Putting the person in personalized medicine

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“Personalized medicine” is both one of the hottest topics in biomedicine today and one of the oldest concepts in the healing arts. Taking the long view reveals some of the trade-offs in trying to personalize diagnosis and treatment—and suggests that truly personalized medicine will involve not only technological advance, but also moral choices.

It is both one of the hottest topics in biomedicine today and one of the oldest concepts in the healing arts. Visionaries of the genome claim that molecular personalized medicine will eliminate “one size fits all” medicine, which treats the disease, and return us to an older approach, in which the patient was pre-eminent. The revolution, they say, will be “predictive, preventive, personalized, and participatory“—it will be possible to identify why this person has this disease now, and even to prevent disease before it starts. Personalized medicine depends on the individual person. But the individual is not a constant. Over the centuries, the medical individual has evolved along with the increasing reductionism of biomedicine. Medicine has narrowed its scope, moving from the whole person, to part of the body, to proteins, DNA sequences, and single nucleotides. Underlying contemporary, genomic personalized medicine are assumptions that, first, molecular medicine operates on a level that unites us all (indeed, all life), and thus it is the best—even the true—way to explore and describe human individuality. And second, that understanding human individuality on a molecular level will lead willy-nilly to better care and a less alienating medical experience for patients. I think a lot of benefit can come out of the study of genetic constitution and idiosyncrasy—and one can hardly oppose the idea of more personal care. But demonizing one-size-fits-all, promising a revolution, and making fuzzy connections between biochemistry and moral philosophy are risky propositions. Personalized medicine today is backed by money and larded with hype. Setting the medical individual in historical context, we can ask what personalized medicine can and cannot claim. In short, what is the difference between personalized and truly personal?

Seed and soil

The Hippocratic physicians, Aristotle, and Galen all used the concept of diathesis to describe the way a person responds to his environment. They used the term flexibly, to describe everything from a tendency to particular diseases to one’s general constitution or temperament. Around 1800, “diathesis” gained a more specific meaning: it came to signify a constitutional type that made one susceptible to a certain class of diseases. Some diatheses, such as scrofulous, cancerous, or gouty, were believed to be inherited. Others, such as syphilitic, verminous, or gangrenous, were understood as acquired. In its original sense, then, diathesis was related to heredity, but not synonymous with it.

Galen of Pergamon

Diathesis and constitution were often discussed in the form of a metaphor of seed and soil. In 1889, the physician Stephen Paget wrote in relation to breast cancer, “When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil…Certain organs may be ‘predisposed’ to cancer.”[1] The “soil,” he said, could be either a predisposition of certain organs, or diminished resistance. The seed and soil metaphor was also applied to infectious disease. Radical germ theorists such as Robert Koch often argued that the germ was both necessary and sufficient to cause disease. Critics observed that not everyone who was exposed to the germ developed the disease, and that the intensity of the disease often varied. Max von Pettenkofer quaffed a beaker of cholera and suffered only a bit of cramping. The seed-and-soil metaphor helped explain why. In 1894, the great physician William Osler argued:

As a factor in tuberculosis, the soil, then, has a value equal almost to that which relates to the seed, and in taking measures to limit the diffusion of the parasite let us not forget the importance to the possible host of combating inherited weakness, of removing acquired debility, and of maintaining the nutrition at a standard of aggressive activity.[2]

It was a losing battle, though. The germ theorists were winning: diathesis and constitutionalism were already becoming outdated.

William Osler
Sir William Osler, from the Chesney Archives at Johns Hopkins

“One size fits all” medicine is a direct legacy of the germ theory of disease and of the notion that you can isolate the causative agent in any disease. This was a remarkable advance in medical history. It didn’t matter whether you were a princess or a hack driver, doctors could figure out what you had and make you better. The great legacy therapies of microbial medicine—salvarsan, penicillin, the polio vaccine—represented the first times in medical history that doctors actually cured anyone. One-size-fits-all medicine, then, was positively brilliant, a medical revolution, in an age and culture where infectious disease killed a dominant fraction of the population. But it always had critics, doctors and others who bemoaned the loss of complexity, artistry, humanity from the medical arts. One of those critics was the London physician Archibald Garrod.

The case of the black nappie

Constitution, or soil, had always been associated with heredity; Garrod linked it to genetics. Garrod was a biochemically oriented doctor, interested in the physiological mechanisms of disease.

Sir Archibald Garrod
Sir Archibald Garrod

In 1898, a woman brought her newborn baby to his clinic. It seemed healthy, but she had noticed that its diapers turned an alarming black. The biochemically trained Garrod identified the condition as alkaptonuria, an exceedingly rare and essentially harmless condition believed at the time to be caused by a microbe. Garrod collected all the cases he could, mapped out pedigrees, and published a short note on it, suggesting that the high frequency within the families of his study could hardly be due to chance. The naturalist and evolutionist William Bateson read Garrod’s paper. He had long been interested in variation as the basis of evolution. Bateson had just discovered Gregor Mendel’s work and was emerging as Mendel’s greatest champion in the English language. He saw in Garrod’s alkaptonuria cases powerful ammunition against Mendelism’s critics–proving Mendelian inheritance in man would silence those who argued it a primitive strategy, restricted to plants and lower animals. Bateson and Garrod collaborated to show that alkaptonuria indeed follows a Mendelian recessive pattern. In 1902, Garrod summarized these and other analyses of alkaptonuria as, “Alkaptonuria: a study in chemical individuality.” It was a classic paper, carefully researched, brilliantly argued, compassionate, rational–and widely ignored. Part of the reason for its lack of medical impact was Garrod’s resolutely non-clinical thrust. He was interested not in finding the genes for disease, but in discovering the harmless idiosyncrasies that make us unique. The 1902 paper began to elaborate a biochemical theory of diathesis, which Garrod developed over the succeeding decades. Predisposition to disease, and constitution generally, he said, were biochemical in nature. “Just as no two individuals of a species are absolutely identical in bodily structure,” he wrote, “neither are their chemical processes carried out on exactly the same lines.” He proposed that physiological traits including responses to drugs would be similarly individual and presumably therefore genetic:

The phenomena of obesity and the various tints of hair, skin, and eyes point in the same direction, and if we pass to differences presumably chemical in their basis idiosyncrasies as regards drugs and the various degrees of natural immunity against infections are only less marked in individual human beings and in the several races of mankind than in distinct genera and species of animals.[3]

Obesity, racial features, drug idiosyncrasies, and sensitivity to infectious disease, of course, are now among the primary targets of genetic medicine.

