter Lobban for permission to reproduce Figure 1 . Much of the work described here was funded in large part by grants to Paul Berg from the National Institutes of Health and the American Cancer Society.

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History, philosophy, and science education: reflections on genetics 20 years after the human genome project

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• Published: 25 April 2023
• Volume 45 , article number  18 , ( 2023 )

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Kampourakis, K. (2017). Making Sense of Genes . Cambridge University Press.

Rheinberger, H.-J., & Müller-Wille, S. (2017). The Gene: From Genetics to Postgenomics . University of Chicago Press.

They did it again! Kostas Kampourakis begins his book Making sense of genes with a few examples of headlines in respectable newspapers. Among them a 2014 headline from The Guardian : “‘Happy gene’ may increase chances of romantic relationships”. On October 20, 2021, the same outlet published a piece titled “Your green credentials may be linked to your genes, study says”. Most likely, there were many similar articles in-between.

The latter reports on a study that surveyed identical and non-identical twins on their concern for nature, environmental movement activism, and personal conservation behavior. The fact that identical twins had more similar responses than non-identical twins is interpreted by the researchers as “suggesting genetic influences on these phenotypes” (Chang et al., 2021 , p. 3). This result is then connected to an evolutionary narrative about altruistic and cooperative behavior.

Of course, the researchers are quick to emphasize that such traits are caused by a “combination of genes and environments” and that this is “just about probability, not determinism.” And for sure, the journalist is critical. As is common for such reports, another expert, “who was not involved in the study,” is asked to evaluate the results. This researcher emphasizes that a large number of genes are involved in many processes, which contribute to such traits. He also points out that climate change, after all, is a “political problem” Footnote 1 .

No outrageous statements are made here. No one identifies a “gene for environmentalism.” The researchers use an established rhetoric to hedge their claims, and the journalist brings in critical peers. And yet, it appears that we haven’t come a long way since the days when the eugenicist Charles Davenport postulated genes “for” about everything, famously including thalassophilia . What will the reader of the Guardian piece come away with? Well, most likely that there are genes for environmentalism. And the outcome could not be more fatal in this case (literally!). Because ever since Francis Galton began to discuss human behavior in terms of heredity, what followed from such allocations of genetic responsibilities has been a deflection from the responsibility of a moral agent. If I do not feel inclined to act in a sustainable manner, then it is probably simply not in my nature.

There is so much amazing science out there that deserves more publicity. But if any third-rate scientific journal publishes a study that links genes to some interesting behavior, be sure some major news outlet picks it up. The fact that humans have different attitudes and show different behaviors never ceases to irritate people. Any claim that seems to explain these differences is welcome, no matter how vague or simplistic (because these are basically the two options available to make such claims).

For someone who knows the science studies literature on genetics (I am following Kampourakis here in using the term ‘genetics’ broadly to include genomic and post-genomic studies concerned with genes or genetic material), the continued prevalence of such reports is remarkable. And it is also the reason why Kostas Kampourakis’ book is so relevant even 20 years after the Human Genome Project (HGP) and the accompanying deluge of books and articles critical of gene centrism and genetic determinism (e.g., Kevles & Hood, 1993 ; Lewontin, 1993 , 2000 ; Nelkin & Lindee, 1995 ; Keller, 2000 ; Sloan, 2000 ; Barnes & Dupré, 2008 ; see also Gannett, 2022 ).

Most people know fairly little about genetics but are nonetheless frequently confronted with claims about genes regarding crucial aspects of their life, from behavior to disease. Accordingly, for most people it is difficult to interpret such claims. Kampourakis’ book addresses anyone who wishes to gain competence in evaluating such information and in particular those who teach genetics in schools and universities, and to biology as well as humanities students. It would also be useful to physicians and health-care professionals as well as biologists who are attentive to the ways in which they communicate their scientific or diagnostic results, and to journalists disseminating research outputs. The book focuses on science education and communication, but it draws on arguments from the history and philosophy of genetics. The historical genealogies of contemporary discourse (Chs. 1–4) as well as the philosophical interpretation of the complexities of genetics (Chs. 9–12) are substantial and constitute an important framing for the discussion of how genes figure in public and professional discourse regarding biology and medicine, which is at the core of the book (Chs. 5–8). However, readers mainly interested in the history of genetics might want to consult the second book discussed below, while readers with a focus on philosophical issues might turn to Griffiths and Stotz’s Genetics and Philosophy ( 2013 ).

Kampourakis’ book is strongest where it explains those biological processes or relations that lie at the heart of the claims about the influence of genes on traits or diseases that lay persons encounter in various contexts from newspaper articles to the results of direct-to-consumer genetic tests. Chapter 7, for instance, uses concrete examples of ‘genetic’ diseases to explain the relation of genes, gene products, and environments to disease phenotypes. Also, the various technologies and approaches by which genetic evidence is produced are explained, for instance, genome-wide association studies (GWAS) in Chap. 6. Most laudably, notoriously difficult to understand concepts such as heritability (Ch. 10) are well explained and made intelligible. The same is true for the statistical nature of most claims about the relation between genes and diseases such as cancer; the meaning and adequate interpretation of such claims is clarified in Chap. 12.

Chapter 5, however, constitutes a conundrum, which points to an inherent problem of the book. The chapter is meant to show that the problem that the book addresses – the prevalence of genetic determinism in public and professional discourse – indeed exists. However, most of the studies cited, which look at messages from newspapers and movies and investigate the attitudes of lay people, students, and health-care professionals cannot really substantiate the claim. In fact, they provide either relatively weak evidence for the alleged problem or even evidence to the contrary. Already Condit ( 1999 ) seems to conclude that genetic determinism neither dominates public discourse on genetics, nor does it increase over the course of the twentieth century. It is very honest to present this evidence that does not fully support the main assumption of the book, as the author admits. At this point, the author goes on to suggest that the intuition of essentialism (underlying determinism) could be inborn (pp. 94–95), a view which would represent exactly the kind of deterministic claim that the book problematizes! All this remains unsatisfactory, especially if you agree with the author that the problem is real.

In my view, part of the problem is that the book operates with a caricature of genetic determinism (as well as genetic essentialism and reductionism). It begins by defining genetic determinism as the view that “genes invariably determine characters, so that the outcomes are just a little, or not at all, affected by changes in the environment” (p. 6). Accordingly, the author (and presumably also the researchers who conducted the cited studies on the prevalence of genetic determinism) interprets as non-deterministic any presentation or perception of genetic claims that acknowledges an interaction of genes and environment or the probabilistic nature of genetic influence etc. For this reason, the only thing these studies can show is that people are not entirely naïve about genetics (i.e., they do not hold the strongest version of determinism as portrayed in the caricature). While this result is reassuring, the point is that even if one gets the basics right (genes only account for variation; genes interact with the environment; genes exert their influence in a probabilistic manner, etc.), one can still get many things wrong. And indeed, the book in other parts does an excellent job in showing just that!

Also the notion of “genes for x”, where x would typically be some morphological or behavioral character or disease, is interpreted in the maximally uncharitable manner by Kampourakis when he debunks it by stating that “genes do not alone produce characters or disease” (p. 8, p. 155, p. 170; note the shift from “determine” to “produce”) or characterizes the notion as referring to “genes as character makers” (p. 32, p. 188; in the latter location the phrase is meant to characterize a quotation which, however, could well be read as depicting genes as “character-difference makers” instead). It would of course be hard to prove, but I would argue that no geneticist in the twentieth century held a view that could be fairly represented by such formulations (i.e., that genes alone ‘produce’ or ‘make’ characters). In fact, not even the organically growing hereditary particles postulated in the speculative theories of the nineteenth century (from Darwin’s “gemmules” to Weismann’s “biophores” and “determinants”, see e.g. Churchill, 2015 ) can be interpreted as character makers. First, because the concept of character always implied a difference (it stems from taxonomy), while what grows is a part; and second, because these particles were mainly meant to explain the presence of various cell types rather than characters which would typically involve (differences in) many cell types. The result of this exaggeration of the determinism that is seemingly implied in common talk about genes, is that the more subtle, but also more common and thus more problematic mis-conceptions are sidelined. In other words, the book could have been stronger if it had acknowledged that views of genes as difference makers, as interacting with the environment, and as acting probabilistically are widely held and that mis-representations and mis-interpretations arise despite this common wisdom.

Unlike the second book discussed in this review, the focus of Kampourakis’ book is not on the science of genetics, but on the way it is communicated and understood by practitioners or lay-audiences. Nonetheless, there are many places where Kampourakis seems to suggest that also genetic research itself is permeated by a problematic understanding of genes. For example, Ch. 9 gives the impression that the inadequate metaphor of the genome as a ‘blueprint’ for an organism constitutes a widely held view in biology. I doubt that this is the case. It has, of course, often been shown by science studies scholars that scientists are metaphysically or ideologically biased or use misleading metaphors. But then, again, the target of criticism here, at least regarding the role of genes in development, behavior, and disease, often seems to be a strawman. When philosophers or other commentators of the life sciences debunk a deterministic ‘received view’ in genetics, they typically marshal a host of genetic mechanisms that illustrate the complexity of genetic processes, from alternative splicing to RNA editing to epigenetics. These insights, however, come from the science of genetics. One might argue that they were – at least for a considerable amount of time – marginalized. There are indeed reasons for conservatism in science (see e.g., Bedessem, 2021 ) and, in any case, new ideas have to be scrutinized by several communities before they become generally accepted. Nonetheless, there are also incentives to pick up new findings that complicate the received picture, as they open up new avenues for original research and publications. Accordingly, those actually concerned with the role of genes in development, usually do not hold a simplistic picture of gene action. Not rarely the quotes taken to represent the naïve and allegedly mainstream view are either quite old, found in the literature belonging to a biological discipline not directly concerned with development or disease genetics (e.g., in population genetics texts), or taken from public-facing promissory statements. It is important therefore, when criticizing scientific views on the basis of other scientific findings, to be very explicit and precise about who holds a criticized view or neglects an alternative view and when exactly. The second book discussed in this essay seems to mainly resist the temptation to bash genetics as overly deterministic, reductionist, or as negligent of a variety of processes, by showing that the gene as well as the gene concept function as tools in illuminating the very complexities that appear to undermine the notion of the gene.

Hans-Jörg Rheinberger and Staffan Müller-Wille in their slim volume The Gene: From Genetics to Postgenomics keep their focus firmly on the gene in biological research. The broader social and cultural context is largely excluded. One could see this as a disadvantage of the book, especially in light of Kampourakis’ emphasis on the impact of genetics on public discourse. However, first, the book would not have been as short as it is had the authors included these dimensions, and its compactness is a true advantage, for instance, when using the book as teaching resource. Second, the authors have already presented a previous account that highlights the cultural context in which hereditary thinking developed and which it influenced in turn (Müller-Wille & Rheinberger, 2012 ). In contrast to this earlier book, which begins its narrative in the early modern period, the book discussed here deals primarily with the period from the late nineteenth to the twenty-first century and focusses – as the title suggests – on the gene, rather than on hereditary thinking broadly conceived. Unlike Kampourakis’ book, which addresses a broad audience interested in understanding genetic claims, this book mainly targets a scholarly audience. Given its introductory character, however, it will be suitable for teaching purposes in a variety of disciplines concerned with genetics either from a reflective or a practical perspective.

One might ask if such a book is needed, given that there are already many histories of genetics and the gene concept. The book is far from being redundant, however. One obvious reason is that the life sciences are moving at fast pace. Early histories, such as Carlson’s The Gene: A Conceptual History ( 1966 ) can still be informative about the early decades of genetic research and later accounts such as Keller’s The Century of the Gene ( 2000 ) can still stand as reflections about how genetics became molecular. However, each of these are influenced by the concerns at the time of writing and aged in particular ways, and, most of all, they do not contain accounts of developments in the twenty-first century. There have been many individual studies looking specifically at one or the other recent development in the life sciences, such as epigenetics, metagenomics, or systems and synthetic biology. But at this point, there are few works which discuss these developments in the context of a long-term history of genetics and the gene; Rheinberger and Müller-Wille discuss the latest developments in Chap. 9. The only contender that comes to mind is Michel Morange’s recent book The Black Box of Biology ( 2020 ), which constitutes an update and extension of his earlier History of Molecular Biology ( 1998 ); this book features whole chapters on post-genomic themes, but it is also much longer.

For sure, compacting a long and multidimensional history of a prominent concept such as the gene does not come without choices, omissions, and synopsis. Rheinberger and Müller-Wille’s book only highlights turning points in the trajectory of the concept; but for readers who need to zoom in on a particular historical episode, it provides references to the relevant literature. The text offers more, however, than a mere overview in the sense of displaying key developments in biology diachronically and synchronically. It develops a narrative that highlights historical as much as systematic connections between events. Sometimes these connections are more of pedagogical value rather than representing a deeper historical pattern. Such is the case when the development of classical genetics and molecular genetics are narrated as analogous movements from simple to complex models and methods (Chs. 3–6) or when the impact of genetics on evolutionary biology on the one hand and developmental biology on the other hand are implicitly parallelized (Chs. 5 and 8). However, the most important and insightful notion emerging from the narrative is that genes have such a central position in biology not necessarily for ontological reasons, but for heuristic or pragmatic reasons. DNA elements can be used as instruments for manipulation to study a vast variety of processes and mechanisms from development to diseases and from epigenetics to molecular interaction network dynamics. Hence, also the concept of the gene is a starting point for planning experiments and interpreting results.

The authors begin with the insight that – despite all the complications of cellular biology and their consequences for heredity, development, and evolution seemingly undermining the gene concept – reference to genes remains omnipresent and central not only outside science, but also at the cutting-edge of research in the life sciences (Ch. 1). A key to making sense of this paradoxical situation is provided in Chap. 7, where the focus is on the development of molecular technologies. Already before, but certainly after the introduction of recombinant DNA technologies and other sophisticated devices of the molecular toolbox, genes were not only epistemic objects that continuously changed regarding the properties and relations ascribed to them when new analytic technologies were applied to them, but they became technical objects themselves that were used to study other objects or processes (see Rheinberger, 1997 on epistemic vs technical objects). The focus on research technologies then also ties the latest, post-genomic developments into the picture, e.g., regarding the impact of microarrays and next-generation sequencing (Ch. 9). Throughout the book, the authors emphasize the context of experimental systems from early hybridization experiments to recent high-throughput technologies to show how genes – as concepts and as objects singled out by the concept at given times or in specific situations – functioned to elucidate processes that undermined deterministic or essentialist interpretations of genetics, from the role of environmental factors to the system properties of cells.

It is this insight into the epistemic and pragmatic roles of genes in biological research (discussed also by others, e.g., Waters, 2007 or Gannett, 1999 ) that enables a view that departs from the usual bashing of gene-centrism. One is tempted to employ the notorious pendulum metaphor here. Where earlier histories on the occasion of the Mendel centennial and in the wake of the elucidation of the structure of DNA and the genetic code tended to be caught up in heroic and progressive success narratives of science, histories written in response to overblown claims in the context of the HGP tended to be overly critical, often vigorously attacking the same reductionist/determinist strawman that still haunts Kampourakis’ book in certain places. But rather than locating the account by Rheinberger and Müller-Wille in a sober middle position, it seems more appropriate to say that these authors have their own specific perspective that is equally located in its time. As scholars who contributed strongly to the practice turn in the history and philosophy of science, their account is informed by the way the gene as a concept but also as an epistemic and a technical object functions in the pragmatics of research. That is to say, rather than focusing on what researchers at a given time said about what genes are or do, they focus on how this understanding is mediated by the ways in which researchers at a given time were able to interact with genetic materials, use these interactions to find out yet other things about these materials or about other objects or processes, or control processes in agricultural or medical contexts. Likewise, the concept of the gene is a tool to represent and communicate this practical knowledge across disciplinary boundaries rather than a term used to express immutable truths about life.

If there is something missing in the book, one might say that the authors missed the chance of historicizing the philosophical and historiographic discourses about the gene. This then is a task that is still open for others to pursue. In fact, a special issue from 2022 focusing on Rheinberger’s work contains many interesting perspectives on the recent history of science studies scholarship concerning the life sciences (Keuck & Nickelsen, 2022 ).

When I spilled some ink on certain shortcomings of Kampourakis’ book, then that was only because they moderately diminish the value of an otherwise extremely relevant and well-written book. Looking at the two books discussed here together with Griffiths and Stotz’s Philosophy and Genetics and Morange’s recently updated detailed history, it is fair to say that the last ten years have equipped us with a high-quality library of books for a critical and historically informed understanding of genetic discourse, which is suitable for designing curricula of HPS courses as much as in science education, as well as serving as a starting point for further scholarly discussions of related topics (for a more compressed overview, see also Meunier, 2022 ).

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Acknowledgements

While writing this review I was a visiting postdoctoral fellow in the MPRG “Practices of Validation in the Biomedical Sciences” at the Max Planck Institute for the History of Science, Berlin.

Open Access funding enabled and organized by Projekt DEAL. Robert Meunier received funding from the German Research Foundation (DFG), projects nr. 362545428 and 390884018.

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Meunier, R. History, philosophy, and science education: reflections on genetics 20 years after the human genome project. HPLS 45 , 18 (2023). https://doi.org/10.1007/s40656-023-00569-4

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Published : 25 April 2023

DOI : https://doi.org/10.1007/s40656-023-00569-4

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THE GENE: one reader’s reflection on a review of the history of genetics

by Sara M. Nolte | Oct 11, 2018

Mukherjee, S. (2016). THE GENE: An Intimate History. New York, New York: Scribner.