Malaria, drugs, and race

They are also interrelated. For example, take primaquine. After WWI, Germany was cut off from the quinine plantations of Indonesia. German pharmaceutical companies such as Bayer developed synthetic antimalarial drugs, the best of which was primaquine. Primaquine was field-tested in malarial regions such as banana plantations in South America and the Caribbean, especially those run by United Fruit Company. Most of the banana-pickers were black Caribbeans. Researchers found that primaquine was effective, but that about one in ten blacks developed severe anemia when they took it. In whites, this response was extremely rare. This response became known as “primaquine sensitivity.” Today it is recognized as an expression of G6PD deficiency, the most common genetic disease in the world.

Stateville Prison
The interior of Stateville Prison

During WWII, the Indonesian quinine fields went over to the Germans; now it was the US that needed synthetic anti-malarial drugs. The Army set up research programs in several American prisons—the largest and best-run of these was at Stateville Prison in Illinois. Prisoners were given experimental malaria of different types, and then experimental drugs were tested on them. Racial differences manifested in different roles in the experiments. Ernest Beutler, one of the researchers on the project, said in an interview:

We knew it was only the blacks who were primaquine sensitive. So that was very important. Second place, the blacks didn’t get malaria. They’re resistant to vivax. So we used black prisoners for studies of hemolysis, we used white prisoners usually for malaria.[4]

Thus, skin color became a proxy for susceptibility to malaria. There are other examples, with other drugs, other diseases. Isoniazid was billed as a miracle drug for tuberculosis. But it was soon found that half of all whites and blacks were extremely sensitive to the drug. Physiological studies showed that they metabolized the drug more slowly; their blood drug levels built up quickly, leading to adverse side effects. In such slow acetylators, isoniazid could trigger peripheral neuropathy and even a lupus-like autoimmune reaction. Interestingly, only 15 percent of Asians were slow acetylators. Another drug, succinylcholine, is a muscle relaxant used primarily as a premedication for electroconvulsive therapy. D. R. Gunn and Werner Kalow found that rarely, in one out of 2500 Caucasians, it paralyzes breathing.[5] By the mid-fifties, then, idiosyncratic drug response, susceptibility to infectious disease, and the “various tints of hair, skin, and eyes” were linked in the study of genetic individuality. In 1954, the brilliant and visionary geneticist JBS Haldane could write a small book on biochemistry and genetics. Concluding, he suggested:

The future of biochemical genetics applied to medicine is largely in the study of diatheses and idiosyncrasies, differences of innate make-up which do not necessarily lead to disease, but may do so.[6]

Pharmacogenetics

The young physician Arno Motulsky, of the University of Washington, took that notion as a call to arms. In 1957, he reviewed the literature on drug idiosyncrasy and gave it both context and an audience. “Hereditary, gene-controlled enzymatic factors,” he wrote, “determine why, with identical exposure, certain individuals become ‘sick,’ whereas others are not affected. It is becoming increasingly probable that many of our common diseases depend on genetic-susceptibility determinants of this type.” His short article became a classic and is often cited as the founding paper of pharmacogenetics. The actual term wasn’t coined until two years later, and then in German, by the German researcher Friedrich Vogel: “pharmacogenetik.” In 1962, Werner Kalow published a monograph (in English) on pharmacogenetics. The field soon stalled, however; little was published on the subject through the ‘60s and ‘70s. Pharmacogenetics only really gained traction after the development of gene cloning.[7]

Molecular disease

Molecular approaches to variation had been developing since the late 1940s. In 1949, using the new electrophoresis apparatus—biology’s equivalent of a cyclotron—the great physical chemist Linus Pauling found that the hemoglobin of sickle-cell patients had different mobility than normal hemoglobin. He called sickle cell “a molecular disease.” It was also, of course, considered a “black disease,” for reasons connected to primaquine sensitivity.[8] Pauling once suggested that carriers of sickle cell and other genetic diseases should have their disease status tattooed on their foreheads as a public health measure. It was the kind of step eugenicists of the Progressive Era might have applauded. Pauling was a brilliant and imaginative analyst, but he was not a visionary. He did not foresee that all diseases would become genetic. The study of molecular diseases was greatly aided by technological developments that aided the separation, visualization, and purification of the proteins in biological fluids. Searching for alternative media to replace paper, researchers experimented with glass beads, glass powders, sands, gels, resins, and plant starch. Henry Kunkel used powdered potato starch, available at any grocery. Although inexpensive and compact enough to fit on a tabletop, one could use it to analyze a fairly large sample. Still, electrophoresis with starch grains had its drawbacks. In 1955, Oliver Smithies, working in Toronto, tried cooking the starch grains, so that they formed a gel.