While it’s been years since I’ve been in school or academia, I can’t help but feel nostalgic this time of year, when fall marks the beginning of a new year (and the return of the pumpkin spice latte, mmm!). Many of you are hunkering down in your courses, starting new projects (or trying to put a fresh look on an old one), writing grants, midterm papers, and exams, and mentoring new students – so the last thing any of you want to do is more reading. Nevertheless, I’m going to suggest a book that may not be on your syllabus.

I recently finished reading THE GENE: An Intimate History by Siddhartha Mukherjee (author of The Emperor of All Maladies: A Biography of Cancer ; physician and researcher at Columbia University), and I can’t imagine a more complementary book for those studying genetics in some way.

While reading THE GENE , I was constantly reminded of how much I didn’t know about genetics. I’m far from an expert in the field, but as someone who has taken genetics courses, taught students in biochemistry, worked in labs studying cancer genetics, and even edited a genetics textbook – I thought I knew a thing or two about genetics…. Turns out I only knew a thing or two.

Anyone who has taken genetics knows about Mendel and Darwin . Mendel and his peas are at the beginning of the textbook, where heredity and the concept of genes are introduced. Darwin and Origin of Species show up much later in the textbook, in the chapters on evolution and population genetics. For this reason alone (I may have been more of a “skimmer” of textbooks than I realized – please don’t judge), it never really dawned on me that Mendel and Darwin were not only contemporaries, but perfectly complementary:

In fact, Mukherjee made it near comedic how perfectly their research would fit together, if only they could meet and exchange ideas, like a never-answered “Missed Connection” on Craigslist. My favorite nugget:

Mukherjee helped me appreciate just how far we’ve come, and that we take a lot of things for granted. I’m not just talking about the obvious things like having access to the Human Genome Project data, being able to BLAST-search a DNA/RNA/protein sequence , or new CRISPR strategies for targeted DNA manipulation.

I’m talking about the “little” things that are so integral and basic for our work, that we don’t even give them a second thought.

Things like using PubMed to look up hundreds of articles on any given topic (sure there may be a pay-wall). Could you imagine having to wait months, or years, for someone to mail you a copy of a paper you didn’t know existed, trusting that someone had heard of you and your work, and thought enough of you to send you a copy of their manuscript?

Or even more basic: could you imagine a time when people didn’t know what a gene was? Before genetic pioneers like Darwin and Mendel came to prominence (and even they didn’t know specifically what a gene was), there were the inheritance theories of the ancient Greeks , where body organ “vapours” were thought to be transmitted from males to females. It seems ludicrous that these were considered valid theories of heredity to us now , but that’s only because of all that we’ve learned.

Not only did Mukherjee make me re-appreciate the very foundations of genetics, but he made me relive the horror of the Nazi “eugenics program” across Europe that led to thousands of deaths, and the equally disturbing methods of the eugenics movement in North America (confinement and sterilization of the “less-ideal” and mentally ill). We’ve certainly moved past this dark period in genetics, having (hopefully) learned from our mistakes, but I can’t help but feel a lingering sense of shame for what our predecessors had done.

The last third of THE GENE highlights how our connectivity, the advent of embryonic stem cells, and CRISPR-based gene-editing has brought genetics to new frontiers in gene therapies. In the midst of this excitement, Mukherjee leaves a sobering reminder of what has happened in the past, cautioning us against the new social and moral implications of such research, imbuing readers with a strong sense of responsibility for what comes next.

Whether you’re a seasoned researcher, new student, or someone with a keen interest in biology, Mukherjee’s THE GENE is a thought-provoking read that adds some much-needed humanity to genetics. And who knows, it might just add some flavour to that midterm paper (or grant, or editorial, or presentation) that’s due in just a few short weeks (or days)!

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PERSPECTIVE article

Reflections on the field of human genetics: a call for increased disease genetics theory.

• 1 Marshfield Clinic Research Foundation, Center for Human Genetics, Marshfield, WI, USA
• 2 Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI, USA

Development of human genetics theoretical models and the integration of those models with experiment and statistical evaluation are critical for scientific progress. This perspective argues that increased effort in disease genetics theory, complementing experimental, and statistical efforts, will escalate the unraveling of molecular etiologies of complex diseases. In particular, the development of new, realistic disease genetics models will help elucidate complex disease pathogenesis, and the predicted patterns in genetic data made by these models will enable the concurrent, more comprehensive statistical testing of multiple aspects of disease genetics predictions, thereby better identifying disease loci. By theoretical human genetics, I intend to encompass all investigations devoted to modeling the heritable architecture underlying disease traits and studies of the resulting principles and dynamics of such models. Hence, the scope of theoretical disease genetics work includes construction and analysis of models describing how disease-predisposing alleles (1) arise, (2) are transmitted across families and populations, and (3) interact with other risk and protective alleles across both the genome and environmental factors to produce disease states. Theoretical work improves insight into viable genetic models of diseases consistent with empirical results from linkage, transmission, and association studies as well as population genetics. Furthermore, understanding the patterns of genetic data expected under realistic disease models will enable more powerful approaches to discover disease-predisposing alleles and additional heritable factors important in common diseases. In spite of the pivotal role of disease genetics theory, such investigation is not particularly vibrant.

Introduction

Development of human genetics theoretical models and the integration of those models with experiment and statistical evaluation are critical for scientific progress. This perspective argues that increased effort in disease genetics theory, complementing experimental, and statistical efforts, will escalate the unraveling of molecular etiologies of complex diseases. In particular, the development of new, realistic disease genetics models will help elucidate complex disease pathogenesis, and the predicted patterns in genetic data made by these models will enable the concurrent, more comprehensive statistical testing of multiple aspects of disease genetics predictions, thereby better identifying disease loci. By theoretical human genetics, I intend to encompass all investigations devoted to modeling the heritable architecture underlying disease traits and studies of the resulting principles and dynamics of such models. Hence, the scope of theoretical disease genetics work includes construction and analysis of models describing how disease-predisposing alleles (1) arise, (2) are transmitted across families and populations, and (3) interact with other risk and protective alleles across both the genome and environmental factors to produce disease states. Theoretical work improves insight into viable genetic models of diseases consistent with empirical results from linkage, transmission, and association studies as well as population genetics. Furthermore, understanding the patterns of genetic data expected under realistic disease models will enable more powerful approaches to discover disease-predisposing alleles and additional heritable factors important in common diseases. In spite of the pivotal role of disease genetics theory, such investigation is not particularly vibrant. Currently, activities in human disease genetics are primarily centered upon large-scale empirical studies and, to a lesser extent, statistical methods, with limited contribution to theory.

Background and Framework

Broadly speaking, scientific progress is predicated on a robust interplay between three activities: (1) empirical experimentation and observation, (2) the development of theoretical models and extraction of predicted patterns thereof, and (3) the statistical evaluation of the probabilistic correspondence between the predicted patterns and empirical data. Highly impactful discoveries can certainly occur in the absence of formalization of these activities, but these three aspects are nonetheless critical. To exemplify, consider the relatively recent remarkable finding of complex, low-level admixture between modern humans and archaic humans ( Green et al., 2010 ; Reich et al., 2010 ; Gronau et al., 2011 ; Li and Durbin, 2011 ; Sankararaman et al., 2016 ). This discovery was made through heroic efforts to isolate, sequence, assemble, and align archaic DNA from Neanderthal and Denisovan remains. In parallel, predictions of genetic architecture, divergence patterns, and shared chromosomal regions from admixture models were developed using both molecular phylogenetics and population genetics theory involving mutation, genetic drift, migration, and demographics. Lastly, correspondence between the observed genetic data and theoretical predictions were accomplished through a variety of likelihood-based, Bayesian, and Fisherian approaches. It is not overreaching to claim that this advance of our scientific knowledge hinged on careful empirical observations/experiments, the development of population genetics theory, and the formal evaluation of rich theoretical predictions against observed data through rigorous statistical methods. The most casual of observers will note legions of additional examples of this paradigm from a diverse set of scientific fields such as particle physics ( Glashow, 1961 ; Higgs, 1964 ; Weinberg, 1967 ), mechanics ( Einstein, 1916 ; Schrodinger, 1926 ), enzyme kinetics ( Michaelis and Menten, 1913 ), semiconductors ( Hall, 1879 ; Wilson, 1931 ; Mott, 1938 ; Schottky, 1938 ), atomic chemistry ( Hund, 1926 ; Mulliken, 1932 ; Huckel, 1934 ), classical genetics ( Mendel, 1866 ; Fisher, 1918 ), heredity and evolution ( Fisher, 1930 ; Wright, 1932 ; Price, 1970 ), population genetics ( Hardy, 1908 ; Weinberg, 1908 ; Hudson, 1982 , 1983 ; Kingman, 1982a ; Gillespie, 1993 , 2000 ), and predator-prey ecology ( Lotka, 1925 ). Across these and many other fields, theoretical work is a dynamic component of the scientific process: unexplained empirical phenomena motivate new theory, often in a relatively seamless manner, and, conversely, predicted patterns stemming from mechanistic models are digested by experimenters and promptly tested, leading to an expeditious and efficient expansion in our understanding of these phenomena.

Comparatively, disease gene mapping has grown a relatively barren landscape of theory. Largely motivated by the desire to impact clinical practice, human disease genetics has historically been a highly pragmatic field where technological advancement in genotyping and sequencing has spurred large-scale studies and the bulk of quantitative work has focused on statistical methods of analysis, rather than a more equitable partition of statistics and theory. This has continued despite instances where profound shifts in approaches have been driven by insights from theory. For example, an extended stagnation in mapping common, complex diseases was fractured by theoretical developments in the mid- to late-1990s showing that high density genotyping using population-based samples would have dramatically increased power to detect high frequency disease-predisposing alleles of moderate effect sizes, motivating the GWAS paradigm from an overly-simplistic disease genetics model ( Kaplan et al., 1995 ; Risch and Merikangas, 1996 ; Long et al., 1997 ; Xiong and Guo, 1998 ; Kruglyak, 1999 ; Long and Langley, 1999 ).

Although not commonplace, there are other historical examples of disease genetics theory driving accelerated progress in human genetics, including the heterozygote selective advantage theory of malaria and sickle-cell disease ( Allison, 1954 ), that complex diseases do have a heritable component ( Steinberg et al., 1951 ; Pickering, 1978 ; Debray et al., 1979 ; Kendler and Diehl, 1993 ; DeBraekeleer, 1991 ; Lynn et al., 1995 ; Stein et al., 2005 ), that large multiplex families were ideal for linkage studies of diseases under Mendelian disease models ( Thompson, 1978 ; Botstein et al., 1980 ), and the more diffuse impact of theoretical ideas from population genetics such as allele frequency spectra being highly skewed toward very rare alleles ( Ewens, 1972 ; Watterson, 1975 ; Slatkin and Rannala, 1997 ; Long and Langley, 1999 ; Eyre-Walker, 2010 ; Hudson, 2015 )—accentuated in rapidly expanding populations, haplotypes exhibiting block-like structure in LD patterns ( Hill and Robertson, 1968 ; Hudson and Kaplan, 1985 ; Nothnagel et al., 2002 ; Wiuf and Posada, 2003 ), population bottlenecks followed by expansion accentuates allelic dominance effects on fitness ( Balick et al., 2015 ), and alleles with deleterious effects on fitness originating more recently than those neutral with respect to fitness given the same allele frequency ( Maruyama, 1974 ; Ziezun et al., 2013 ). Theoretical work has been done on applying the highly polygenic, additive model to common diseases, offering some testable predictions ( Yang et al., 2010 , 2011a ; Vinkhuyzen et al., 2013 ; Loh et al., 2015 ). Additional, useful efforts have focused on widespread epistatic interactions ( Hodge, 1981 ; Neuman and Rice, 1992 ; Majewski et al., 2001 ; Zuk et al., 2012 ). However, competing theoretical models of common disease genetics are sparse even though both history and reason argue for a more vigorous theoretician community and heightened interaction between theory, experiment and statistical methods.

What Constitutes a Useful Theory of Disease Genetics?

Although many areas of investigation rightly fall under this rubric, the general focus should be the development of testable models that describe the set of heritable factors and interactions that generate disease states. This includes allele and genotype frequencies, numbers of susceptibility loci, numbers and types of susceptibility alleles, penetrances, epistatic interactions, properties of familial transmission, and effect modification with environmental variables. It is important to draw a distinction between the genetics that predispose an individual to a disease and the genetic repertoire that underlies the predisposition to a disease across a population of affected individuals, for we do not know the extent in which each individual's disease etiology is unique for complex disease phenotypes. That is, although it is well established from population-level analyses that complex diseases are polygenic, we currently have little evidence that definitively speaks to the level of allelic and locus heterogeneity in any complex disease. What set of genotypes at a set of loci are sufficient to generate disease in an individual? What is the variation in these disease-predisposing sets of genotypes and loci across diseased individuals? Do the alleles co-segregate with disease states across relatedness structures? Coherent, useful theories of disease genetics must address these questions.

Theoretical population genetics, with numerous practitioners using coalescent theory and similar tools to study the maintenance of alleles in populations and elucidate the evolutionary forces responsible for genetic variation, is relatively advanced ( Kaplan et al., 1988 ; Hudson, 1991 ; Charlesworth et al., 1997 ; Calafell et al., 2001 ). As population genetics is concerned with the dynamics and distributions of alleles in populations ( Ewens, 1972 ; Moran, 1975 ; Watterson, 1975 ; Kingman, 1982a , b ; Charlesworth and Jain, 2014 ; Greenbaum, 2015 ), the relevance of population genetics theory to disease gene mapping—particularly for case-control association studies, fine-scale mapping, and population stratification—is undeniably clear, with several important advances demonstrating applicability ( Pritchard et al., 2000 ; Morris et al., 2002 ; Molitor et al., 2003 ; Burkett et al., 2014 ). However, population genetics theory, in and of itself, is inadequate to serve as a complete theory for modeling the disease genetics: (1) coalescent theory is largely concerned with samples of random chromosomes from a population, rather than from disease-affected individuals; (2) there is limited focus on the treatment of related individuals; (3) whereas population genetics aims to delineate the relative impact of natural selection, genetic drift, mutation and demographic effects, diseases have a complex, enigmatic relationship to fitness—some diseases may result from mutation-selection balance, other diseases may carry susceptibility genes that are neutral with respect to selection, while some disease genes may be subjected to directional selection, and many diseases, such as type 2 diabetes ( Hu, 2011 ), may result from a shift to a modern environment; (4) theoretical population genetics concentrates on the dynamics of individual loci in isolation; and (5) somatic mutations and heritable epigenetic factors, which play important roles in at least some common diseases, are often not the subject of mainstream population genetics theory.

Similarly, the theoretical models from quantitative genetics are also problematic in their direct applicability to investigations of disease genetics architecture. These models are almost exclusively direct derivatives of the infinitely polygenic, miniscule additive effects model (IPMAE model) ( Falconer and MacKay, 1996 ; Frank, 2011 ). Often, when applied to a dichotomous outcome, a threshold ( Wright, 1934 ) or liability function ( Falconer, 1965 ; Curnow and Smith, 1972 ) is overlaid on the IPMAE model. Historically, work on the IPMAE model was designed for the study of quantitative traits, such as livestock lean body weight and crop yield, in agriculturally important organisms and specifically-designed pedigrees to assess measures such as breeding values ( Falconer and MacKay, 1996 ; Lynch and Walsh, 1998 ). Although this model carries utility for analysis of quantitative traits in general populations, and the application to human disease is strongly argued by some ( Hill et al., 2008 ; Plomin et al., 2009 ), whether or not the coupling of a liability function with the IPMAE model is indeed the appropriate model of allelic architecture for any dichotomous complex disease is currently unknown. Many, if not most disease physiologies are fundamentally different than naturally-occurring phenotype variation investigated by quantitative geneticists, and it is reasonable to assume that their underlying allelic architecture also differs. Recently, several have strongly argued against the continued use of the IPMAE model for the purpose of dissecting complex diseases ( Nelson et al., 2013 ; Génin and Clerget-Darpoux, 2015 ). Although I personally favor models other than the IPMAE model for complex diseases, I do not think that either theoretical nor empirical evidence is currently sufficient to completely dismiss the IPMAE model. It is certainly possible, a priori , that tens or hundreds of thousands loci across the genome harbor alleles of very small effect sizes, all marginally contributing to additively increase disease risk. Moreover, many types of models may appear to have additive and nearly independent effects as those effect sizes become small. If complex diseases are a conglomeration of distinct physiological entities with their own genetic etiologies, erroneously aggregated by physicians, it appears possible that the IPMAE model may be reasonable, at least for interpreting data from population-based studies. If molecular networks are highly redundant and numerous pathogenic changes are necessary to compromise the function of these networks, then the IPMAE model might be appropriate. So, rather than disbanding the IPMAE model entirely, a prudent direction would be encouraging the development of alternative theoretical models. A competitive marketplace of disease genetics models is a critically important cog in the unraveling the genetic architecture of all diseases. Certainly, the correspondence between IPMAE predictions and experimental data will be the ultimate arbitrator. Empirically, the jury is mixed with some studies offering moderate evidence of consistency between genetic association data and the IPMAE model ( Yang et al., 2010 , 2011a ; Vinkhuyzen et al., 2013 ; Bulik-Sullivan et al., 2015 ; Loh et al., 2015 ), while others do not ( Ritchie et al., 2001 ; Kirino et al., 2013 ; Ridge et al., 2013 ; Fritsche et al., 2014 ), and familial data has yet to definitively support or refute the model. Of note, a useful global measure of the magnitude of polygenic inheritance has been discussed by Yang et al. (2011b) . Interestingly, testing polygenetic architecture models on GWAS data for four complex diseases—rheumatoid arthritis, celiac disease, myocardial infarction/coronary artery disease, and type 2 diabetes—using Bayesian Approximate Computation, Stahl and colleagues estimated the joint density of the number of independent disease-predisposing SNPs and the liability-scale variance explained showing consistency with models using roughly 2000 SNPs ( Stahl et al., 2012 ).