Oliver Smithies
Oliver Smithies, from nobelprize.org

This not only made the medium easier to handle and stain; it made the proteins under study easier to isolate and analyze. Starch gel democratized electrophoresis. Immediately, all sorts of studies emerged characterizing differences in protein mobility; many of these correlated biochemistry with genetic differences. Bateson’s variation had been brought to the molecular level. Sickle cell, the black and molecular disease, continued to play a leading role in the study of genetic idiosyncrasy. In 1957, using both paper electrophoresis and paper chromatography, Vernon Ingram identified the specific amino acid difference between sickle cell hemoglobin and “normal” hemoglobin—specifying Pauling’s “molecular disease.” An idiosyncrasy—or diathesis—now had a specific molecular correlate.[9]

Polymorphism, from proteins to nucleotides

Polymorphism is a population approach to idiosyncrasy. Imported from evolutionary ecology, as a genetic term polymorphism came to connote a regular variation that occurs in at least one percent of the population. Where the ecologist E. B. Ford had studied polymorphisms in moth wing coloration, the physician Harry Harris studied it in human blood proteins. Like Garrod, Harris wanted to know how much non-pathological genetic variation there was in human enzymes. He concluded that polymorphism was likely quite common in humans. Indeed, Harris identified strongly with Garrod; in 1963, he edited a reissue of Garrod’s Croonian Lectures of 1909, Inborn Errors of Metabolism. Together with Lionel Penrose, an English psychologist interested in the genetics of mental disorders, Harris headed up an informal “English school” of Garrodian individualism and biochemical genetics, located at London’s Galton Institute. Harris fulfilled Garrod’s vision by categorizing amino acid polymorphisms and relating them to human biology.

childs1950s
Barton Childs and family in the 1950s (courtesy Anne Childs).

Through the ‘50s and ‘60s, young researchers interested in human biochemical genetics streamed through the Galton to learn at the knobby knees of Penrose and Harris. Arno Motulsky penned his 1957 review just after visiting. The Johns Hopkins physician Barton Childs also spent time at the Galton, and later went on to articulate a Garrodian “logic of disease,” based on Garrod’s and Harris’s principles of biochemical individuality. Childs’s vision is now the basis of medical education at Hopkins and elsewhere. Charles Scriver, of McGill University, also studied under Harris and Penrose. He is best known for his work on phenylketonuria, a hereditary metabolic disorder that leads to severe mental retardation, but which is treatable with a low-protein, phenylalanine-free diet. In the 1970s, recombinant DNA and sequencing technologies helped bring polymorphism down to the level of DNA. In 1978, Y. W. Kan and Andreé Dozy returned once again to sickle cell disease, and showed that sickle cell hemoglobin could be distinguished from normal hemoglobin by DNA electrophoresis. The difference can be detected by chopping up the DNA with restriction enzymes, which cut at a characteristic short sequence. The sickle cell mutation disrupts one of those restriction sites, so that the enzyme passes it over, making that fragment longer than normal. Ingram’s single amino acid difference could now be detected by the presence of a particular band on a gel. This became known as a restriction fragment length polymorphism, or RFLP. It was a new way of visualizing polymorphism. In 1980, David Botstein, Ray White, Mark Skolnick, and Ron Davis combined Harry Harris with Kan and Dozy. They realized that the genome must be full of RFLPs. They proposed making a reference map of them, a set of polymorphic mile markers along the chromosomes. “The application of a set of probes for DNA polymorphism to DNA available to us from large pedigrees should provide a new horizon in human genetics,” they wrote grandly. Medical geneticists were beginning to think in terms of databases. Further, Botstein & Co. recognized their method’s potential for medically singling out individuals: “With linkage based on DNA markers, parents whose pedigrees might indicate the possibility of their carrying a deleterious allele could determine prior to pregnancy whether or not they actually carry the allele and, consequently, whether amniocentesis might be necessary.” [10] In other words, whether abortion might be indicated. One should also be able to determine, they continued, whether cancer patients are at risk in advance of symptoms. These are basic principles of personalized or genetic medicine. Further, they wrote, the method would be useful for determining population structure—i.e., identifying racial characteristics by geography and genetics. With RFLP mapping, polymorphism was now divorced from phenotype—it was a purely genetic construct. Researchers then took polymorphism down to the level of single nucleotides. The first single nucleotide polymorphisms, or SNPs, were identified in the late ‘80s—an estimated 1 every 2000 nucleotides. And late in 1998, a database was created to pool all this data. Researchers imagined a high-resolution map of genetic variation—an estimated 10 million variants. It was the ultimate in Garrodian genetic variation. The vision was to use dbSNP to identify any individual’s sensitivities and resiliencies. The end of race? A romantic ideal emerged that the discovery of such enormous variation at the DNA level was not merely a scientific but a social triumph. In 2000, on the announcement of the completion of the draft sequence of the human genome, Craig Venter proclaimed, “the concept of race has no scientific basis.”[11] And NIH director Francis Collins strummed his guitar and sang (to the tune of This Land is Your Land),

We only do this once, it’s our inheritance, Joined by this common thread — black, yellow, white or red, It is our family bond, and now its day has dawned. This draft was made for you and me.[12]

Francis Collins
NIH Director Francis Collins, from nih.gov

Since then, the genome’s supposed refutation of a biological race concept has become a standard trope among scientists, journalists, and historians.[13] But the SNP database turned out to be too data-rich. Human genetic diversity is far too great to be useful to our poor small brains and computers. Circa 2001, it was discovered that SNPs cluster into groups, or “haplotypes.” Most of the information in a complete SNP map lies in 5% of the SNPs. This brings the number from ten million down to half a million or so. Conveniently, haplotypes cluster by race. In October, 2002, an International HapMap Consortium convened. The HapMap project sampled humanity with 270 people drawn from four populations. There were thirty “trios”—father, mother, and adult child—from the Yoruba of Nigeria—part of an African diaspora widely and condescendingly noted for its literacy. Thirty more trios were white Utahns of European ancestry. Forty-five unrelated individuals were drawn from Japanese in Tokyo and Han Chinese in Beijing (China boasts more than fifty ethnic groups, the largest of which is the Han). No native Australians or Americans, North or South, were included. Conceptually, the HapMap project was a mess. It claimed to explore human diversity while genetically inscribing and condensing racial categories—which in turn were defined by the project in terms of highly cosmopolitan and otherwise problematic groups. It implied that the Yoruba were representative of “Africans,” the Japanese and Chinese of “Asians.” Framed as a corrective to the disastrous but well-intentioned Human Genome Diversity Project of the 1990s, it nevertheless reinforced the racial categories that the genome project was supposed to have shattered. Indeed, Venter’s proclamations and Collins’s corny folksongs notwithstanding, the use of race has actually increased in studies of genetic polymorphism in response to drugs. I looked at the number of papers listed in PubMed that had “pharmacology” as a keyword, and the fraction of those papers that also had “race” as a keyword. That proportion held fairly steady at about a third of a percent from the ‘70s through the ‘90s. But it nearly tripled in the decade after we got the genome, to more than three quarters of a percent: from 34 to 359 publications. Once a sport, a rare mutation in the pharmacological literature, race is now approaching the frequency of a polymorphism. So either race does have a scientific basis after all, or scientists are using a social construct as if it were a biological variable. Either way, there’s a problem.