Within human genetics, the majority of models of common disease genetic architecture used in practice fall into two overly-simplistic camps: (1) monogenic and two-locus models with a biallelic markers and typically one of four classical modes of inheritance (fully dominant, fully recessive, additive, or multiplicative), and (2) direct derivatives of the IPMAE model. One only has to go as far as to look at commonly-used power calculators for genetic association or linkage studies to observe this rather ubiquitous, long-standing, yet fairly impotent state of affairs. Parametric linkage studies using monogenic models produced spurious results for complex diseases ( Génin and Clerget-Darpoux, 2015 ). Much of their use has resulted from convenience—both the monogenic/two-locus models and the IPMAE model are mathematically tractable and other, more realistic models may necessitate complex mathematical treatment or computational approaches. Not only do these two classes of models represent the ends of a wide spectrum of models, but this limited number of disease genetics models is symptomatic of an anemic theoretical effort. That said, what we have learned about the properties and dynamics of the IPMAE ( Blangero et al., 2013 ; Zhou et al., 2013 ) and monogenic/two-locus models ( Li and Reich, 2000 ; Zaykin et al., 2006 ; Schrodi et al., 2007 ; Zaykin and Shibata, 2008 ) will serve us well for the development of the next generation of theoretical disease genetics models. For example, the finite, additive polygenic model relaxes from the extremely large number of disease loci assumption of the IPMAE ( Cannings et al., 1978 ; Lange, 1997 ). Further, new statistical approaches, explicitly harnessing theoretical models of polygenic inheritance to better understand genetic variation of complex traits are starting to be developed ( Zhou et al., 2013 ). In my view, finite rare allele models of moderately high effect sizes, high allelic, and high locus heterogeneity with effect modification by genetic background deserve attention. Importantly, very recent results from simulations appear to favor incomplete recessivity models for complex trait etiologies, demonstrating consistency with both realistic population genetic models, heritability data, and GWAS findings ( Sanjak et al., 2016 ). Such work suggests prioritizing tests of recessive modes of inheritance and compound heterozygosity testing for common disease mapping.

While it is undeniable that substantial biological insights and clinical utility have resulted from identifying alleles truly associated/linked with complex diseases ( Sabbagh and Darlu, 2006 ; Roychowdhury and Chinnaiyan, 2013 ; Bottini and Peterson, 2014 ; Kavanaugh et al., 2014 ; Everett et al., 2015 ; Lueck et al., 2015 ), we are currently in the infancy of understanding disease genetics where prediction of any common, complex disease is not yet clinically practicable ( Schrodi et al., 2014 ), and efficacious, highly targeted therapies are sparse. One bright point for disease prediction, borrowed from quantitative genetics and work on highly polygenic additive models, is the use of best linear unbiased prediction (BLUP) ( Speed and Balding, 2014 ; Vilhjalmsson et al., 2015 ). That said, the overall lack of realistic theoretical models dramatically hinders our progress, for powerful experimental designs and analysis techniques could be optimized to suit the predictions of such models. Yet the tools are available to make significant theoretical inroads. Data processing approaches ( Fan et al., 2014 ) and machine learning has become incorporated into development of genetic models and their evaluation ( Libbrecht and Noble, 2015 ). Graphical modeling programming software are well-developed ( Hall et al., 2009 ). In addition, the investigation and use of causal models may also advance human genetics theory ( Pearl, 2000 ; Madsen et al., 2011a , b ). Fast Markov-chain-Monte-Carlo algorithms to screen complicated, vast parameter spaces are accessible. And, most importantly, the accumulated results from multiplex linkage studies, affected sibling pair studies, studies assessing disease concordance between relative pairs of varying relatedness, twin studies, family-based transmission/disequilibrium studies, GWAS, and familial and population-based sequencing studies are available. Moreover, high-throughput genotyping and sequencing have painted a detailed picture of the raw materials from which disease genetics are sampled: the allele frequency spectrum and LD patterns. Disease genetics models must be consistent with these results. Ideally, an abundant assortment of viable theoretical disease genetics models will be developed, generating informative, distinguishing predictions. These predictions can then be tested against the accumulated patterns of genetic data, producing posterior probabilities, or likelihoods for each model. As the empirical data accumulates, the posterior probability density across the parameter space of the models will indicate those models with reasonably high posterior probabilities, with many models being ruled out. Not only would such work illuminate plausible etiological models of complex diseases, but it would suggest highly-powered experimental designs and statistical methods. In particular, with the determination of likely disease genetics models, one could harness a variety of predicted patterns to improve the discovery and assessment of casual loci.

A more detailed example may provide additional weight and clarity to this argument. Consider a standard common disease case/control GWAS study. With notable exceptions of issues such as clustering of subjects using dimensional reduction methods ( Price et al., 2006 ), most such studies are designed and analyzed to solely test the simple hypothesis of independence between disease status and genotype frequencies at single sites. However, formal disease genetics models could offer a wealth of predictions concerning genetic architecture patterns in the data: (1) Diseases with early onset and probable ancestral effects on fitness predict selection against disease-predisposing alleles which would generate departures from neutrality as measured by metrics such as Tajima's (1989) . (2) Departures from Hardy-Weinberg Equilibrium differ between cases and controls under several disease models ( Nielsen et al., 1999 ). (3) The linkage disequilibrium patterns within cases at the susceptibility locus are expected to differ from those patterns observed in controls ( Zaykin et al., 2006 ; Schrodi et al., 2007 ; Pan, 2010 ). (4) The decay of disease association with declining linkage disequilibrium between a causal site and closely-linked markers follows a particular form ( Lai et al., 1994 ; Pritchard and Przeworski, 2001 ; Garcia et al., 2008 ; Schrodi et al., 2009 ; Maadooliat et al., 2016 ). (5) Cases are expected to exhibit increased sharing of chromosomal segments compared to controls ( Houwen et al., 1994 ; Te Meerman et al., 1995 ; Browning and Thompson, 2012 ). (6) Models generating allelic heterogeneity such as the rare allele/large effect (RALE) model suggest investigating multiple predisposing sequence variants segregating at each gene/functional motif ( Personal communication with Ray White, 2000-2010 ; Terwilliger and Göring, 2000 ; Pritchard, 2001 ; Thornton et al., 2013 ) and perhaps testing for linkage. Little imagination is necessary to presume that additional, highly useful predicted genetic patterns exist under disease genetics models, hereto underutilized. So long as the disease genetics model is sufficiently accurate or the predictions are robust across models, concurrently testing the rich panoply of theoretical predictions extracts increased information, enabling more refined, credible, and localized discovery of pathogenic alleles. Notably, Agarwala and colleagues have conducted excellent work in this area for type 2 diabetes ( Agarwala et al., 2013 ). They have used a combination of simulation results and results from affected sibling linkage studies, GWAS, a polygenic score logistic regression, and sequencing studies to reduce the model space of possible architecture models. They foresee further reduction in the space of possible models being dependent on the findings from very large-scale sequencing studies. I applaud this considerable effort and hope that further work in this area is strongly supported.

There are similar implications for such theoretical disease genetics when applied to family-based studies. Predictions from realistic disease genetics models enable the coherent exploration of critical questions such as (1) Is the distribution of chromosomal regions shared by affected individuals indicative of disease loci? (2) Are the observed phenotypic variance within families and familial aggregation patterns consistent with specific disease genetics models? (3) Are the transmission patterns within families consistent with disease genetics models? And (4) Given a specific disease genetics model, what is the optimal size of family structure for finding chromosomal regions linked and associated with complex diseases (i.e., siblings, multiplex families, founder populations, or general populations)? Just as with population-based studies, the development of theoretical models of disease genetics illuminates the path to jointly testing numerous observed genetic patterns within familial structures. Wray and Goddard have started to explore some of these issues and have shown that three disease models are roughly consistent with data on disease risk in relatives ( Wray and Goddard, 2010 ).

Related Areas of Theory Development

One area of active research that would profit from the advancement of disease genetics theory is the development of fine mapping methods to identify causal variants within a disease-associated region. Discovering causal variants is critically important for several reasons, most notably that expensive, time-consuming, follow-up laboratory experiments are predicated on which gene or functional motif are indicted by the genetic evidence. This problem of identifying disease-causing variants in regions of often complex linkage disequilibrium patterns and allelic heterogeneity, although dramatically understudied in the past, has now been increasingly recognized as being vital in the human genetics toolbox. One example is the fine-mapping method of Maller and colleagues which uses a ranked set of Bayes factors (one for each polymorphism in an associated region) ( Wellcome Trust Case Control Consortium et al., 2012 ). Other approaches include Bim-Bam ( Servin and Stephens, 2007 ), CAVIAR ( Hormozdiari et al., 2014 ), CAVIARBF ( Chen et al., 2015 ), coalescent-based methods ( Graham, 1998 ; Morris et al., 2002 ; Zollner and Pritchard, 2005 ), and PAINTOR ( Kichaev et al., 2014 ), which incorporates functional information probabilistically. While I applaud these excellent, thoughtful methods, as a generalization these approaches are statistically appropriate and easily interpretable, but use overly simplistic disease genetics models. If we held a more complete understanding of the theoretical properties of alleles that underlie complex diseases and their correlation patterns with linked variants, one could incorporate this information into more powerful fine mapping methods.

Aside from the need for the development and analysis of DNA-based models of disease predisposition, similar models of other heritable factors involved in pathogenesis such as inherited RNA pools, histone acetylation, and DNA methylation effects are essential for the rapid advancement of disease genetics. It is becoming increasingly clear that epigenetic factors play a role in heritable diseases ( Uddin et al., 2010 ; Williams et al., 2010 ; Allum et al., 2015 ; Montano et al., 2016 ). However, just as clear is the near absence of theoretical models describing epigenetics as an etiological factor in diseases. Several simple questions need investigation: What are the probabilistic laws that govern the transmission of these epigenetic factors? That is, what is the distribution of probabilities that a given epigenetic state is transmitted to a subsequent generation? How do these probabilities attenuate across multiple generations? What are the frequencies of various epigenetic changes and the corresponding effects on disease risk? What is the fraction of an individual's disease risk that is generated by epigenetic changes? And how is this fraction distributed across a population? Development of these theoretical models will allow for the calculation of testable predictions and aid in the construction of more powerful experimental designs.

To be balanced, there certainly are efforts in human genetics theory, several of which have been discussed, enabling statistical methods that harness informative theoretical predictions ( Reich and Lander, 2001 ; Zhu et al., 2015 ). The crux of the argument made here, however, is one of degree: Additional training of human geneticists in theoretical models, complementing, and motivating statistical methods, would be beneficial. Additional construction of disease genetics models to evaluate against empirical data is vitally needed. Additional work on identifying the patterns of genetic data expected under theoretical models is essential. Additional evaluation of empirical data from large multiplex families, affected sibling pairs, isolated populations, founder populations, transmission-based tests, GWAS, whole genome/exome sequencing studies in families, and population-based sequencing studies to determine which disease models are supported and which can be excluded based on these results would be highly productive. And additional interplay between theory, experiment, and analysis is critical. My central thesis is that funding and effort must be balanced in a way that produces complementarily functioning triad of theory, experiment, and statistics, so that the entire field of human genetics moves forward unabated. Currently, experimental studies and statistical methods are clearly active and highly-functioning subfields, whereas, the field has a dearth of theoretical disease genetics models, impeding the entire disease gene mapping enterprise. The timing is ideal for the institution of these changes. We have amassed vast amounts of genetic data for many hundreds of common diseases and rarer, related conditions and yet the heritable causes of each common disease remain poorly understood. Colossal, expensive shifts in focus have been historically driven by simplistic, undeveloped theoretical models, e.g., common disease/common variant hypothesis ( Reich and Lander, 2001 ), so it may be more fruitful for our field to further develop resources and capabilities that generate more fully developed theoretical models of disease genetics. Perhaps it is time for a new field of theoretical disease genetics.

Author Contributions

The author confirms being the sole contributor of this work and approved it for publication.

This work was supported by generous donors to the Marshfield Clinic Research Foundation, a pilot grant award from the NIH-NCATS/University of Wisconsin-Madison Institute for Clinical and Translational Research (UL1TR000427) and NIMH RO1MH097464. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This manuscript benefited from conversations with Louis Ptacek, Andreas Ziegler, Murray Brilliant, Scott Hebbring, Harold Ye, Sarah Murray, Mark Leppert, Nori Matsunami, and Ingrid Borecki, and comments from reviewers. The editorial comments were especially insightful and played an instrumental role in greatly improving the manuscript. I would like to particularly thank Tony Long and Ray White for sharing their keen observations and highly refined insights into genetic architectures of traits over many years. This work was supported by generous donors to the Marshfield Clinic Research Foundation, a pilot grant award from the NIH-NCATS/University of Wisconsin-Madison Institute for Clinical and Translational Research (UL1TR000427) and NIMH RO1MH097464. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.

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Keywords: disease genetics, theoretical model, human genetics, GWAS (genome-wide association study), complex diseases, statistical genetics and genomics

Citation: Schrodi SJ (2016) Reflections on the Field of Human Genetics: A Call for Increased Disease Genetics Theory. Front. Genet . 7:106. doi: 10.3389/fgene.2016.00106

Received: 26 February 2016; Accepted: 25 May 2016; Published: 08 June 2016.

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Open questions: Reflections on plant development and genetics

• Virginia Walbot 1  

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Genomics has given us a new appreciation for the many ways genes and genomes evolve

At the turn of the millennium, the most we could hope for was a few small genomes completed and hordes of ESTs and genomic snippets from most species. What a difference a decade makes. Now that whole genome sequencing is routine and there are sufficient numbers of plant genomes with near complete assemblies with strong support, it will be routine to ‘paste on’ the genomes of related genera and even families. Furthermore, using the multiple (hundreds or thousands) of distinct genomes of inbred lines or ecotypes, allelic diversity and micro-heterogeneity in chromosome organization can be analyzed directly. These assemblages can be used to test ideas about genome rearrangement, the timing and extent of transposon amplification, gene duplications and losses, and both promoter region and transcription unit conservation and change. But has genomics explained development or physiology?

Genetics still has a role because mechanistic insights emerge from detailed analysis of a particular organism and with genomics we can tackle very difficult phenotypes

Despite the success of genomics, biological details are best viewed by close observation and analysis of a single species. In the context of all genes in that organism, what is the impact of mutation in one gene? What are the details of biochemical and gene expression regulation in the cells of this particular plant under specific environmental conditions? In the past 10 years, genomics has given us the ability to observe and dissect the small accretions in phenotype typical of multi-locus traits. We have unprecedented access to analysis of quantitative traits, that is, how a few or even dozens of specific allelic combinations at many loci add up to a particular trait such as days to flowering or ability to resist salt damage. Of course, classical genetics found the major players - lethal mutations always prove that something is essential - but the small number of major players do not explain the endless variety of intermediate types and just slightly more somatically and reproductively fit individuals under specific conditions.

Real plants live in a variable environment and integrate environmental conditions into developmental decisions

As a corn geneticist, I’ve always faced the variability of growing conditions - day length, temperature, winter Hawaii compared to summer California, and so on. We observe phenotypic plasticity all the time, and now we are joined by those studying ‘growth chamber’ species who have begun to aggressively and effectively assess phenotypes in natural environments and diverse ecotypes in common gardens. The unprecedented combination of genome markers and high-throughput phenotyping is inspiring a new generation of ecophysiologists. It has been nearly 75 years since Clausen, Keck and Hiesey of Stanford/Carnegie Institution began publishing their common garden experiments that established that ecotypes differ genetically and that plants can show significant acclimations in form.

This latter point was noted by Charles Darwin, with particular reference to reproduction in his book The Different Forms of Flowers on Plants of the Same Species [ 1 ]. Typical open pollinated species that suffer low seed set can subsequently switch to making cleistogamous (closed bud), self-fertile flowers to ensure reproduction. It is endlessly fascinating to me how well plants cope with a variable environment and can, for example, produce a succession of leaves of different phenotypes to avoid sun, wind or other damage. Although the common wisdom is that physiology feeds into development by fine-tuning organ growth, our own work points to a deeper connection in that hypoxia is the regulator of the differentiation of maize anther cells competent for meiosis [ 2 ] and provides an example of a direct connection between cell fate setting and environmental conditions.

The meaning of stem cells and the fundamental differences between plants and animals

Since the 1950s it has been clear that some individual adult plant cells can regenerate an entire organism. This was thought impossible in multicellular animals, but in the past few years it has become clear that animal stem cells can be reprogrammed in vitro to exhibit pluripotency or totipotency. But this is not easy! Why can plant cells dedifferentiate and redifferentiate autonomously, without a somatic niche helper cell population or an onslaught of special factors applied exogenously? One could argue that even a large tree is just cells that are currently cooperating to make a larger organism but that most of the cells retain a somewhat ‘single cell’ perspective on survival. The absence of a plant germ line may be the fundamental feature that divides plants from animals and may in ways we will ultimately understand determine the plasticity of plant cells within a complex multicellular organism. There is no doubt that a typical animal stem cell is so much more limited in what it can do, or does do in the body, than a shoot apical meristem cell from a flowering plant. In effect the plant stem cells are building entire new organs all the time - new limbs, new trunk - solving polarity issues and the other key developmental decisions that are resolved in animal embryos. Furthermore, in the very act of generating a new leaf, the shoot apex not only regenerates itself but it makes an axillary meristem, doubling the growth potential of the organism.