chart
“Race” and “pharmacology” in PubMed, 1970-2011

BiDil and BRCA2 As Beutler used skin color as a proxy for primaquine sensitivity and malaria susceptibility, so physicians today are using it as a proxy for haplotype. For example, take the heart-failure medication BiDil. In 1999, this drug was rejected by the American Food and Drug Administration, because clinical trials did not show sufficient benefit over existing medications. Investigators went back and broke down the data by race. Their study suggested that “therapy for heart failure might appropriately be racially tailored.”[14] The licensing rights were bought by NitroMed, a Boston-area biotech company. Permission was sought and granted to test the drug exclusively in blacks, whose heart failure tends to involve nitric oxide deficiency more often than in people of European descent. On June 23, 2005, FDA approved it for heart failure in black patients. As a result, it became the first drug to be marketed exclusively to blacks. The study’s author claims congestive heart failure is “a different disease” in blacks. This argument thus presupposes that “black” is an objective biological reality, and then identifies health correlates for it. Ethnicity is not so black-and-white. Another well-known case is  the gene BRCA2, a polymorphism of which increases the risk of breast cancer. Myriad Genetics, founded by Mark Skolnick, cloned BRCA1 and 2, and took out patents on tests to detect them. Myriad gets a licensing fee for all tests. The BRCA2 mutation is found mainly in Ashkenazi Jews. Due to the wording of the European patent, women being offered the test legally must be asked if they are Ashkenazi-Jewish; if a clinic has not purchased the (quite expensive) license, it can’t administer the test. Gert Matthijs, of the Catholic University of Leuven and head of the patenting and licensing committee of the European Society of Human Genetics, said, “There is something fundamentally wrong if one ethnic group can be singled out by patenting.”[15] The case has been controversial. The patent was challenged, and in 2005, the European Patent Office upheld it. The next year, the EU challenged Myriad. In 2010, an American judge invalidated the Myriad patents. This spring, opening arguments began in the appeal. No one can predict the outcome, but some investors are betting on Myriad. The point is not hypocrisy but internal contradiction. As the ethicist Jonathan Kahn points out, “Biomedical researchers may at once acknowledge concerns about the use of race as a biomedical category, while in practice affirming race as an objective genetic classification.”[16] There’s a deep cognitive dissonance within biomedicine between the public rhetoric and the actual methodology of fields such as pharmacogenetics over the question of whether or not race is real. And this of course has a strong bearing on the question of individuality. Which is it, doctor: are we members of a group, or are we individuals?

Reifying race

So although biomedicine claims to be moving from “one size fits all” to personalized medicine, in practice, researchers find that race is a necessary intermediate step in getting from the entire population to the individual.

The claim is that individuality is on the horizon—once the databases fill out and testing costs come down, medicine will be truly personalized. In the meantime, though, we’ll put you in a smaller group, which is better than treating everyone the same.

The history shows that treating the individual always involves putting that individual into one or another group. It is neither possible nor even desirable to treat everyone uniquely. When faced with the vastness of human variation, the complexity quickly becomes overwhelming. One has to look for patterns in the data, to group people by their responses. In practice, this often seems to mean typing people according to familiar categories. These categories are of course drawn from the experience of the researchers: if you grow up in a culture where race is real, then those are the categories into which your data fall. Biomedicine is not separate from culture; so long as race exists in our society, it will imprint itself on our science. In this way, the drive for individualism often leads to its opposite: typology. Race becomes reified—it now has an empirical and apparently unbiased basis.

Does personalized equal personal?

Individuality in biomedicine, then, has long been an elusive concept. Biomedical researchers claim with justifiable pride that medicine is beginning to take the individual seriously once again. Specialties such as pharmacogenomics and personalized medicine are increasingly recognizing that not everyone responds the same way to a given disease or a drug. This is a good thing, and could both improve therapeutic effectiveness and reduce incidence of idiosyncratic toxic responses. On the level of technical diagnostics and therapeutics, I see many benefits from tailoring care to whatever extent possible. But that doesn’t make it personal. Science can’t eliminate the concept of race, let alone racial prejudice. It can’t make our doctor take us seriously and treat us respectfully. It’s at best naive and at worst cynical for clinicians and researchers to suggest otherwise.  We should always be wary of claims that science & technology will solve social problems. Truly personalized medicine is more than a problem of technology, data collection, and computation. It has to be a moral choice.   Acknowledgments This essay is based on a talk delivered to PhD Day in the Division of the Pharmaceutical Sciences, University of Geneva, and was shaped by questions, comments, and discussion afterward. Michiko Kobayashi provided valuable comments and criticisms on both the talk and the essay.

 

References

Ackerknecht, Erwin. “Diathesis: The Word and the Concept in Medical History.” Bull. Hist. Med. 56 (1982): 317-25.

Bateson, William. “An Address on Mendelian Heredity and Its Application to Man.” British Medical Journal (1906): 61-67.

Bearn, Alexander G. Archibald Garrod and the Individuality of Man.  Oxford, U.K.: Clarendon Press, 1993.

Burgio, G. R. “Diathesis and Predisposition: The Evolution of a Concept.” Eur J Pediatr 155, no. 3 (1996): 163-4.

Childs, Barton. “Sir Archibald Garrod’s Conception of Chemical Individuality: A Modern Appreciation.” N Engl J Med 282, no. 2 (1970): 71-77.

Comfort, Nathaniel C. “The Prisoner as Model Organism: Malaria Research at Stateville Penitentiary.” Studies in History and Philosophy of Science, Part C: Studies in History and Philosophy of Biological and Biomedical Sciences 40 (2009): 190-203 (available at academia.edu: http://bit.ly/mjn2CJ)

Comfort, Nathaniel C. “Archibald Edward Garrod.” In Dictionary of Nineteenth-Century British Scientists, edited by Bernard Lightman. London, Chicago: Thoemmes Press/University of Chicago Press, 2004.

Garrod, Archibald Edward. Inborn Errors of Metabolism: The Croonian Lectures Delivered before the Royal College of Physicians of London in June 1908.  London: H. Frowde and Hodder & Stoughton, 1909.

———. The Inborn Factors in Disease; an Essay.  Oxford: The Clarendon Press, 1931. Hamilton, J. A. “Revitalizing Difference in the Hapmap: Race and Contemporary Human Genetic Variation Research.” The Journal of Law, Medicine & Ethics 36, no. 3 (Fall 2008): 471-7.

Jones, David S., and Roy H. Perlis. “Pharmacogenetics, Race, and Psychiatry: Prospects and Challenges.” Harvard Review of Psychiatry 14, no. 2 (2006): 92-108.

Kay, Lily E. “Laboratory Technology and Biological Knowledge: The Tiselius Electrophoresis Apparatus, 1930-1945.” Hist Philos Life Sci 10, no. 1 (1988): 51-72.

Nicholls, A. G. “What Is a Diathesis?” Canadian Medical Association Journal 18, no. 5 (May 1928): 585-6.

Wailoo, Keith, and Stephen Gregory Pemberton. The Troubled Dream of Genetic Medicine: Ethnicity and Innovation in Tay-Sachs, Cystic Fibrosis, and Sickle Cell Disease.  Baltimore: Johns Hopkins University Press, 2006.

Slater, L. B. “Malaria Chemotherapy and the “Kaleidoscopic” Organisation of Biomedical Research During World War II.” [In eng]. Ambix 51, no. 2 (Jul 2004): 107-34.

Snyder, Laurence H. “The Genetic Approach to Human Individuality.” Scientific Monthly 68, no. 3 (1949): 165-71.

Strasser, B. J., and B. Fantini. “Molecular Diseases and Diseased Molecules: Ontological and Epistemological Dimensions.” History and Philosophy of the Life Sciences 20 (1998): 189-214.

Strasser, Bruno J. “Linus Pauling’s “Molecular Diseases”: Between History and Memory.” American Journal of Medical Genetics 115, no. 2 (2002): 83-93.

[1] Paget, Stephen. “The Distribution of Secondary Growths of Cancer of the Breast.” The Lancet 133, no. 3421 (1889): 571-73@571.
[2] Various. “Discussion of the Advisability of the Registration of Tuberculosis.” Transactions and Studies of the College of Physicians of Philadelphia 16 (1894): 1-27@15.
[3] Garrod, Archibald Edward. “The Incidence of Alkaptonuria: A Study in Chemical Individuality.” The Lancet 2, no. 4137 (1902): 1616-20@1620 (http://www.esp.org/foundations/genetics/classical/ag-02.pdf)
[4] Beutler, Ernest, interview with Andrea Maestrejuan, March 8, 2007, La Jolla, CA, Oral history of human genetics project (http://ohhgp.pendari.com/).
[5] Kalow, W., and D. R. Gunn. “The Relation between Dose of Succinylcholine and Duration of Apnea in Man.”  J Pharmacol Exp Ther 120, no. 2 (Jun 1957): 203-14.
[6] Haldane, J. B. S. The Biochemistry of Genetics.  London: George Allen & Unwin, 1954 @ 125.
[7] Motulsky, Arno G. “Drug Reactions, Enzymes and Biochemical Genetics.” JAMA 165 (1957): 835-37; Vogel, Friedrich. “Moderne Problem Der Humangenetik.” Ergeb. Inn. Med. U. Kinderheilk. 12 (1959): 52-125; Kalow, Werner. Pharmacogenetics; Heredity and the Response to Drugs.  Philadelphia: W.B. Saunders Co., 1962. See also Price Evans, David A., and Cyril A. Clarke. “Pharmacogenetics.” British Medical Bulletin 17, no. 3 (1961): 234-40; Price Evans, David A. “Pharmacogenetics.” American Journal of Medicine 34 (1963): 639-62. See also Jones (2006) in Deep Background.
[8] The well-known malaria resistance conferred by a single dose of the sickle cell allele is in the same biochemical pathway as the glucose-6-phosphate deficiency involved in primaquine sensitivity. Those sensitive to artificial antimalarials are resistant to malaria anyway.
[9] Ingram, V. M. “A Specific Chemical Difference between the Globins of Normal Human and Sickle-Cell Anaemia Haemoglobin.” Nature 178, no. 4537 (Oct 13 1956): 792-4; “Gene Mutations in Human Haemoglobin: The Chemical Difference between Normal and Sickle Cell Haemoglobin.” Nature 180 (1957): 326-28.
[10] Botstein, D., R. L. White, M. Skolnick, and R. W. Davis. “Construction of a Genetic Linkage Map in Man Using Restriction Fragment Length Polymorphisms.” Am J Hum Genet 32, no. 3 (1980): 314-31@328.
[11] Venter, J. C. “Remarks at the Human Genome Announcement.” Functional & Integrative Genomics 1, no. 3 (Nov 2000): 154-5.
[12] Henig, Robin Marantz. “The Genome in Black and White (and Gray).” New York Times, Oct. 10 2004 (http://www.nytimes.com/2004/10/10/magazine/10GENETIC.html)
[13] Hamilton, J. A. “Revitalizing Difference in the Hapmap: Race and Contemporary Human Genetic Variation Research.” [The Journal of Law, Medicine & Ethics 36, no. 3 (Fall 2008): 471-7; McElheny, Victor K. Drawing the Map of Life : Inside the Human Genome Project.  New York, NY: Basic Books, 2010@197.
[14] Kahn, Jonathan. “How a Drug Becomes ‘Ethnic’: Law, Commerce, and the Production of Racial Categories in Medicine.” Yale Journal of Health Policy, Law, and Ethics 4, Winter (2004): 1-46 (http://academic.udayton.edu/health/08research/drug01.pdf).
[15] “Patent Singles Out Ashkenazi Jewish Women. New Scientist, 9 July 2005. (http://www.newscientist.com/article/mg18725073.300).
[16] Kahn, “How a Drug Becomes ‘Ethnic’” @27.