A favorite thought of mine is that this vegetative diversification of growing points - a kind of distributive growth - permits plants the luxury of mutation and an immediate assessment of fitness vegetatively. Animals sequester their germ line and stem cells to prevent mutation while plants may allow, even promote through activation of transposons, genome mutation. Novelty such as bud sports is the foundation for viticulture and tree crop diversification, evidence that some somatic mutations are highly favorable. And then when apices switch to making flowers the more successful branches will make more flowers and hence have the potential to make more offspring inheriting a ‘pre-tested’ allele that confers novel somatic properties. As a bonus, with gametophytic selection acting on the haploid phase of the life cycle, many highly deleterious mutations are eliminated from the plant gene pool, curtailing an increase in genetic load.

In summary, the past decade has provided many exciting scientific advances and a few solutions to long-standing questions. Yet the frontier of unanswered questions is still vast, and the challenge is to marshal our new resources to design appropriate and clever (and in these times, economical) approaches to resolving the mechanisms underlying the fundamental properties of the green world.

Darwin C: The Different Forms of Flowers on Plants of the Same Species. 1877, New York: D Appleton and Co.

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The Wonder of DNA: Reflections from Dr. Francis Collins on the 20th Anniversary of the Human Genome Project

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Every year on the 25th of April, the world celebrates National DNA Day; an awareness day celebrating the discovery of the DNA double helix. This year however, commemorates the 70th anniversary of the discovery of the DNA double helix alongside the 20th anniversary of the completion of the Human Genome Project making it extra special. 

To highlight how far the field of genetics has come since the discovery of DNA's structure, we sat down with Dr. Francis Collins, the leader of the Human Genome Project and former Director of the NIH, about his incredible career in genetics from his initial interest in science and involvement in the Human Genome Project, all the way through to his work in the NIH and White House as a Special Advisor to the President for Special Projects. Read the full interview below to learn more about the past, present, and future of genetics research. 

Please can you introduce yourself and tell us what inspired your career within the life sciences?

I am Francis Collins. In graduate school, I became interested in the life sciences, studying physical chemistry. I got excited about DNA and realized there were really cool things happening in life science that I had previously ignored because I was focused on simpler questions in physics and chemistry.

This made me change my direction, which was a bit disruptive to life planning, but it was a good thing. I went to medical school, and there figured out that I was really excited about bringing together the science of the human body, which is medicine with genetics and the study of the DNA molecule.

Your predominant research focus in genetics is surrounding the genes responsible for diseases. Why did you choose to focus on this particular area of genetics research, and how has the discovery of new genes responsible for various diseases impacted the field of drug discovery and therapeutics?

For me, the interest in this wonderful molecule, which we are now celebrating the 70th anniversary of its original description, that double helix, was so compelling in this instruction book for human life and all other organisms.

To understand the most fundamental level of how disease happens and what you could do about it, you had to focus on DNA. The idea that one could discover misspellings in this instruction book that would have significant consequences for people's future seemed like something I wanted to be involved in.

When I started, there were not many genetic diseases where we knew this answer, but over the course of the next 35 years, particularly because of the Human Genome Project, which I had the privilege of leading, we developed the tools to elegantly examine 3 billion letters of the human instruction book and find maybe just one that was out of place.

So-called positional cloning, which I had the chance to be involved in early on, enabled finding the cause of cystic fibrosis with colleagues and has now been conducted for almost 7,000 diseases, giving us hope for better diagnoses and ultimately discovering how to treat or even cure them.

Image Credit: Elena Sharipova/Shutterstock.com

As well as your research surrounding disease genes, you were appointed the leader for the Human Genome Project, an international research project set out to map, identify, and sequence all the genes that make up the human genome. Can you tell us more about your involvement in this project and what impact the success of this project has had on the field of genomics?

I never expected to be asked to lead a big, complicated international project, but I was really excited about being able to read out for the first time all the letters of our own DNA code.  

Thirty years ago, I left my academic position at the University of Michigan and came to the National Institutes of Health to try to organize this international effort. Many people were skeptical about it with the limited technology and possible costs.

It was tough initially, but then many got excited about the potential, and I was able to bring on board some of the best and brightest of this generation of scientists who wanted to be part of this.

Momentum began to build, and with ultimately 20 different groups in six countries, we were able to deliver on the promise of the Human Genome Project, discovering that 3 billion letter code, all in the public domain and two years ahead of the expected schedule and at a lower cost, which made a lot of people happy in the US Congress.

This was profound. The foundation of everything about humanity, as far as its biological nature, is written in that code.

It still amazes me, as we are celebrating the 70th anniversary and 20 years since the Genome Project was completed, that 3 billion letters in an instruction book is enough to go from a single cell, which we all once were, to this amazingly complicated developmental process that results in people with consciousness in a brain with 86 billion neurons.

The medical consequences are beginning to appear in a significant way, and this is the part for me as a physician that I am excited about, that the genome is not an academic exercise but may be the best hope we have for the future of medicine for preventing suffering and curing terrible disease.

Every year, the world celebrates National DNA Day, celebrating the discovery of the DNA double helix. However, this year is extra special as it will also commemorate the 20 th anniversary of the Human Genome Project as well as the 70 th anniversary of the discovery of the DNA double helix. Why is it important to recognize how far genomics research has come over the last 70 years, and what does this day mean to you?

We all note these anniversaries as an opportunity to reflect on where we have been, where we are, and where we might be going next. When history looks back at the scientific achievements of the 20th and 21st centuries, what is going to be on that shortlist?

I think splitting the atom, going to the moon, but also sequencing the human genome because it is so profound in terms of a transformation in our understanding of ourselves and what it means about life and disease and how to manage that. It is not a bad idea to stop and think for a minute about what happened over those 70 years to get us to today and how did that Genome Project effort, completed essentially 20 years ago, begin to empower many aspects of who we are.

It is not all about medicine, either. Another learning is how we are all related to each other. There is no biological basis for anybody to think of other people as not part of the same group. We are all part of one family descendant from a common set of ancestors; genomics made that clear. This is good for us to keep in mind when we seem to be divided from each other.

For the medical aspects, the advances with cancer and where we will be able to go are hugely important. Cancer is a disease of the genome, and now, in any patient who has the disease, we can figure out exactly what is driving those good cells to go bad and what to do about it.

This is transformative and is already becoming almost a standard of care. We can use sequencing of the genome to understand what is happening in a mysterious circumstance where somebody has a disorder, and nobody understands. About 40% of the time, genome sequencing gives the answer.

Discovering all these genes involved in diseases means that we are now on the path to understanding how to cure those diseases. There are some dramatic examples, such as spinal muscular atrophy, where kids never used to live more than a year or two but are now able to go to school.

Sickle cell disease, the first molecular disorder, has one letter that should have been an A but instead is a T, and this causes a very serious illness. We are now curing this using genetic approaches.

Genetic sequencing is still complicated and expensive, and it needs to be more accessible to places like Africa. But the proof of principle is there. I did not know that would happen in my lifetime, and I bet there are many other things I have not expected that will happen in the next ten years.

For people reading this, particularly young people trying to figure out what they want to do with their life, career, and interests if you happen to be interested in science in any way, this is the moment for life science to explode with potential and have all kinds of applications that some of us have not even thought of yet, but are going to be amazing to be part of. We need you.

Image Credit: National Human Genome Research Institute 

In 2021, you stepped down from being the Director of the NIH after serving as the longest presidentially appointed director. Whilst serving as the director, you watched the world navigate through a global crisis; the COVID-19 pandemic. As someone responsible for spearheading the NIH's response to the pandemic, what impact did the pandemic have on the health of the nation, and how important was it to you to design a strategy that mitigated its impact?

When COVID-19 emerged in January 2020, this was the greatest challenge the scientific community had ever really faced, and the response was phenomenal. From every sector, from academic investigators, from the government, from the industry, we all got together and said, "This is a crisis. We cannot worry too much about who is going to get the credit. We just have to bring every kind of skill and talent to bear on this."

The results were remarkable, including the vaccines. In the past, the shortest timetable to develop a vaccine against an illness was perhaps five years. Most vaccines failed, and the ones that worked generally had a success rate in terms of protecting you of perhaps 50-60%. With the new approach of mRNA vaccines, 11 months from the first glimmer of what the virus was to having those approved for emergency use and with a 95% efficacy better than anybody had almost dared to hope.

That is a truly remarkable demonstration of what science can do in a circumstance like this. I think history will notice that for decades to come. We also had to find therapeutics, and initially, we had to start with things already approved for other diseases to see if they would work, such as Remdesivir. Steroids and monoclonal antibodies also were developed.

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We were always chasing the next variant, which was one of the challenges with SARS-CoV-2, and so much of what we tried to do, we had to revise the approach again. This is why the vaccines are now boosters that are so-called bivalent because they include the Omicron as well as the original variant of the virus.

In the diagnostic arena, with a rough start regarding the testing capacity in the US, we brought to bear all of the technological talent, the engineers, and the people who knew how to take things and turn them into tests that you could do at home.

Now, these tests are widely available. It was a stress, and it is still a stress. COVID is not entirely over; let us be clear about that. Unfortunately, there was a lot of confusion, and misinformation and politics got involved, but when you look at the scientific response, it was astounding.

Despite the devastation the pandemic caused worldwide, we saw that when international strategies are aligned, scientific progress can be made at an unprecedented level. How can we take lessons learned from the pandemic to help continue the acceleration of scientific discoveries?

Science has always been international. Scientists like the idea of collaborating with people who are not necessarily in the same building, town, or even country. The Genome Project was a good example, involving six countries substantively, and many others played other roles.

The pandemic built upon that tradition of trusting each other to do things together across country boundaries and further strengthened it. A lot of the combined effort is now focused on preparing for the next pandemic.

There are efforts to try to look at what happened with COVID-19 and say, "Could we better prepare ourselves the next time by actually starting some of the processes for vaccines and treatments, even before we know exactly what virus we are going to have to address?" If we manage to stick to our determination there, to actually do that preparation and not sink back into complacency, then I think we have a better chance with the next one.

But this is going to require the same kind of international collaborative effort. The good news is that science has always been this way. It is not like we must invent relationships that were not there. We need to be sure they are strengthened and kept in as vigorous and open an environment as possible.

Throughout your career, you have had numerous incredible achievements, including receiving the Presidential Medal of Freedom and the National Medal of Science as well as serving 12 years as the Director of the NIH and being the scientific advisor to the President. For you, what has been your proudest achievement?

I have indeed been fortunate in a way that I would never have expected, having been a boy who grew up on a small farm with no indoor plumbing. To end up in this circumstance of having the chance to take part in all these projects has been beyond any expectation I could have had.

It is hard to pick one thing because all of these matters, including things I am working on right now, such as trying to find a cure for one of the rarest forms of premature aging, a disease called progeria. I care deeply about those kids; I want to find an answer for them. But considering everything and the context of history, having the chance to lead the Human Genome Project would probably climb its way up to the top of the list, but not by much.

Image Credit: E-ART/Shutterstock.com

We have seen the field of genetics transform significantly just in the last decade, with the sector now entering a new era surrounding automation, AI, and increased cross-sector collaborations. What are you personally most excited about for the future of the life sciences? Are there any particular breakthroughs you are looking forward to?

Several areas are full of potential for a breakthrough. One is the brain. We have the ability now, with the tools of genomics, to ask each cell in the brain, "What are you doing?" This single-cell biology approach begins to build information about circuits and discover how they work. There is an initiative underway that is now seven years along that is making really good progress there, with a lot of it being engineering and technology.

We are going to understand how you lay down a memory and retrieve it, as well as many things that we do without thinking about it, these complex functions that are ingrained somehow in that genome we were all born with.

I would say another area is the general application of single-cell biology. It opens all these potential opportunities for understanding the biology and how these things sometimes go awry and cause disease. We have the opportunity to do precision medicine, which I am excited about. Not just about how to manage disease but how to prevent it.

In many countries and certainly in the US, in the All of Us Project, the aim is to answer these questions by enrolling a very large number of people (1 million for the US) and tracking them over time with complete access to their medical records, their genome sequence, their behaviors, their health practices and examining how all these things play out with environmental exposure to keep people healthy or to have them fall ill.

How can we take that advantage forward to have a preventive approach to disease that is not just a one-size-fits-all that people tend to ignore but an individual recommendation?

There is a revolution in gene therapy cures for diseases, and this is focused particularly on rare diseases caused by a single gene that has gone awry, but it will play out also in more complicated polygenic conditions like heart disease, hypertension, etc. This will be transformative, as it gives us a whole new approach to understanding how to address the wide range of illnesses that afflict this.

Image Credit: Julia Lazebnaya/Shutterstock.com

What is next for you? Are you involved in any exciting upcoming projects? 

When I stepped down as NIH director, I got asked to come to the White House and serve as the president's acting science advisor, which I did for seven or eight months. It was interesting covering a wide range of things that I had not thought about much before, such as fusion energy.

Now I am serving as a special project advisor to the president, and I am focused very much on what could be one of the more dramatic public health achievements of this era, which is to eliminate hepatitis C as it is killing 15,000 people in the US. We have a cure for that disease. One of the most remarkable achievements of medical research is just one pill a day for 12 weeks gives a 95% cure with no side effects. But people are not receiving it for various complicated reasons relating to healthcare delivery and cost.

If we care about all our people, we need to do something about this. This is what I am doing right now, trying to convince Congress and the public health system that this is an opportunity we cannot pass up. It will save tens of thousands of lives and save tens of billions of dollars for people who once have cured their hepatitis C, will no longer need a liver transplant or treatment for liver cancer, and will not get diabetes or kidney disease because these can all be prevented. Instead of waiting for people to get sick, let us prevent it.

About Dr. Francis Collins

Dr. Collins is a physician-geneticist noted for his landmark discoveries of disease genes and his previous leadership of the international Human Genome Project, which culminated in April 2003 with the completion of a finished sequence of the human DNA instruction book. He served as director of the National Human Genome Research Institute at NIH from 1993-2008.

Dr. Collins then served as the 16 th  Director of the National Institutes of Health (NIH), appointed by President Barack Obama and confirmed by the Senate in 2009. In 2017, President Donald Trump asked Dr. Collins to continue to serve as the NIH Director. President Joe Biden did the same in 2021.  For those 12 years, serving an unprecedented three administrations, Dr. Collins oversaw the work of the largest supporter of biomedical research in the world, spanning the spectrum from basic to clinical research.  Dr. Collins stepped down as NIH Director on December 19, 2021. 

From February 2022 to October 2022, Dr. Collins served as Acting Science Advisor to President Biden.  From November 2022 to May 2023 he continued his White House service as a Special Advisor to the President for Special Projects, leading the development of a bold program to eliminate hepatitis C in the United States.

Dr. Collins is an elected member of both the National Academy of Medicine and the National Academy of Sciences, was awarded the Presidential Medal of Freedom in November 2007, and received the National Medal of Science in 2009. In 2020, he was elected as a Foreign Member of the Royal Society (UK) and was also named the 50th winner of the Templeton Prize, which celebrates scientific and spiritual curiosity.

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An epigenetic reflection

Opinion by Ulf Kristoffersson, Consultant at the Genetics Clinic, Laboratory Medicine, Region Skåne and Reader in Clinical Genetics

“I have no responsibility for my own health – it’s my genes that determine whether or not I become ill.”

With greater knowledge of the role of our genes in health and disease, some deterministic ideas have taken root among the public. This determinism, which has never been embraced by scientists in the field, does not agree with the new theories. Our lives and lifestyles affect how our genes are expressed and this quashes the reasoning of genetic determinism.

What significance does this have for our relationship to health and health services: do we have greater responsibility for our own health than previously? Maybe, maybe not. We are already encouraged to think about all aspects of our health on a daily basis – not smoking, not drinking, eating a balanced diet and exercising.

The growing awareness of how epigenetic changes regulate gene expression could lead to the personalisation of this advice, which would be of benefit to the individual. However, the knowledge could also be turned against the individual – if you smoke or eat unhealthily, you run a much higher risk of suffering from disease. Knowledge of your epigenome could also reveal that certain medical treatments will not have any effect, or alternatively, will be particularly effective.

Once such new diagnostic possibilities become available, it will mean that some people will not get treatment. This group have sometimes been referred to as “the new orphans” – those for whom there is no effective treatment. This will entail savings for society because we will not have to pay for ineffective treatments, and overall treatment will become more cost-effective.

On the positive side for the individual, there will be more opportunity to personalise treatment. The individual will receive a better tailored treatment than at present.

From the perspective of society, it is of course possible that we could see discrimination against those who increase their risk of disease by their lifestyle. However, epigenetic tests will never lead to a 100% causal link between an individual’s lifestyle and ill health; there are always other factors involved. Epigenetics will simply provide a new way of classifying individuals into different risk groups. I therefore do not think that greater knowledge of the origins of our different phenotypes will have a direct impact on how we approach others, but of course it could be used to classify people in the same way that we can divide them into fat and thin, smokers and non-smokers, etc. The individual will probably not change his or her behaviour; why should we expect they would? We already know that our bad habits lead to ill health and yet so many of us continue with them. It is more likely that there is a risk of a new hype – overconfidence that I can influence my epigenome to achieve a better life, a life more in line with the prevailing norms.