 

End Times (The Telos of Telomeres)

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For Aristotle, both ethics and politics flowed from the telos, the end or purpose of all things. In what may be record time for translating Nobel Prize benchwork to biotech snake oil, telomeres are the latest rage in high-tech diagnostics. Several startups are now pitching them as a way to tell your “biological age,” a new health metric that is as baffling as it is troubling.[1]

The 2009 Physiology or Medicine prize went “for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase.” Telomeres, as I wrote in 1991, are like aglets—the plastic tips on the ends of your shoelaces—for your chromosomes. They’re long stretches of repetitive DNA that essentially keep chromosome ends from unraveling. The thing is, unlike shoelaces, chromosomes duplicate themselves. They have to—otherwise half your cells would have no genes. And every time they do, because of one of those ubiquitous little design flaws that show there’s Nobody Home Upstairs, your telomeres get a tiny bit shorter. The telomere is therefore a sort of clock, ticking down the mitoses until a cell reaches the Hayflick Limit, at which point basically chromosomal Fukushima occurs. Telomerase counteracts that shortening in certain cell types, making those cells effectively immortal.

There have always been a few people who find it irresistible to think that cellular aging determines organismal aging. Seems logical, right? I mean, we all know an organism is made of cells. When you get old, doesn’t it have to be because your cells are getting old?

Well, sort of, sometimes, in some cases, but not in any simple way. Senescence is an incredibly complex process—and nowhere more so than in humans, naturally—and it mostly happens independently of your telomere length. It’s certain that your telomeres will be shorter when you’re old than they were when you were young, but old people can have long telomeres, and young people can have short ones. For that matter, short people can have old telomeres.

Further, cellular immortality is a mixed blessing, to say the least. On the one hand, slowing cellular senescence could in principle forestall certain degrading diseases of disintegration. On the other, there’s already a name for immortalized cells: cancer.

Anyway, cellular and organismal aging operate on different time scales, and the latter involves a lot of processes that have nothing to do with the former. To equate them is to confuse variation at two different levels—the same sort of error found in claims that racial differences in IQ result from genetics rather than systematic discrimination.[2]

That neat little fallacy is the foundation of the business plan at several new biotech companies, in Spain, Houston, and of course, in Menlo Park, CA. They claim to be able to take a few of your cells, open them like sacrificial goats, spread out their entrails, and tell you how old you “really” are. These new longevity companies claim to only be raising a warning flag, pointing you toward medical treatments you might want to consider.

A century ago, the Life Extension Institute had a similar model. The New York-based company offered medical exams, denying that they were offering any medical treatment. They pitched their product directly to individuals, but their biggest customers were employers and the many life insurance companies springing up in the Progressive Era. They eventually shut down in the wake of numerous lawsuits and accusations of fraud and misrepresentation. And LEI’s cofounder, Irving Fisher, went on to found the American Eugenics Society.[3]

For a few hundred bucks, these new companies will give you one-stop diagnostic shopping. With one measurement, they claim, they can tell you all sorts of things about your overall health and well-being. You even get to pick your metaphor: you either get a “wake-up call” about how fast you are really aging, or you can have your “check engine light” checked, according to spokesmen for the companies quoted in the Times article. The check-engine light in my car goes on for free, but after that I guess that in both cases it means a lot of expensive, computer-based diagnostics, and a lot of fervent hopes that all you did was pop a circuit-breaker.

Some of the scientists involved show a refreshing degree of candor. Jerry Shay, of UT Southwestern and on the board of the company Life Length (didn’t I get email from Nigeria about a similar product the other day?), acknowledged that although they won’t tell anyone how long they will live, insurance companies might want this information “to set rates or deny coverage.” In other words, they’re perfectly happy to sell the actuarial illusion that they can tell anyone how long they will live.

A Spanish telomerista, Maria Blasco, said the telomere test might prove helpful to people “especially keen on knowing how healthy they are.” Never mind the deeply problematic notion of playing to the fears of bored upper middle-class hypochondriacs; outside of a couple of risk factors for very specific and rare diseases, no one has any idea what this tells you about how healthy you are. But hard data and actual products tend to be hell on stock prices anyway.

Everyone got that? They’re telling us this is a scam. Now look, I am not saying these folks are dishonest, or even cynical. I think they are a bunch of basically honest scientists swayed by the allure of high-tech translational biomedicine. It’s the scientific version of the American Dream. And it comes with the always-handy Biomedical Moral Pass. It’s a great example of overfunded, overhyped science that benefits corporations and stockholders but may well do patients more harm than good.

The thing I wonder about most, though, is this idea of “biological age.” Apparently, the age I think I am—which I have until now naively correlated to the number of birthdays I’ve had, and never mind—is now “non-biological.” It’s like an acoustic guitar. There was no such thing as an acoustic guitar until the electric guitar was invented. All guitars were acoustic. Are there now multiple kinds of time—chronlogical, biological, and who knows what else—where I can be getting older in one dimension and younger in another? Have these biologists have actually reinvented time?

Or have they figured out what time really is? Is my chronological age now merely a figment, a simulacrum—a fictive representation of some supra-biological horological process? If so, I don’t think I like where this is going. We’re not headed down the sunny, leafy lane of, “You’re only as old as you feel! Have another bran muffin and go enjoy the morning.” This is more like the gray, trash-strewn alley of, “You poor dumb bastard. You only think you want to go to that punk show downtown this weekend. Sit down, shut up, and drink your Mylanta.”

It sounds like the beginning of the end.

[1] Andrew Pollack, “A blood test offers clues to longevity,” 2011-05-18 (http://nyti.ms/iIO3gv).
[2] In other words, conflating within-group and between-group variation. Whatever IQ is, it is highly heritable. But heritability is a measure of variation within a group. The heritability of IQ is different for different groups under different conditions. It simply cannot be used as a measure of how “innate” a trait is.
[3] I write about Fisher in chapter 2 of my forthcoming book, “A Science of Human Perfection.”

Horace Judson: a eulogy

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On May 6, at the age of 80, the writer Horace Freeland Judson died. He didn’t pass away; he would have insisted that he simply die. We worked together for five years, from 1997 to 2002, at The Center for History of Recent Science, George Washington University. Here is my appreciation.*

He was six feet in his stockings, which were certainly silk. He dressed impeccably. His leather shoes were glossy, his slacks pressed, even on writing days. His collar was crisp, his cufflinks shone. His houndstooth jacket might be a little worn at the seams, as if from catching too many brambles, but it was always clean. He wore a pocketwatch, and spoke with a vaguely “U” (upper-class, to the English) accent. He was raised in Chicago. A black, broad-brimmed hat, molded just so and rakishly tilted, cravat, and even a cape were not unknown on special occasions. I once saw him open a bottle of New Year’s champagne with a sword. Horace Judson was more than a little vain. But judgment should be tempered by the knowledge of two facts: his preening both reflected and masked enormous effort; and he had terrific taste. He seemed to put thought into every stitch of clothing on his body, every stick of furniture in his house, every book in his library, every word in his books.


His meticulous appearance was, like a peacock’s tail, a display of vigor, for he zipped his pants, buttoned his shirt, oiled his hair, and tied his shoelaces with only one good hand. The left. Childhood polio had withered the other, leaving it floppy and florid. The handicap slowed him down a little—he reconfigured that slowness into a magisterial pace—but prevented him from doing nothing. He shook hands cross-handed (I soon learned to shake left-to-left with him). He opened wine, canned tomatoes, and drove a stick-shift, flamboyantly flouting his disability. He never asked for help. His pride was his strength.

Of course, he typed the quarter million or so words of The Eighth Day of Creation, and everything else he wrote, with one hand. The deliberation this required contributed to the precision and elegance of his prose. Though a journalist by training, he wrote not like a reporter but like an essayist or a novelist. His style was always formal, never slangy (though he was not averse to the occasional earthy vulgarity), and occasionally pompous. He used every rhetorical trick in Aristotle, and had a flair for the dramatic. But his prose was always muscular, and he regularly knocked off passages of such clarity, insight, and grace as to leave the attentive reader breathless.

Consider his definition of X-ray crystallography, an arcane science if ever there was one, from chapter 2 of The Eighth Day. He begins with an analogy simultaneously quantitative and yet immediately apprehensible: “The X-rays used in crystallography are shorter than visible light by some four thousand times.” That does what good writing must, especially when it is on a technical subject: it connects the unknown to the known. Any educated person has a rough idea about visible light, and a sense of how big four thousand times is. Judson then explains the one thing everyone wants to know about X-rays. “Their wavelength is 1.5 Angstroms, which is the same order of size as the spacing between atoms in many solids, and that is why X-rays go through substances that are opaque to the eye.” Did you know that? “Penetrated by a thin beam”—thin beam is nice, both as explanation and in sonority—“the orderly array of atoms in a crystal, layer upon layer, scatters the X-rays in an orderly way, causing a repeating series of overlapping circles of waves.” Note the repetition of orderly…orderly, prefiguring the repeating series of the following clause. Powerful rhetoric illustrates the underlying concept. “At intersection with the flat sheet of film”—note the alliteration, intercalated by the contrasting long vowel sound—“the troughs and peaks of these waves reinforce each other at some points and cancel each other out elsewhere.” The image recalls every child’s game of dropping two stones into a pond and watching the ripples crash. Here is the crucial insight: “The interference pattern that results is characteristic of the structure that produced it,” he writes, and he abruptly ends the lesson by waving a hand at the Nobel-winning mathematics behind it, which would confuse and bore his audience: “…though to figure back to the structure takes mathematics and experience.” That’s all you need to know, really, and not a word more than it takes to describe it.

He never matched that book. How many of us get even one book of that magnitude? Judson is by far the non-PhD most quoted by historians and philosophers of twentieth-century biology, and scholars hate the fact. “Molecular biology is a discipline, a level of analysis, a kit of tools,” he wrote at the beginning of chapter 4. “Which is to say, it is unified by style as much as by content.” There’s a dissertation in that casual observation. He had hundreds like it. At the same time, the book is notoriously difficult to teach, and so few do. (I like to assign chapter 3. Students love it, but find it challenging.) Teachable books show their scaffolding and leave their beams exposed, so that students can skim for argument and get on to their orgo problem sets. Not so Judson. He draws you in, makes you read slowly. The paragraphs are meticulously constructed, but the themes are buried a sentence or two deep, and the arguments build incrementally. You end up highlighting every line.

That quality, combined with his pomp and occasional arrogance, alienated many historians of science. He could be difficult. Yet three things saved him for me. First, his intelligence and his skill as a writer and editor. Many times he annoyed me by ignoring my requests to comment on my green prose, only to read through it once and mark it up on the fly, effortlessly extracting the voice and meaning that I had buried in murk and flab and cliché. He still sits on my shoulder as I write, insisting that I justify the sequence of items in a list, put a twist on every cliché, and, unless I have a specific reason to do otherwise, narrate my story in strict chronological order. Second, his generosity. He often went far out of his way for people, with no expectation of recognition. Behind the formality was a genuinely warm person who loved sentiment but hated sentimentality. And third, his tragedy. He wanted to be accepted as a historian, and never quite was. I think he idealized the university as only someone can who doesn’t have the professorial press pass. Which is too bad, because he was better—gave more insight and more pleasure—than many credentialed scholars. His obituary in the Times listed him as a historian of science, which would have pleased him but which underestimated him. He was a writer.