Tags: Health epigenetics discrimination societal perspective Ulf Kristoffersson

2014-10-16, at 14:41

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Do you know your epigenome, learn more about genetics and epigenetics, the cancer detectives, identical twins not identical.

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Ancient theories of pangenesis and blood in heredity

Preformation and natural selection.

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What is genetics?

Genetics is the study of  heredity  in general and of  genes  in particular. Genetics forms one of the central pillars of  biology  and overlaps with many other areas, such as agriculture,  medicine , and  biotechnology .

Is intelligence genetic?

Intelligence  is a very complex human trait, the genetics of which has been a subject of controversy for some time. Even roughly measured via diverse cognitive tests, intelligence shows a strong contribution from the environment.

Genetic testing typically is issued only after a medical history, a physical examination, and the construction of a family pedigree documenting familial  genetic diseases  have been considered. The genetic tests themselves are carried out using chemical, radiological, histopathologic, and electrodiagnostic procedures. Genetic testing may involve cytogenetic analyses to investigate chromosomes, molecular assays to investigate genes and DNA, or biochemical assays to investigate enzymes, hormones, or amino acids.

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genetics , study of heredity in general and of genes in particular. Genetics forms one of the central pillars of biology and overlaps with many other areas, such as agriculture, medicine , and biotechnology .

Since the dawn of civilization, humankind has recognized the influence of heredity and applied its principles to the improvement of cultivated crops and domestic animals. A Babylonian tablet more than 6,000 years old, for example, shows pedigree s of horses and indicates possible inherited characteristics. Other old carvings show cross- pollination of date palm trees. Most of the mechanisms of heredity, however, remained a mystery until the 19th century, when genetics as a systematic science began.

Genetics arose out of the identification of genes, the fundamental units responsible for heredity. Genetics may be defined as the study of gene s at all levels, including the ways in which they act in the cell and the ways in which they are transmitted from parents to offspring. Modern genetics focuses on the chemical substance that genes are made of, called deoxyribonucleic acid, or DNA , and the ways in which it affects the chemical reactions that constitute the living processes within the cell. Gene action depends on interaction with the environment . Green plant s, for example, have genes containing the information necessary to synthesize the photosynthetic pigment chlorophyll that gives them their green colour. Chlorophyll is synthesized in an environment containing light because the gene for chlorophyll is expressed only when it interacts with light. If a plant is placed in a dark environment, chlorophyll synthesis stops because the gene is no longer expressed.

Genetics as a scientific discipline stemmed from the work of Gregor Mendel in the middle of the 19th century. Mendel suspected that traits were inherited as discrete units, and, although he knew nothing of the physical or chemical nature of genes at the time, his units became the basis for the development of the present understanding of heredity. All present research in genetics can be traced back to Mendel’s discovery of the laws governing the inheritance of traits. The word genetics was introduced in 1905 by English biologist William Bateson , who was one of the discoverers of Mendel’s work and who became a champion of Mendel’s principles of inheritance.

Historical background

Although scientific evidence for patterns of genetic inheritance did not appear until Mendel’s work, history shows that humankind must have been interested in heredity long before the dawn of civilization. Curiosity must first have been based on human family resemblances, such as similarity in body structure, voice, gait, and gestures. Such notions were instrumental in the establishment of family and royal dynasties . Early nomadic tribes were interested in the qualities of the animals that they herded and domesticated and, undoubtedly, bred selectively. The first human settlements that practiced farming appear to have selected crop plants with favourable qualities. Ancient tomb paintings show racehorse breeding pedigrees containing clear depictions of the inheritance of several distinct physical traits in the horses. Despite this interest, the first recorded speculations on heredity did not exist until the time of the ancient Greeks; some aspects of their ideas are still considered relevant today.

Hippocrates ( c. 460– c. 375 bce ), known as the father of medicine, believed in the inheritance of acquired characteristics, and, to account for this, he devised the hypothesis known as pangenesis . He postulated that all organs of the body of a parent gave off invisible “seeds,” which were like miniaturized building components and were transmitted during sexual intercourse , reassembling themselves in the mother’s womb to form a baby.

Aristotle (384–322 bce ) emphasized the importance of blood in heredity. He thought that the blood supplied generative material for building all parts of the adult body, and he reasoned that blood was the basis for passing on this generative power to the next generation. In fact, he believed that the male’s semen was purified blood and that a woman’s menstrual blood was her equivalent of semen. These male and female contributions united in the womb to produce a baby. The blood contained some type of hereditary essences, but he believed that the baby would develop under the influence of these essences, rather than being built from the essences themselves.

Aristotle’s ideas about the role of blood in procreation were probably the origin of the still prevalent notion that somehow the blood is involved in heredity. Today people still speak of certain traits as being “in the blood” and of “blood lines” and “blood ties.” The Greek model of inheritance, in which a teeming multitude of substances was invoked , differed from that of the Mendelian model. Mendel’s idea was that distinct differences between individuals are determined by differences in single yet powerful hereditary factors. These single hereditary factors were identified as genes. Copies of genes are transmitted through sperm and egg and guide the development of the offspring. Genes are also responsible for reproducing the distinct features of both parents that are visible in their children.

In the two millennia between the lives of Aristotle and Mendel , few new ideas were recorded on the nature of heredity . In the 17th and 18th centuries the idea of preformation was introduced. Scientists using the newly developed microscope s imagined that they could see miniature replicas of human beings inside sperm heads. French biologist Jean-Baptiste Lamarck invoked the idea of “the inheritance of acquired characters,” not as an explanation for heredity but as a model for evolution . He lived at a time when the fixity of species was taken for granted, yet he maintained that this fixity was only found in a constant environment. He enunciated the law of use and disuse, which states that when certain organs become specially developed as a result of some environmental need, then that state of development is hereditary and can be passed on to progeny. He believed that in this way, over many generations, giraffe s could arise from deerlike animals that had to keep stretching their necks to reach high leaves on trees.

British naturalist Alfred Russel Wallace originally postulated the theory of evolution by natural selection . However, Charles Darwin ’s observations during his circumnavigation of the globe aboard the HMS Beagle (1831–36) provided evidence for natural selection and his suggestion that humans and animals shared a common ancestry. Many scientists at the time believed in a hereditary mechanism that was a version of the ancient Greek idea of pangenesis, and Darwin’s ideas did not appear to fit with the theory of heredity that sprang from the experiments of Mendel.

The role of genetics in development Essay

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Genetic factors have a significant role in determining human development. It involves understanding the inheritance of genes from parents to offspring and gene processes that may have impacts on human development. Researchers have concentrated on understanding human growth and differentiation right from the fertilized ova to adulthood. They have noted that development and various characteristics result from the expression of some specific genes (Berger, 2000).

Therefore, genetic factors influence how a child develops. Genetics provides specific and basic blueprint that determines child development. However, it is important to recognize the role of environment in influencing a child’s development.

For instance, some environmental factors like nutrition may alter the gene setup of an individual. In such cases, they may deter growth to achieve full potential or inhibit development of certain body composition, which could result in genetic disorders. One must note that genetics composition and environmental factors interact to determine development in individuals (Mossler, 2011).

Genes of the two parents could influence the traits of an offspring. However, expressions of genes from parents depend on two different factors. These include interactions among genes and further interaction in genotype and with the environment. Interactions between genes could result in conflicting information.

In some cases, one gene could dominate the other. Not all genes have the same manner of interaction because others may be additive. For instance, a child could have both short and tall parents. The genes may not dominate each other and such a child could end up with an average height.

In some cases, the child may exhibit “dominant-recessive gene patterns” (Miko, 2008). This is common in eye colors where brown eye genes are “dominant while blue eye genes become recessive” (Miko, 2008). One parent may pass a dominant gene to the child. In this case, the dominant gene will win over the recessive gene, and the child may exhibit the characteristics of a parent who produced dominant genes (Miko, 2008).

Genes also interact with environments. The environment may affect gene expression in children for the rest of their lives. For example, pregnant women who expose their fetuses to harmful chemicals could create conditions that would later affect their children’s development.

In addition, environmental factors could affect genes responsible for a child’s height. For instance, persistent illness or poor diets could deter the expressions of genes responsible for the child’s height. In such cases, the child would not be tall as the genetic code had shown.

Parents may also pass hereditary conditions to their offspring. This could result in genetic disorder. It is important to recognize that genes interaction processes are not infallible. Thus, defects may occur during the process. Under some circumstances, the number of chromosomes in a sperm or ovum may not be even. This may result in either more or less chromosomes than in normal circumstances (the number of normal chromosomes are 23).

In situations where abnormal cells interact and stick together with normal cells, “the resultant fertilized ovum (zygote) will also have abnormal number of chromosomes” (Miko, 2008). Some studies have hinted that most of the fertilized eggs normally result in abnormal genes with more or less than 23 chromosomes. However, the body aborts most of these abnormal zygotes, and they never develop to achieve a full-term period of a fetus.

Disorders result from zygotes, which develop to full-term fetuses. Such disorders affect child development. Researchers have linked some disorders entirely with genetic interactions, whereas in other cases, genetic factors may have partial roles.

Tay-Sachs disease is an “inherited condition of the nervous system” (Jasmin, 2012). The disease progressively affects “neurons in the brain and spinal cord” (Jasmin, 2012). The defective gene on “chromosome 15 is responsible for Tay-Sachs condition” (Jasmin, 2012). Both parents must be “carriers of the Tay-Sachs gene in order for the child to develop the condition” (Jasmin, 2012).

Every parent must contribute the responsible gene. However, the child may be “a carrier of Tay-Sachs disease only if one parent passes the abnormal gene him or her” (Jasmin, 2012). This would not result in Tay-Sachs condition, but the child will have the possibility of passing the condition to his or her children.

One can observe Tay-Sachs disease between “the age of three and six months after birth” (Jasmin, 2012). At infancy, children with Tay-Sachs disease experience slow developments and weaknesses in their muscles.

Infants progressively lose motor skills, they may not move. Later on, children with the condition may develop “seizures, vision and hearing loss, intellectual disability, and paralysis” (Jasmin, 2012). Examination of the eye can reveal a cherry-red spot in such children. Children with extreme conditions may not live beyond their early childhood stage.

There are other rare forms of the condition, which have mild symptoms relative to severe cases during infancy stage. Children with mild forms of Tay-Sachs also have weak muscles, ataxia, speech, mental, and movement challenges.

Tay-Sachs disease has no cure, but physicians can only improve conditions of children with it. There are no existing methods of preventing Tay-Sachs disease. However, genetic testing can reveal a carrier, and a couple can decide before starting a family.

Evidently, genetics have critical influences on child development. However, genetic factors may interact with environmental factors in order to control a child’s development.

Berger, K. (2000). The developing person: Through childhood and adolescence. New York: Worth Publishers.

Jasmin, L. (2012). Tay-Sachs disease . Web.

Miko, I. (2008). Genetic dominance: genotype-phenotype relationships. Nature Education 1 (1).

Mossler, A. (2011). Child and adolescent development. San Diego: Bridgepoint Education, Inc.

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Genetic Genealogy Reflective Paper Activity

Genetic genealogy and the biology behind the science..

 “Inside the Genetic Genealogy being used to solve crimes.”   Learning Objectives  • Explore what technology and techniques are used by criminal justice investigators to crack cold cases with DNA technology. • Understand the strengths and limitations of the technology • Be able to think critically about the technology.  Introduction  • Ancestory.com and 23andme.com are mainstream in American life and the use of technology is very important for cold cases. So, in this activity, we will learn more about the applications, strengths, and limitations of this DNA technology.  • In recent years, advances in genetics and genomics have brought new dimensions to genetic testing. Genetic genealogy is the use of DNA testing in combination with traditional genealogical and historical records. Genetic genealogy involves the use of genealogical DNA testing together with documentary evidence to infer the relationship between individuals.  • In a recent 60 minutes, a new story from October 21, 2018, genetic genealogy was featured as a new tool to fight crime and solve cold cases.  Instructions  • View each of the two videos listed below and answer the following questions.  Be sure to turn the sound on your computer on so you can hear the narration.  I recommend opening each video in a separate browser tab and leaving them open so you may easily go back and forth among them throughout the assignment.  You may need to watch them multiple times to answer the questions.  

Introduction to Genetic Genealogy:

Video #1 https://youtu.be/ovqkr2TFFuc    Video #2 Moore, Expert: Genetic Genealogist - Tales from the Genome: https://youtu.be/PwmU6XVYn3A  ( 15-17 minutes into the video CeCe spells out exactly how she does itand apparently she is the best in the field of genetic genealogy)    Background Reading Article 1:  Scientific Paper: "Inferring genetic ancestry: opportunities, challenges, and implications."  From: https://www.ncbi.nlm.nih.gov/pubmed/20466090    Activity  Complete this assignment by typing the answers into this document or another word document (Google docs) on your computer and printing it out to turn in before lab begins.  Write  one page under 500-word reflective essay on the topic.  The essay should be three paragraphs long and have proper grammar, sentence and paragraph structure. All citations should be in either APA or MLA style.   Research the topic online and use a minimum of 3 scientific outside sources.  Answer the following questions (at least 2-3 of them) in your reflective paper:  ·        What do we mean by ancestry?  ·        How exactly is ancestry measured?  ·        Do you think that genetic genealogy is an effective tool to help law enforcement crack cold cases?  3    ·        What are the advantages and limitations of genetic genealogy for law enforcement?  ·        What are the possible limitations of using genetic genealogy?     ·        How far back can such ancestry be defined and by which genetic tools?   Evaluation  Your paper will be evaluated by the following criteria:    Item NEEDED Research/Sources 15 points    Credibility (academic/nonacademic) 5     References (outside secondary sources) 10 Discipline-specific Knowledge/Content 50 points    Explanation (define, describe, restate) 15    Analysis (strengths and weaknesses of technology) 25    Critique your own opinion and why) 10 Composition    Clarity (5 points)     Sentence and paragraph structure, grammar, punctuation and    appropriate length. 20 points) 25 

Genetic Genealogy Reflective Paper

Make sure to reference 3 outside sources for this activity.

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How Genes Influence Child Development

Nature vs. nurture, prenatal child development, environmental influences, gene expression, genetic abnormalities.

What determines how a child develops? While it is impossible to account for each and every influence that contributes to who a child eventually becomes, today, most researchers view development as a combination of both a child's heredity and environment.

This involves considering factors such as genetics, parenting, experiences , friends, family, education, and relationships. By understanding the role that these factors play, researchers are better able to identify how such influences contribute to child development.

Think of these influences as building blocks. While most people tend to have the same basic building blocks, these components can be put together in an infinite number of ways. Consider your own overall personality . How much of who you are today was shaped by your genetic background and how much is a result of your lifetime of experiences?

This question has puzzled philosophers, psychologists , and educators for hundreds of years and is frequently referred to as the nature versus nurture debate. Are we the result of nature (our genetic background) or nurture (our environment)? Today, most researchers agree that child development involves a complex interaction of both nature and nurture.  

While some aspects of development may be strongly influenced by biology, environmental influences may also play a role. For example, the timing of when the onset of puberty occurs is largely the result of heredity, but environmental factors such as nutrition can also have an effect.

From the earliest moments of life, the interaction of heredity and the environment works to shape who children are and who they will become. While the genetic instructions a child inherits from their parents may set out a road map for development, the environment can impact how these directions are expressed, shaped, or even silenced.

The complex interaction of nature and nurture does not just occur at certain moments or at certain periods of time; it is persistent and lifelong.

In order to understand child development, it is important to look at the biological influences that help shape child development, how experiences interact with genetics, and some of the genetic disorders that can have an impact on child psychology and development.

At its very beginning, the development of a child starts when the male reproductive cell, or sperm, penetrates the protective outer membrane of the female reproductive cell, or ovum. The sperm and ovum each contain chromosomes that act as a blueprint for human life.

The genes contained in these chromosomes are made up of a chemical structure known as DNA (deoxyribonucleic acid) that contains the genetic code, or instructions, that make up all life. Except for the sperm and ova, all cells in the body contain 46 chromosomes.

As you might guess, the sperm and ova each contain only contain 23 chromosomes. This ensures that when the two cells meet, the resulting new organism has the correct 46 chromosomes.

So how exactly do the genetic instructions passed down from both parents influence how a child develops and the traits they will have? In order to fully understand this, it is important to first distinguish between a child's genetic inheritance and the actual expression of those genes.

A genotype refers to all of the genes that a person has inherited. A phenotype is how these genes are actually expressed. The phenotype can include physical traits, such as height and color of the eyes, as well as nonphysical traits such as shyness and extroversion.

While your genotype may represent a blueprint for how children grow up, the way that these building blocks are put together determines how these genes will be expressed. Think of it as a bit like building a house. The same blueprint can result in a range of different homes that look quite similar but have important differences based on the material and color choices used during construction.

Whether or not a gene is expressed depends on two different things: the interaction of the gene with other genes and the continual interaction between the genotype and the environment.

• Genetic Interactions: Genes can sometimes contain conflicting information, and in most cases, one gene will win the battle for dominance. Some genes act in an additive way. For example, if a child has one tall parent and one short parent, the child may end up splitting the difference by being of average height. In other cases, some genes follow a dominant-recessive pattern. Eye color is one example of dominant-recessive genes at work. The gene for brown eyes is dominant and the gene for blue eyes is recessive. If one parent hands down a dominant brown eye gene while the other parent hands down a recessive blue eye gene, the dominant gene will win out and the child will have brown eyes.
• Gene-Environment Interactions: The environment a child is exposed to both in utero and throughout the rest of his or her life can also impact how genes are expressed. For example, exposure to harmful drugs while in utero can have a dramatic impact on later child development. Height is a good example of a genetic trait that can be influenced by environmental factors.   While a child's genetic code may provide instructions for tallness, the expression of this height might be suppressed if the child has poor nutrition or chronic illness.

Genetic instructions are not infallible and can go off track at times. Sometimes when a sperm or ovum is formed, the number of chromosomes may divide unevenly, causing the organism to have more or less than the normal 23 chromosomes. When one of these abnormal cells joins with a normal cell, the resulting zygote will have an uneven number of chromosomes.

Researchers suggest that as many as half of all zygotes that form have more or less than 23 chromosomes, but most of these are spontaneously aborted and never develop into a full-term baby.

In some cases, babies are born with an abnormal number of chromosomes. In every case, the result is some type of syndrome with a set of distinguishing characteristics.

Sex Chromosome Abnormalities

The vast majority of newborns, both boys and girls, have at least one X chromosome. In some cases, about 1 in every 500 births, children are born with either a missing X chromosome or an additional sex chromosome. Klinefelter syndrome, Fragile X syndrome, and Turner syndrome are all examples of abnormalities involving the sex chromosomes.

Kleinfelter's syndrome is caused by an extra X chromosome and is characterized by a lack of development of secondary sex characteristics, as well as learning disabilities.

Fragile X syndrome is caused when part of the X chromosome is attached to the other chromosomes by such a thin string of molecules that it seems in danger of breaking off. It can affect both males and females, but the impact can vary. Some with Fragile X show few if any signs, while others develop mild to severe intellectual disability.

Turner syndrome occurs when only one sex chromosome (the X chromosome) is present. It affects only females and can result in short stature, a "webbed" neck, and a lack of secondary sex characteristics. Psychological impairments associated with Turner syndrome include learning disabilities and difficulty recognizing emotions conveyed through facial expressions .

Down Syndrome

The most common type of chromosomal disorder is known as trisomy 21, or Down syndrome. In this case, the child has three chromosomes at the site of the 21st chromosome instead of the normal two.

Down syndrome is characterized by facial characteristics including a round face, slanted eyes, and a thick tongue. Individuals with Down syndrome may also face other physical problems including heart defects and hearing problems. Nearly all individuals with Down syndrome experience some type of intellectual impairment, but the exact severity can vary dramatically.

A Word From Verywell

Clearly, genetic influences have an enormous influence on how a child develops. However, it is important to remember that genetics is just one piece of the intricate puzzle that makes up a child's life. Environmental variables including parenting, culture, education, and social relationships also play a vital role.

Levitt M. Perceptions of nature, nurture and behaviour .  Life Sci Soc Policy . 2013;9:13. doi:10.1186/2195-7819-9-13

Day FR, Perry JR, Ong KK. Genetic regulation of puberty timing in humans .  Neuroendocrinology . 2015;102(4):247–255. doi:10.1159/000431023

National Human Genome Research Institute. Phenotype .

Jelenkovic A, Sund R, Hur YM, et al. Genetic and environmental influences on height from infancy to early adulthood: An individual-based pooled analysis of 45 twin cohorts .  Sci Rep . 2016;6:28496. doi:10.1038/srep28496

U.S. National Library of Medicine. Klinefelter syndrome .

Centers for Disease Control and Prevention. What is fragile X syndrome? .

U.S. National Library of Medicine. Turner syndrome .

Centers for Disease Control and Prevention. Facts about Down syndrome .

By Kendra Cherry, MSEd Kendra Cherry, MS, is a psychosocial rehabilitation specialist, psychology educator, and author of the "Everything Psychology Book."

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Essay Contest Reveals Misconceptions of High School Students in Genetics Content

National educational organizations have called upon scientists to become involved in K–12 education reform. From sporadic interaction with students to more sustained partnerships with teachers, the engagement of scientists takes many forms. In this case, scientists from the American Society of Human Genetics (ASHG), the Genetics Society of America (GSA), and the National Society of Genetic Counselors (NSGC) have partnered to organize an essay contest for high school students as part of the activities surrounding National DNA Day. We describe a systematic analysis of 500 of 2443 total essays submitted in response to this contest over 2 years. Our analysis reveals the nature of student misconceptions in genetics, the possible sources of these misconceptions, and potential ways to galvanize genetics education.

THE rapid advances in genetic research, the popularity of the topic in the news and in current popular television shows ( e.g. , CSI: Crime Scene Investigation), and the direct role that genetics plays in human health and reproduction make it a scientific discipline that everyone needs to understand. Yet, several studies reveal that students fail to critically understand the genetics knowledge taught in the classroom, and this lack of understanding translates to an inability to apply basic knowledge to their everyday lives ( L ewis and W ood -R obinson 2000 ; L ewis and K attmann 2004 ).

State science standards reflect the important role that genetic advances are playing in our lives. More than 80% of middle and high school science standards adopted since 2003 include terminology on the Human Genome Project, bioethics, cloning, stem cells, and/or other biotechnology terminology that did not exist in previous versions of the standards. However, even the adoption of national science standards, which include the coverage of genetics concepts, does not guarantee understanding of the concepts. The compulsory science education standards in England and Wales, for example, failed to yield deep conceptual understanding in genetics for their students ( L ewis and W ood -R obinson 2000 ). The important role genetics plays in society, human health, and our responses to the environment makes these deficiencies in genetics content knowledge revealed by state, national, and international standardized tests even more troubling. Therefore, a strategic effort to improve secondary genetics education is especially needed.

MISCONCEPTIONS AND CRITICAL THINKING

One strategy that can have an impact on student understanding of a specific discipline is to encourage deep, critical thinking about that discipline. In an age where at least superficial information is at our fingertips on a limitless number of topics including genetics, we must find methods of ensuring an enduring understanding of this information. Because students often learn only passively through lectures, reading assignments, or cursory searching of the Internet, developing critical thinking skills is necessary to ensure a level of literacy and the eventual ability to apply the knowledge ( C onnally and V ilardi 1989 ; R ivard 1994 ; K eys 1999 ). Providing students with an opportunity to explore challenging areas in genetics through writing is one manner of achieving this goal.

Research on student learning suggests that student misconceptions serve as barriers to student achievement. These misconceptions are often based on personal experiences and are difficult to bypass en route to meaningful understanding in any content area ( G elman and G allistel 1986 ; W ellman 1990 ). Even after instruction designed to address scientific content in an area where misconceptions are held, many students do not reconstruct their thinking. Only those students able to deconstruct their knowledge and reconstruct it using critical thinking and logical reasoning appear to have fewer misconceptions even after high-quality instruction ( L awson and T hompson 1988 ). Similarly, conceptual change generally occurs only if a learning experience can demonstrate both that a student's explanation is insufficient and that an alternative explanation is more applicable ( P osner et al. 1982 ).

The National Assessment of Education Progress (NAEP) assesses proficiency of U.S. students in a variety of content areas, including science, using a random sampling of students from the 4th, 8th, and 12th grades. The last NAEP tests in science were administered in 1996, 2000, and 2005. Unfortunately, the data from the 2005 test is still not completely accessible to the public. However, an analysis of the 2000 NAEP test results reveals dramatic deficiencies in genetics content knowledge at both 8th and 12th grades. Mastery of 12 concepts from earth, physical, and life sciences is required for students to demonstrate proficient or advanced knowledge in the sciences; one-quarter of these concepts are in the field of genetics ( O'S ullivan et al. 2003 ). The NAEP test results reveal specific deficits in student understanding of classification, evolution, mutation, and DNA technology as shown in Table 1 . Publicly available data on the 2000 NAEP science assessment (at http://nces.ed.gov/ ) provides sample questions and answers from students, as well as the criteria for scoring answers as “complete or essential, partial, or unsatisfactory.” We specifically examined the subset of data regarding the broad category of molecular and human genetics (footnote a in Table 1 ).

NAEP test results in 2000 for science reveal a deficit in student understanding of core genetics concepts ( O'S ullivan et al. 2003 )

Percentages may not total to 100 due to rounding and student omission ( i.e ., no answer was given).

All questions referring to genes, mutation, cell differentiation, genetic disease, and recombinant DNA usage for 12th grade students had a difficulty of “hard” and required a written response. This type of question enables investigators to explore student thinking in more depth. The example for the year 2000 provided an adapted text that was taken from an article in the March 1990 issue of Discover magazine. This article was based on the work of Richard Mulligan and other geneticists that are currently examining the use of viruses as vehicles for introducing genes into human cells as a form of therapy for genetic diseases in humans. A majority of students were not able to describe a gene, its structure, or its function. It was very rare for students to have a thorough understanding of the types of mutations that occur, the causes of those mutations, and the physiological effect of gene alterations. Moreover, few were able to transfer the knowledge from the article to the information they had learned in class about inherited diseases.

Therefore, to encourage a transformation from passive knowledge in genetics gained via classroom lectures, the National DNA Day Essay Contest ( http://www.genednet.org/pages/k12_dnaday08.shtml ) was established by K. R. Mills Shaw, Director of Education at the American Society of Human Genetics (ASHG), to provide a distinct opportunity for students to think critically and articulate scientific arguments related to genetics. Teachers from across the country were invited to participate through list serves, blast e-mails, and the ASHG education website, http://www.genednet.org . Each year two questions have been provided: one to allow students to explore the methods and research that genetics entails and the second to explore the ethical, legal, and social issues influenced by genetics (see Table 2 ). Table 3 summarizes the number of essays submitted during each year of the contest. The students who wrote the top three essays for each question were declared first, second, and third place winners through the judging process described in methods . These students were awarded $350, $250, and $150, respectively. The monetary awards were made possible by the sponsorship of Applied Biosystems (Foster City, CA). While many essays demonstrated a clear understanding of genetics and its implications, a significant number of contributed essays revealed firmly held misinformation and misconceptions by U.S. students in grades 9–12. This article examines those misconceptions, provides possible explanations for their origins, and suggests ways that scientists, professors, and teachers can collaborate to improve genetics education at the K–12 level.

Essay contest questions in 2006 and 2007

Essay contest participation in 2006 and 2007

Judging of essays:

All aspects of the National DNA Day Essay Contest were managed online from initial advertisement to final judging. Information technology specialists from ASHG and the Genetics Society of America (GSA) were able to adapt existing society resources to facilitate essay acceptance, cataloging, and scoring. Judges were recruited from the active membership of ASHG, GSA, and the National Society of Genetics Counselors (NSGC). Three groups of judges were utilized. Each year students were given a choice between two essay questions. The questions from 2006 and 2007 are highlighted in Table 2 . The first group of judges read large groups of essays on either of the two essay topics, scanning these essays to ensure they fulfilled all criteria and addressed all aspects of the judging criteria. The criteria were slightly different for each of the two questions and were all published online for all students and teachers. The scoring criteria for the 2007 questions are documented in Table 4 . Essays not fulfilling these criteria after being reviewed by at least two judges were removed from more detailed consideration. The second group of judges scored ∼10–15 essays in depth, providing a score (from 1 to 10) in each of the five categories. Each essay was scored by at least three independent judges. Scores were tabulated and the 10 essays with the highest scores for each topic were named as finalists. The last set of judges reviewed and scored each of the finalist essays with the highest-scoring essays being chosen as winners. One hundred ten members of the ASHG, GSA, or NSGC membership served as judges each year. The entire adjudication process is reviewed in Figure 1 . This system allowed us to perform all judging anonymously and ensure that each essay was read and scored by multiple independent reviewers while simultaneously investigating each essay for scientific accuracy.

Schematic of process involved in selecting finalist essays.

Essay contest scoring guidelines for 2007

Identification of misconceptions:

All judges, along with scientists on ASHG staff, were asked to examine each essay for misconceptions or incorrect statements and forward this information along with their scores. All misconceptions were collected over 2 years from individual judges but were placed into categories by two individual coders (K. R. Mills Shaw and K. Van Horne) on the basis of the genetic topic that the misconception addressed ( Table 5 ). These topics were generated de novo after reviewing all the misconceptions submitted from judges and after K. R. Mills Shaw and K. Van Horne additionally independently evaluated 125 randomly selected essays from each year (2006 and 2007). All misconceptions were then cataloged under these specific topic areas to better characterize the areas where misconceptions are most common (seen in Table 6 ). Five hundred essays, or 20%, were randomly selected for this level of systematic review. Specifically, every fourth essay was analyzed in detail. If, however, essays were deemed completely unsatisfactory for review ( e.g. , too short, too poorly defined, too poorly written), the essay was not included in the systematically reviewed sample of 500. A misconception/misunderstanding was identified as any clearly written statement that did not accurately reflect the nature of genetic science, technology, or research as defined by K. R. Mills Shaw and J. A. Boughman, both Ph.D. scientists with a background in genetics. Essays where language or communication barriers were obvious (due to vocabulary, grammatical, and spelling errors) were not included as part of this review. Once misconceptions were identified, coders both independently and in communication with each other cataloged misconceptions according to topic to ensure consistency in grouping. The quantitation of the examples revealed in this article reflects observations from analysis of the critical writing from 500 high school essays (9th–12th grade submissions).

Key ideas/subtopics used to categorize misconceptions

Common misconceptions revealed in student essays

Essays collected represent data from multiple states, grades, and classroom teachers:

All essays were submitted online. In the online submission form we collected demographic data on all students and their teachers, including their grade, city, state, and school. In both years of the contest we included a rule that stated only three essays per teacher for each question, for a total of six essays per teacher, would be accepted. However, this rule was often overlooked, and teachers would submit essays from their entire classrooms. Thus, while we collected more essays in 2006, this total number of essays reflects a representation of fewer classrooms. In 2007 we rectified this problem by adding an algorithm that blocked any more than three essays from the same teacher. The data presented in Table 3 show that the essay contest grew between years 1 and 2 in the overall number of classrooms reached and that the essays collected represent a wide geographical distribution. In 2007, we did not receive essays from Alaska, Hawaii, Vermont, South Dakota, Wyoming, Maine, Washington, DC, Nebraska, or Mississippi despite sending out multiple e-mail solicitations to teacher contacts in those states.

Identification of misconceptions and misinformation from student essays:

During the process of reading and scoring essays, judges were asked to identify and document examples of misconceptions in their essays. Additionally, all essays were cursorily scanned by either K. R. Mills Shaw or K. Van Horne. Tables 5 and ​ and6 6 provide an overview of the topics where misconceptions are common as well sample statements taken directly from student essays. While several hundred individual misconceptions were identified during the course of judging and review, many of the individual misconceptions could be categorized under broad topics in genetics (summarized in Table 5 ). To quantify the frequency of these common misconceptions we reanalyzed 500 (∼20%) of the essays, which included 250 essays chosen at random from each year's submissions. Individual misconceptions were identified and cataloged. After cataloging each misconception in the 500 essays and defining the categories of genetics in which they fell, “common” categories were defined by those being present in at least 5% of the essays examined. Of the 500 systematically reviewed essays, 278 (55.6%) revealed at least one obvious misconception. Another 101 essays (20.2%) were recognized for having two or more misconceptions. Misconceptions that were linked to essays with obvious language or writing barriers were excluded from quantitative analysis to avoid overrepresentation in our quantitative analysis. The prevalence of misconceptions per topic area is summarized in Figure 2 .

Prevalence of misconceptions by genetics topic. A total of 500 essays were chosen at random (20% of total submitted) and were systematically reviewed for misconceptions. Frequently observed topics of misconceptions were identified and essays were cataloged on the basis of the type(s) of misconception(s) they revealed.

Standards and common areas of misconceptions:

Misconceptions were identified and categorized into a general topic area. We then examined how standards were related to these main topic areas, specifically patterns of inheritance and the deterministic nature of genes. We analyzed 20 sets of state biology standards at random to determine the nature of the standards in patterns of inheritance at the introductory biology or life science level in high school. Supplemental Table 1 at http://www.genetics.org/supplemental/ highlights four sets of these standards that provide a range of coverage of patterns of inheritance. A majority of these basic genetics/cell biology standards (15/20) included an examination of Mendel's laws of inheritance, some specifically describing the requirement to understand probability, Punnett squares, and the differences between autosomal dominant, autosomal recessive, and sex-linked traits. Other states included only more broad descriptions where a student would, for example, “Explain current scientific ideas and information about the molecular and genetic basis of heredity” (see supplemental Table 1). These are important data because they reflect the highly diverse nature of the level of detail required of students in U.S. high schools. While standards that fail to provide comprehensive detail allow talented teachers to provide creative and challenging learning opportunities for students, they can often also result in learning experiences that fail to effectively teach students even the most basic concepts in biology.

Genetic technologies:

The single greatest number of misconceptions identified from student essays could be broadly defined as falling into the category of “genetic technologies.” When answering the question “If you were a genetics researcher, what would you study and why?” students often expressed their goal of curing multiple unrelated diseases. The reality is that most genetics researchers are often several steps removed from work on specific cures but instead devote their efforts to improving the molecular understanding of disease with the ultimate goal of improved treatments. Moreover, scientists generally study only one specific illness or class or related diseases. The work scientists currently perform to identify a disease-causing mutation is prominent in student essays with the common extrapolation to the “curing” of disease through gene replacement. Often, student essays also suggested that genetic engineering allows us to put a gene from any species into another species to have that trait expressed in exactly the same manner as in the original species. Students do not understand the complexity of biotechnology and genetic engineering. They make broad leaps without demonstrating an understanding for the multiple genetic and epigenetic (or environmental) factors that play a role in genetic regulation and manipulation of genetic materials in the laboratory setting. Moreover, there is a disconnect between observed characteristics and the physiological function of genes:

We could eliminate all the premature deaths of people dying around the world from thirst if we genetically modified people to inherit some of the characteristics of the camel, allowing them to go for months at a time without drinking water.

Finally, we note the prevalence of essays that included information on the importance of stem cell research. While clearly a prevalent topic in the popular literature and press, students often discussed stem cell biology without ever discussing the genetics of stem cells. We did not include essays that included information on stem cells in our quantitative analysis. However, we note that scanning our database from 2006 for all references of “stem cells” revealed that almost one-quarter of essay submissions included this terminology without actively exploring the genetic nature of these cells despite the clear genetics-oriented nature of the essay questions.

Deterministic nature of genes:

Another common misconception we observed is that one gene is always responsible for one trait or one gene with one mutation always causes one disease. The discovery of genes that convey and determine a specific phenotype is often displayed and hyped in the media. A cursory search of online news outlets yielded example headlines that could easily be misinterpreted, adding credibility to students' misconceptions. Some examples include the following titles: “Turning Off Suspect Gene Makes Mice Smarter” (nytimes.com, May 29, 2007) and “Researchers narrow search for longevity gene” (cnn.com, August 28, 2001). It is important for students to understand that it is rare that a single gene has complete control over an exhibited phenotype. Instead, multiple factors contribute to phenotype. Multiple genes often work together, with the environment, to determine ultimate phenotype. Our examination of standards revealed that only 3 of 20 state standards specifically mentioned that students should learn about polygenic inheritance (that more than one gene can contribute to a specific phenotype) and only 2 described the role of the environment in controlling phenotype. Thus, it is not surprising that we would see a common misconception that single genes are the cause of most traits and inherited diseases. Compared to the general nature of genetic inheritance, far fewer students would have necessarily been exposed to the concepts of non-Mendelian and polygenic inheritance.

Patterns of inheritance:

Patterns of inheritance was another topic that revealed numerous misconceptions and misunderstandings of students. Not only were students often unable to correctly describe the nature of simple dominant and recessive patterns of inheritance, but also they were not able to go into any level of depth regarding genes or alleles, the physiological function of genes (proteins), or non-Mendelian patterns of inheritance. Some students even described genetic technologies as being able to “prevent the inheritance” of disease genes. Students focused primarily on simple Mendelian inheritance that was able to be analyzed via Punnett square analysis. All students described only monogenic traits that followed simple autosomal dominant, autosomal recessive, or X-linked inheritance. Students were often unable to adequately describe sources of abnormal chromosome numbers. Essays did not mention errors during meiotic cell division and generation of gametes as the source of monosomies or trisomies. Our review of state science standards for high school students in biology suggests, not surprisingly, that the majority of states provide specific, detailed standards that mandate teaching students, even at the earliest levels of their life science education in high school, the basic biology of inheritance patterns. Although 15 of the 20 biology standards included basic patterns of inheritance knowledge, when we reviewed the essays that were cataloged as having an error or a misconception falling under “patterns of inheritance,” 80% of those essays inaccurately described a basic tenet of Mendelian inheritance, despite their expected coverage of this material at their current grade level or in previous biology courses.

Nature of genes and genetic material:

All 20 state standards examined require coverage of the nature of DNA as the hereditary material in living things. Nevertheless, students suggested that lower organisms, including bacteria and fungi, often do not carry DNA. We also noted student confusion regarding the hierarchal organization of genetic material. Notably, students were frequently unable to accurately define DNA, genes, and chromosomes. Often, these terms were instead used interchangeably. In 2007, <1% of essays included any information on additional genetic material in the genome. Students did not mention gene expression control elements, repetitive sequences (unless discussing Huntington's disease), or other nongene elements in the genome. Finally, students often described specific protein-encoding segments, or genes, as discrete elements that could easily be removed from one context and added in a separate context. While this view likely extends from students learning basic biotechnology and bacterial transformation techniques (for example, adding the green fluorescent protein from jellyfish to bacterial strains), likening this process to the adding of a chemical to a solution is an oversimplification, at best.

Genetic basis of disease:

One of the principle errors observed in this category was the confusion of “hereditary” and “genetic” when describing diseases. In a small subset of cases, ∼10% of the total essays categorized as having a misconception in this topic, students completely misrepresented the genetic nature of a specific illness ( e.g. , calling HIV-1 an inherited disorder). While most illnesses have a genetic component, this does not make them hereditary. Moreover, while even infectious diseases can be considered to have a genetic component whether it be of the genetics of the virus itself or how individual genetics could result in different manifestations of the same illness, students must learn to clarify these differences. Cancer is a genetic disease. Only rare cancers, however, are hereditary. However, students often described breast and ovarian cancer as hereditary due to the mutations in BRCA1 or BRCA2. While mutations in these genes often do result in a cancer predisposition that appears to be inherited in a dominant-like fashion, the majority of breast cancer cases are not due to mutations in these genes.

Genetics research:

A large number of student essays focused on the promise of genetic engineering in human health and reproduction (see also the Reproductive technologies section). While superficially this reflects that students recognize the positive influence that the study of genetics can have in their lives, numerous misconceptions suggest that students still fail to truly understand the nature and limitations of genetic research. An examination of state science standards, briefly described above, reveals that while state and national process (not necessarily content) standards require coverage of the nature of scientific research, inquiry, and discovery, this does not necessarily equate to students learning about how scientists actively perform research. Instead, these process standards reflect the fact that teachers are expected to provide students with opportunities for inquiry and investigation in the context of their own classroom laboratory experiments and activities. In short, state science standards do not require students to learn about the nature of scientific research.

Reproductive technologies:

Misconceptions falling under the category of “reproductive technologies” could have been accurately cataloged under genetic technologies. However, this class of misconceptions was frequent enough to require special treatment. In these cases students continued to explore their ideas of genetic engineering and cloning to describe the future of reproductive control where prospective parents would “improve” and “design” their offspring, with the ultimate goal of having the “perfect” child. Eugenics, either in specific use of terminology or in concept, appeared in 15% of essays collected in 2007. This percentage is not reflective of the goals or ongoing work of genetics research. Unfortunately, its prevalence in student essays is likely due to both its historical role in research as well as the “genohype.” Interestingly, the idea behind eugenics is not overtly described in the standards of any state science standards that we explored. The frequency of students describing using genetics to improve genotypes and design human beings, however, suggests that this is either the hook that teachers are using or the message that students are hearing from the media. More research would be required to determine which of these options is most prevalent.

Role of standards:

State science standards are not the only source of direction for what is taught in public schools; textbooks, laboratories, statewide assessments, and teacher quality also play significant roles. These benchmarks serve as the cornerstone of “standards-based reform,” which has become prominent since the adoption of the “No Child Left Behind” legislation's requirement for stricter accountability of student achievement. After examining multiple state standards, it became clear that there is extreme variation between the levels of breadth and depth that individual states require of students at the same educational level (supplemental Table 1). Teachers rightly demand a balance between rigorous standards and flexibility, allowing them to establish creative and effective teaching methods. However, the current teaching environment makes it difficult for teachers to include information in the classroom not explicitly included in their state standards and therefore presumably their state content assessments. Thus, as states consider revisions of their next content standards in genetics, they should reevaluate their requirements in light of the body of literature that suggests that neither current standards nor current pedagogical methods being employed for conveying genetics to students are sufficient to produce enduring understanding of the material.

Misconceptions, scientific literacy, and genetic citizenry:

Interestingly, many of the errors observed in the NAEP questions were also observed in our essays, reaffirming the wide-scale deficiency in genetics knowledge of high school students. While the data sets cannot be directly compared, it is of some concern that students in 2007 hold the same misconceptions as students in 2000 despite the rapid pace of advances in genetics technology and knowledge that occurred during that same period.

In genetics, anecdotal evidence from practitioners of high school life science (teacher e-mails and listserv communications) and direct evidence collected through these 2 years of ASHG-sponsored nationwide essay contests suggest that genetics is an area where many high school students harbor multiple misconceptions and significant misinformation. Some of this is likely due the exaggeration of the benefits and risks of genetics research and health information ( L oo et al. 1998 ; M oynihan et al. 2000 ; R ansohoff and R ansohoff 2001 ). Students are clearly getting significant quantities of information from the Internet (most student essays referenced stories from a variety of different websites, but not from scientific references); students often rely on their teachers for ultimate validation of their information through discussions and grading. Scientists must work proactively with professional science writers to ensure that information in their field is accurately represented in the press. One study compared the text of original scientific articles with news reports about them ( R ansohoff and R ansohoff 2001 ). Interestingly, these authors reported that when “hype” was identified in the popular press, it was the result of the original article and the scientists' own interpretations of their results.

Due to advances in genetic screening, genetic technology, the promise of individual genome sequencing, and other progress in the field of genetic research, it is more important than ever for the public to have a critical understanding of basic genetic information. This understanding will be vital for individuals to be informed advocates for their own health care when it comes to providing consent for testing and treatment as well as for being able to understand and interpret test results accurately. This will become an even greater need as private companies begin to provide genetic tests through mail order such that individuals can test themselves at home without the consultation of a physician ( A dvisory C ommittee on G enetic T esting 1998 ). For patients to understand the tests and results, and their own risk, they must be able to understand the biological underpinning of the tests themselves. Furthermore, as genetic research becomes more firmly embedded in medical practice and care, the public must be able to make informed decisions regarding specific pieces of legislation. Multiple studies, including this one, demonstrate that the current classroom methods for genetics instruction are not developing a citizenry with accurate mental models of inheritance and the genetic basis of disease ( H enderson and M aguire 2000 ).

Similar to our analysis, work from L ewis and K attmann (2004 ) reveals that students equate genotype and phenotype. Their work suggests that this is at least in part due to an incomplete understanding of genetic terminology. Other work suggests that acceptance of genetic determinism might negatively influence individual behavior and lifestyle choices. Believing a genetic illness is “something that is inherited that nothing can be done about,” individuals may not heed the advice of clinicians to alter diet or behavior ( H enderson and M aguire 2000 ).

Lack of precision in student writing results in difficulty in differentiating misconception from poor writing skills:

Another significant observation we made after reviewing 2446 student essays is that students need to be instructed in writing with precision. In science, terminology and specialized vocabularies are important and can be problematic for students. Words used in everyday language can carry different meanings in science. Simply, it is clear that students are not being taught to write using technical language and appear to approach their scientific writing in the same way they might as an essay for an English or Social Studies assignment. For example, students often related that people “carry obesity” or that they have the “disease gene.” But, neither of these is a precise description of the biological concept. Perhaps it is reasonable to extract that the first student meant that people “carry alleles that predispose them toward obesity” and the second student meant that a person with a genetic disease inherited a “mutation in a gene that caused a disease.” But these inaccuracies leave us with the perception that students do not understand these intricacies in the language of science. While we can infer that a student understood a topic but was ineffective in the communication of that knowledge, this might be a leap that is ultimately damaging. Investigators have demonstrated that precise language usage appears even more important in scientific fields because it is not merely a vehicle for communicating understanding, but itself actively facilitates learning and comprehension ( C onnally and V ilardi 1989 ; H alliday and M artin 1993 ; R oth and R oychoudhury 1992 , 1993 ; R ivard 1994 ). It is reasonable to suggest that writing-to-learn strategies that are successful in other disciplines and levels should be considered for inclusion in the high school science curriculum. Unfortunately, some work suggests that the adoption of writing across the curriculum programs—specifically those that engage students in scientific written discourse—is not widely used in the United States, despite success in Australia and the United Kingdom ( K eys 1999 ).

Implications for undergraduate biology education:

Another interesting observation from our work is that individual teacher knowledge, interest, and bias were clearly observed in student essays. Up to six students from a particular teacher could submit an essay to the contest. Frequently, similar themes were seen to run through many of the essays from a shared teacher–sponsor. For example, 3 essays in 2006 from the same teacher noted an interest in studying “gene doping.” Yet, of the 2443 other essays collected over 2 years, not a single other essay mentioned this as a topic. Examples such as this reflect the critical influence individual teachers have on student interest, knowledge, comprehension, and possible misconception. Moreover, it is important to note that teachers were asked to submit their “top” essays. While it is impossible to determine if teachers vetted each essay prior to submission, it is reasonable to assume that many of the essays that were submitted were reviewed. Yet, 55.6% of essays reviewed exhibited a major misconception. This, in combination with the observation that student writing often clearly reflected specific information learned in the classroom, implies that student writing might be indicative of misconceptions held and perpetuated by the teachers.

This conclusion has important implications for instructors of undergraduate biology and genetics courses. Most high school biology educators receive their training in genetics through their undergraduate coursework in biology. Therefore, students are likely entering their undergraduate courses with these misconceptions and leaving with the same misconceptions. Our work should provide undergraduate science educators with the information they need to begin to eliminate the perpetuation of these misconceptions.

Responsibility of scientists for marshaling change:

In addition to scientists recognizing these misconceptions when they direct their classroom agenda at the undergraduate level, this research calls on those practicing genetic research to adopt other changes in their communication about their research. Scientists must model accurate language and terminology usage when communicating to their peers, the press, and the community about their own work and the work of others. Genetics has a precise vocabulary ( e.g. , it is a mutation in the cystic fibrosis gene, not the “cystic fibrosis gene,” that results in a disease phenotype), and scientists must ensure that misconceptions are not perpetuated through their own misuse of these terms.

Another potential way for scientists to make significant inroads into correcting misconceptions at the K–12 level is to dedicate themselves to spending time in the classroom with teachers and students. Multiple programs offer the opportunity for scientists to mentor classroom teachers and students through either long- or short-term experiences. Indeed, many different scientific disciplinary societies foster such programs. Descriptions and information about these programs can be found at http://hub.mspnet.org/ . Scientists can use these opportunities to promote accurate information to students and teachers about the nature of their discipline and scientific research. Unfortunately, this type of work is often viewed as secondary to professors' main responsibilities in their departments, especially in research-oriented departments. New programs must be developed to encourage, promote, and provide infrastructural support to scientists who dedicate themselves to this type of work. Indeed, the National Science Foundation has recently funded one such program currently sponsored by a scientific society ( http://www.genednet.org/pages/GENA_about.shtml ).

Challenges for change—Is it time to switch the paradigm?

Gregor Mendel's work is clearly among the most important in genetics. However, the relatively simple view of one gene, one trait has yielded generations of students who can predict that “tt” will result in a small plant and “TT” will result in a tall plant. Unfortunately, this monogenic view of the world, while accurate for a small subset of characteristics, is clearly a limited one. While students that have an understanding of genetics consistent with a “Mendelian model” reflect a certain depth of understanding of genetic disease, can describe dominant and recessive patterns, and can grasp the concept of carrier vs. affected status ( H enderson and M aguire 2000 ), the reality is that the nature of most traits and human disease is more complicated than this model. Only a minority of state standards require the coverage of alleles. Even in cases where dihybrid crosses are required per their inclusion in state standards, this still represents only monogenic inheritance of two separate traits (the tall, yellow pea plant vs. the short, green pea plant). But in the case of both traits, a single gene contributes wholly to the observed (height or color) phenotype.

Additionally, the requirement of teaching basic Mendelian genetics likely is a factor contributing to student confusion regarding the deterministic nature of a single gene in phenotype control. For example, multiple students specifically selected human height as a character to explain how genetics is involved in phenotype. One example, also shown above, is “If everyone on both sides of your family is tall, you are going to be tall.” Students take concepts of true-breeding plants (everyone being tall) and extrapolate them to human development. While we teach students that the genetic material is common between plants, animals, and humans, we must be careful to also teach them that genes and phenotypes are often under distinctly different molecular and biochemical controls in various organisms.

Despite multiple studies that have enumerated student misconceptions in genetics, no studies have shown that high school curricula have been altered to address these concerns. Additionally, little specific work has been done to determine the classroom curriculum that will most effectively address misconceptions in genetics. Some of the work currently being done in this area is through a program called the Geneticist–Educator Network of Alliances (GENA), a National Science Foundation-funded Math and Science Partnership program of the ASHG ( http://www.genednet.org/pages/GENA_about.shtml ). Several groups have performed extensive analyses of genetics curricula for the K–12 classroom. Reviews of genetics curricula can be found at ( http://genetics-education-partnership.mbt.washington.edu/rev/revres.html and http://genednet.org/pages/GENA_CCRC.shtml ). A number of challenges remain. The first is the question of how to reconcile data from a limited number of research studies that suggest that students do not retain information when taught in a traditional manner, relying on lecture to a prescribed curriculum ( K aufman et al. 1989 ). Then, once data are collected, compiled, and compared, how does one use that data to alter curriculum and textbooks to achieve better student understanding? Finally, while a number of individuals suggest that scientific education would benefit from a retooling that includes the requirement for students to learn information as it applies to their lives today and in the future, as well as the ability to evaluate scientific claims and information, this change is impeded by the need for districts, states, and even entire nations to demonstrate scientific content knowledge instead of deep conceptual understanding ( A llen and T anner 2003 ). Until significant research is performed by scientists and their educator colleagues that demonstrates which methods adequately teach both content and concepts, schools systems are unlikely to change their methods.

Acknowledgments

The authors thank Jane Nelson, Lauren Lum, Sophia Patel, and Dennis Gilbert for their assistance with the programmatic and public relations aspects related to the DNA Day Essay Contest. The essay contest would not have been possible without the generous support of the American Society of Human Genetics, the Genetics Society of America, and the National Society of Genetic Counselors members that volunteered to read and score essays or the financial support of Applied Biosystems. This material is based upon work supported by the National Science Foundation under grant no. 0634296.

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Essay on DNA Replication | Genetics

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In this essay we will discuss about:- 1. Definition of DNA Replication 2. Mechanism of DNA Replication 3. Evidences for Semi-Conservative DNA Replication 4. Models for Replication of Prokaryotic DNA.

Essay # Definition of DNA Replication :

DNA replicates by “unzipping” along the two strands, breaking the hydrogen bonds which link the pairs of nucleotides. Each half then serves as a template for nucleotides available in the cells which are joined together by DNA polymerase. The nucleotides are guanine, cytosine, adenine and thymine. DNA replication or DNA synthesis is the process of copying a double-stranded DNA molecule.

This process is important in all known forms of life and the general mechanisms of DNA replication are the same in prokaryotic and eukaryotic organisms. The process by which a DNA molecule makes its identical copies is referred to as DNA replication. In other words, it is the process of duplicating the DNA to make two identical copies. The main points related to DNA replication are briefly presented below.

1. Time of Replication:

The process of DNA replication takes place during cell division. The DNA replication takes place during S sub stage of interphase. In prokaryotes, DNA replication is initiated before the end of the cell cycle. Eukaryotic cells can only initiate DNA replication at the beginning of S phase.

2. Replication Site:

In humans and other eukaryotes, replication occurs in the cell nucleus, whereas in prokaryotes it occurs in the cytoplasm. Prokaryotes have only one active replication site, but eukaryotes have many.

3. Template Used:

The existing DNA is used as a template for the synthesis of new DNA strands. It is possible that during replication on strand of DNA can replicate continuously and the other discontinuously or in piece. The continuously replicating strand is known as leading strand and the discontinuously replicating strand is known as lagging strand.

When one strand of DNA replicates continuously and other discontinuously, it is called semi-discontinuous replication. Earlier it was thought that DNA replicates discontinuously. But now it is believed that DNA replication is semi-discontinuous.

Short segments of nucleotides are synthesized in the lagging strand of DNA as a result of discontinuous replication. These are called Okazaki after the name of discoverer. Okazaki fragments are about 1,500 bases in length in prokaryotes, and 150 bases in eukaryotes

4. Enzymes Involved:

The process of DNA replication takes place under the control of DNA polymerase. In other words, the process is catalized by the polymerase enzyme. In eukaryotes, four types of polymerase enzymes, viz. alpha, delta, gamma and epsilon are used.

DNA Polymerase alpha and delta replicate the DNA. The alpha is associated with initiation, and delta extends the nascent strands. DNA polymerase epsilon and beta are used for repair. DNA polymerase gamma is used for replication of mitochondrial DNA

In prokaryotes [E. coli], there are three major DNA polymerases: DNA polymerase I, II and III. DNA poly I is found in the highest concentration of all DNA polymerases; it is involved in DNA repair and assists with primary DNA replication. DNA poly II is exclusively involved in repair. DNA poly III is the major DNA polymerase. All DNA polymerases add to the 3′ OH of the existing polynucleotide.

Currently, six families of polymerases (A, B, C. D, X, Y) have been discovered. At least four different types of DNA polymerases are involved in the replication of DNA in animal cells (POLA, POLG, POLD and POLE).

5. Direction of Replication:

The synthesis of one new strand takes place in 5-3 and that of other in opposite (3-5) direction. The replication may take place either in one direction or in both the directions from the point of origin. When replication proceeds in one direction only, it is called unidirectional replication. When the replication proceeds in both the directions, it is called bidirectional replication.

6. Replication Type:

Based on the direction, the replication may be unidirectional or bidirectional. On the basis of continuity, the replication may be continuous or discontinuous.

7. Origin of Replication:

The point of initiation of DNA replication is known as origin. The progress of replication process is measured from the point of origin.

8. Rate of Replication:

In prokaryotic cells the rate of replication is 500 bases per second. In eukaryotic cells the rate of replication- is 50 bases per second. Eukaryotes have 100 to 3,000 times more DNA than prokaryotes.

9. Replication Models:

There are three models which explain the accurate replication of DNA. These are: (i) dispersive replication, (ii) conservative replication, and (iii) semiconservative replication (Fig. 17.1).

These are explained as follows:

(i) Dispersive Replication:

According to this model of replication the two strands of parental DNA break at several points resulting in several pieces of DNA. Each piece replicates and pieces are reunited randomly, resulting in formation of two copies of DNA from single copy. The new DNA molecules are hybrids which have new and DNA in patches (Fig. 17.2). This method of DNA replication is not accepted as it could not be proved experimentally.

(ii) Conservative Replication:

According to this model of DNA replication two DNA molecules are formed from parental DNA. One copy has both parental strands and the other contains both newly synthesized strands (Fig. 17.2). This method is also not accepted as there is no experimental proof in support of this model.

(iii) Semiconservative Replication:

This model of DNA replication was proposed by Watson and Crick. According to this model of DNA replication, both strands of parental DNA separate from each other. Each old strand synthesizes a new strand. Thus each of the two resulting DNA molecules has one parental and one new strand (Fig. 17.3). This model of DNA replication is universally accepted because there are several evidences in support of this mode.

Essay # Mechanism of DNA Replication :

The semi-conservative model (mechanism) of DNA replication consists of six important steps, viz:

(1) Unwinding,

(2) Binding of RNA primase,

(3) Elongation,

(4) Removal of primers,

(5) Termination, and

(6) DNA repair.

These are briefly discussed as follows:

1. Unwinding:

The first major step in the process of DNA, replication is the breaking of hydrogen bonds between bases of the two anti-parallel strands. The unwinding of the two strands is the starting point. The splitting happens in places of the chains which are rich in A-T.

That is because there are only two bonds between Adenine and Thymine, whereas there are three hydrogen bonds between Cytosine and Guanine. The Helicase enzyme splits the two strands. The initiation point where the splitting starts is called “origin of replication”. The structure that is created is known as “Replication Fork”.

2. Binding of RNA Primase:

Synthesis of RNA primer is essential for initiation of DNA replication. RNA primer is synthesized by DNA template near the origin with the help of RNA Primase. RNA Primase can attract RNA nucleotides which bind to the DNA nucleotides of the 3′-5′ strand due to the hydrogen bonds between the bases. RNA nucleotides are the primers (starters) for the binding of DNA nucleotides.

3. Elongation:

The elongation proceeds in both directions, viz. 5′-3′ and 3′-5′ template. The 3′-5′ proceeding daughter strand that uses a 5′-3′ template— is called leading strand because DNA Polymerase ‘a’ can “read” the template and continuously add nucleotides. The 3′-5′ template cannot be “read” by DNA Polymerase a. The replication of this template is complicated and the new strand is called lagging strand.

In the lagging strand the RNA Primase adds more RNA Primers. DNA polymerase a reads the template and lengthens the bubbles. The gap between two RNA primers is called “Okazaki” Fragments. The RNA Primers are necessary for DNA Polymerase a to bind Nucleotides to the 3′ end of them. The daughter strand is elongated with the binding of more DNA nucleotides.

4. Removal of Primers:

The RNA Primers are removed or degraded by DNA polymerase I. This enzyme also catalyzes the synthesis of short DNA segments to replace the primers. The gaps are filled with the action of DNA Polymerase which adds complementary nucleotides to the gaps.

The DNA Ligase enzyme adds phosphate in the remaining gaps of the phosphate-sugar backbone. Each new double helix is consisted of one old and one new chain. This is called semi-conservative replication.

5. Termination:

The termination takes place when the DNA Polymerase reaches to an end of the strands. In other words, it is the separation of replicated linear DNA. After removal of the RNA primer, it is not possible for the DNA Polymerase to seal the gap because there is no primer.

Hence, the end of the parental strand where the last primer binds is not replicated. These ends of linear (chromosomal) DNA consist of noncoding DNA that contains repeat sequences and are called telomeres. A part of the telomere is removed in every cycle of DNA Replication.

6. DNA Repair:

The DNA replication is not completed without DNA repair. The possible errors caused during the DNA replication are repaired by DNA repair mechanism. Enzymes like nucleases remove the wrong nucleotides and the DNA Polymerase fills the gaps. Similar processes also happen during the steps of DNA Replication of prokaryotes though there are some differences.

Essay # Evidences for Semi-Conservative DNA Replication :

Various experiments have demonstrated the semi-conservative mode of DNA replication. Now it is universally accepted that DNA replicates in a semi-conservative manner. There are three important experiments which support that DNA replication is semi-conservative.

These experiments include:

(1) Meselson and Stahl experiment,

(2) Cairns experiment, and

(3) Taylor’s experiment.

1. Meselson and Stahl Experiment [1958] :

Organism Used:

Meselson and Stahl conducted their experiment with common bacteria of human intestine i.e. Escherichia coli.

They used heavy isotope of nitrogen for labelling DNA. The bacteria were grown on culture medium containing heavy isotope of Nitrogen [N15] for 14 generations (30 minutes per generation) to replace the normal nitrogen [N14] of E. coli with heavy nitrogen.

Then the bacteria were transferred to normal nitrogen medium. The density of DNA was determined after one, two and three generations. Principle Involved. It is possible to detect minute differences in density through density gradient centrifugation. District bands are formed in centrifuge tube for different density DNA.

2. Rolling Circle Model of DNA Replication :

This model of circular DNA replication was proposed in 1968. This model explains mechanism of DNA replication in single stranded circular DNA of viruses, e.g. ɸX174, and the transfer of E. coli sex factor (plasmid). The ϕX174 chromosome consists of a single stranded DNA ring (Positive Strand). This model is most widely accepted.

The mechanism of replication consists of following important steps:

(i) Synthesis of New Strand:

First the chromosome becomes double stranded by synthesis of a negative strand. The original strand is positive. The negative strand is synthesized in side of parental positive strand.

(ii) Cut in Outer Strand:

The negative or inner strand remains a close circle and the positive strand is nicked at a specific site by endonuclease enzyme. This enzyme recognizes a particular sequence at this point. Thus a. linear strand with 3′- and 5′-ends is created.

(iii) Formation of Tail:

The original positive strand comes out in the form of a tail of a single linear strand as a consequence of rolling circle. The 5′-end of the broken strand becomes attached to the plasma membrane of the host bacterium.

Such replicating phage DNA is commonly found associated with bacterial membranes. The unbroken parental strand rolls and unwinds as synthesis proceeds, leaving a ‘tail’ which is attached to the membrane.

(iv) Synthesis of New Strand:

The synthesis of new strand takes place along the parental strand at the tail end in a 3-5 direction. The 3′-end serves as a primer for the synthesis of a new DNA strand under the catalytic action of DNA polymerase. The unbroken strand is used as the template for this purpose, and a complementary strand is synthesized. Thus the parental molecule itself is used as a primer for initiating replication.

New DNA is also synthesized in the tail region in discontinuous segments in the 5-3 direction. This synthesis is presumably preceded by the synthesis of an RNA primer under the catalytic action of RNA polymerase. The tail is cut-off by a specific endonuclease into a unit length progeny rod.

(v) Cutting of Tail:

Now the tail is cut-off into a linear segment by endonuclease. The linear segment becomes circular by joining two ends with the help of ligage enzyme. Thus a new circular molecule is formed which can become new rolling circle and replicate further.

Genetic information is preserved in the single stranded template ring which remains circular and serves as an endless template. There is no swiveling problem or creation of torque in the rolling circle model. As the strands unwind the 3′-end is free to rotate on the unbroken strand. The growing point itself thus serves as a swivel.

Evidence for the rolling circle model has been obtained from the replication of several viruses (M13, P2, T4, λ), replication resulting in transfer of genetic material during mating of bacteria, and the special DNA synthesis during oogenesis in Xenopus.

Related Articles:

• 6 Basic Rules for DNA Replication | Genetics
• Replication of DNA: 2 Things to Know About

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Writing with artificial intelligence, reflection essay.

• CC BY-NC-ND 4.0 by Kristen Gay

At first glance, academic and reflection can sound like contradictory concepts. Writing an academic reflection essay often involves striking a balance between a traditional, academic paper and a reflective essay. In order to find this balance, consider the terms that encompass the title of the assignment

The term “academic” suggests that the writer will be expected to observe conventions for academic writing, such as using a professional tone and crafting a thesis statement. On the other hand, the term “reflection” implies that the writer should critically reflect on their work, project, or writing process, depending on the assignment, and draw conclusions based on these observations.

In general, an academic reflection essay is a combination of these two ideas: writers should observe conventions for academic writing while critically reflecting on their experience or project. Note that the term “critically” suggests that the writing should not merely tell the reader what happened, what you did, or what you learned. Critical reflection takes the writing one step further and entails making an evaluative claim about the experience or project under discussion. Beyond telling readers what happened, critical reflection tends to discuss why it matters and how it contributed to the effectiveness of the project.

Striking the proper balance between critical reflection and academic essay is always determined by the demands of the particular writing situation, so writers should first consider their purpose for writing, their audience, and the project guidelines. While the subject matter of academic reflections is not always “academic,” the writer will usually still be expected to adapt their arguments and points to academic conventions for thesis statements, evidence, organization, style, and formatting.

Several strategies for crafting an academic reflection essay are outlined below based on three important areas: focus, evidence, and organization.

Table of Contents

A thesis statement for an academic reflection essay is often an evaluative claim about your experiences with a process or assignment. Several strategies to consider for a thesis statement in an academic reflection essay include:

• Being Critical: It is important to ensure that the evaluative claim does not simply state the obvious, such as that you completed the assignment, or that you did or did not like it. Instead, make a critical claim about whether or not the project was effective in fulfilling its purpose, or whether the project raised new questions for you to consider and somehow changed your perspective on your topic.
• Placement: For some academic reflection essays, the thesis may not come in the introduction but at the end of the paper, once the writer has fully explained their experiences with the project. Think about where the placement of your thesis will be most effective based on your ideas and how your claim relates to them.

Consider the following example of a thesis statement in an academic reflection essay:

By changing my medium from a picture to a pop song, my message that domestic violence disproportionately affects women was more effectively communicated to an audience of my classmates because they found the message to be more memorable when it was accompanied by music.

This thesis makes a critical evaluative claim (that the change of medium was effective) about the project, and is thus a strong thesis for an academic reflection paper.

Evidence for academic reflection essays may include outside sources, but writers are also asked to support their claims by including observations from their own experience. Writers might effectively support their claims by considering the following strategies:

• Incorporating examples: What examples might help support the claims that you make? How might you expand on your points using these examples, and how might you develop this evidence in relation to your thesis?
• Personal anecdotes or observations: How might you choose relevant personal anecdotes/observations to illustrate your points and support your thesis?
• Logical explanations: How might you explain the logic behind a specific point you are making in order to make it more credible to readers?

Consider the following example for incorporating evidence in an academic reflection essay:

Claim: Changing the medium for my project from a picture to a pop song appealed to my audience of fellow classmates.

Evidence: When I performed my pop song remediation for my classmates, they paid attention to me and said that the message, once transformed into song lyrics, was very catchy and memorable. By the end of the presentation, some of them were even singing along.

In this example, the claim (that the change of medium was effective in appealing to the new audience of fellow classmates) is supported because the writer reveals their observation of the audience’s reaction. (For more about using examples and anecdotes as examples, see “Nontraditional Types of Evidence.”)

Organization

For academic reflection essays, the organizational structure may differ from traditional academic or narrative essays because you are reflecting on your own experiences or observations. Consider the following organizational structures for academic reflection essays:

• Chronological Progression: The progression of points will reflect the order of events/insights as they occurred temporally in the project.

Sample Chronological Organization for a Remediation Reflection:

Paragraph 1: Beginning of the project

Paragraph 2: Progression of the remediation process

Paragraph 3: Progression of the remediation process

Paragraph 4: Progression of the remediation process

Paragraph 5: Progression of the remediation process

Paragraph 6: Conclusion—Was the project effective. How and why? How did the process end?

• By Main Idea/Theme: The progression of points will centralize on main ideas or themes of the project.

Sample Organization By Main Idea/Theme for a Remediation Reflection:

Paragraph 1: Introduction

Paragraph 2: Discuss the message being translated

Paragraph 3: Discuss the change of medium

Paragraph 4: Discuss the change of audience

Paragraph 5: Was the change effective? Explain.

Paragraph 6: Conclusion

Remember that while these strategies are intended to help you approach an academic reflection paper with confidence, they are not meant to be prescriptive. Academic reflection essays are often unique to the writer because they ask the writer to consider their observations or reactions to an experience or project. You have distinctive ideas and observations to discuss, so it is likely that your paper will reflect this distinctiveness. With this in mind, consider how to most effectively compose your paper based on your specific project guidelines, instructor suggestions, and your experiences with the project.

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• DiCYT, A. (n.d.). ¿Por qué es tan difícil curar el cáncer? Retrieved from http://www.dicyt.com/noticias/por-que-es-tan-dificil-curar-el-cancer (Iberoamerican Agency for the Dissemination of Science and Technology)
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New Zealand has a lot of people with skin cancer. It has the highest rate of skin cancer in the world, in fact skin cancer is the most common cancer in New Zealand and it is on the rise in every year. ...

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