*Thomas Soderqvist has also posted a piece on Judson. Highly recommended.

DNA Day and Body Modification

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The scientific study of human heredity has and has always had two types of practical application: relief of suffering and human improvement. Research programs with those ends in mind have existed at least since the beginning of the 20th century—maybe earlier, depending on how you define things. But by the Progressive Era (roughly 1890–1920), research in human heredity and genetics explicitly sought to reduce or eliminate human disease, raise the average level of our intelligence, beauty, and longevity, and improve our character.

For a long time, the only way to accomplish those goals was to regulate behavior. At the highest level—i.e., the least invasive of bodies but the most invasive of liberty—you regulate the relationship between people who might have children together. In the Progressive Era, many states passed laws prohibiting marriage between two people who were mentally retarded, or certifiably insane, or had tuberculosis (though its infectious nature was recognized, researchers also understood that there was an inherited predisposition). Immigration restriction laws, too, were a form of regulating behavior in the supposed interest of the national heredity (at least in part). They can’t breed if you don’t let them in in the first place.

Many people at the time saw surgical sterilization as much less invasive than marriage or immigration restriction. Advances in surgical technology and practice shifted the target of modification from the relationship to the individual. Modify the individual body and you can afford to be unconcerned with who that person marries or lives with or next to. From our perspective today, sterilization is an appalling invasion of autonomy, but in the 1930s, the heyday of eugenic sterilization—worldwide, by the way, not just in Germany—many people saw it, like abortion, as a way to loosen restrictions on the behavior of the sick, imperfect, and impure while still working toward improving society.

For a long time, then, “applied” human genetics was synonymous with what we think of as the worst excesses and sins of eugenics. Science historians and historically minded scientists have often written that human genetics got “tangled up” with eugenics because the researchers back then did not have sufficient knowledge. Now that we understand the science better, the argument runs, we can avoid the kinds of simplistic fallacies that drove the eugenics movement—fallacies such as the idea that there is a single gene for “feeblemindedness.” Or, ahem, the love of the sea.

But that argument gets it backward. Eugenicists resorted to marriage laws and sterilization for the same reason that there was so little reliable data on human genetics: genetics required sex. Because human geneticists couldn’t carry out breeding experiments, they couldn’t do backcrosses, self-fertilizations, and all the other kinds of matings that other geneticists could do. They could, though, control who mated with whom to some degree on a broad social scale.

The significance of DNA is that it made it possible to do genetics without sex. It wasn’t just DNA, of course—cell culture as well as lots of advances in biochemistry and microbial genetics also contributed—but by the 1960s DNA had emerged as the emblem of a “new genetics.” From the beginning, the DNA double helix had an iconic aspect. The first published image, in Watson and Crick’s first paper (the anniversary of which is the impetus for DNA Day), had a stripped-down, cartoonish quality, and was described in the figure legend as “purely diagrammatic.” Everyone understands DNA, then, to mean much more than “deoxyribonucleic acid.” It stands for the relationship between heredity and health.

The new, DNA-based, molecular genetics finally made it possible to do genetics without sex. Reducing or preventing disease no longer required controlling who married whom, or (more theoretically) even which babies got born. Technology made it possible to select which genomes made it into the next generation, and even, in principle, to alter and “correct” genes in the individual.

“DNA” thus solved the fundamental ethical problem of eugenics. State-level involuntary coercion of reproductive behavior simply makes no sense in a developed country with sophisticated biomedical facilities. It is pointless and paranoid to fear a “return to eugenics” if what you mean is that good ol’ time Progressive eugenics.

In the DNA era, human genetics is still about relief of suffering and human improvement. The NIH touts the disease side of things, but what counts as a disease is heavily freighted with subjectivity, cultural bias, gender, and racial prejudice. Further, at the molecular level, the difference between preventing disease and genetic enhancement dissolves. If you up-regulate transcription of the gene for Human Growth Factor, for example, it makes no difference technically whether you do it in a dwarf, a short person, or a person of normal stature. And the moral distinction between remediation and enhancement relies on soft, unsatisfying philosophical arguments that basically amount to “Ugh!”—in the same way that a conservative parent reacts when his child comes home with blue hair and a lip piercing.

In 1957, Julian Huxley—grandson of Darwin’s bulldog, a distinguished biologist in his own right, and an articulate, politically liberal eugenicist—coined the term “transhumanism.” He wrote, “The human species can, if it wishes, transcend itself —not just sporadically, an individual here in one way, an individual there in another way, but in its entirety, as humanity.” This is what he defined as transhumanism, and he intended us to accomplish it by a variety of means, but of course at the root of it would be the conscious, deliberate manipulation of the human germ line. Throughout the 1960s, geneticists fantasized about using the new knowledge of the genetic code to control human development and evolution, to tinker with the design of human beings. The overwhelming majority of this fantasizing was done with the noblest of intentions. Huxley, JBS Haldane, HJ Muller, Joshua Lederberg, Edward Tatum—these were not ignorant fools but rather some of the greatest, most sophisticated minds in biology. They wanted not to rule the world but to reduce suffering and improve happiness, compassion, and noble achievement.

Muller’s eugenic scheme was called “germinal choice.” We’ve all heard of the Nobel sperm bank that William Shockley (inventor of the transistor) wanted to establish—that was Muller’s germinal choice. Present-day transhumanists prefer Muller’s term to “eugenics,” which is irritating because it requires so much explanation about how their eugenics isn’t the same eugenics as the bad old eugenics. But it’s eugenics. The only reason to deny it is the bad publicity the term gives you.

Transhumanists such as Gregory Stock and ScienceBlog’s own Eveloce tend to argue that genetic enhancement is coming whether we drag our feet or not, and they may be right. The sociotechnical power of contemporary biomedicine is astonishing—and on the rise. I’m not yet sure how I feel about this. I am inherently suspicious of any structure with such a concentration of technological and economic power, and power leads to hubris. It is a truism that 21st century DNA science has the potential for enormous benefit as well as catastrophic harm.

The problem is that the largest benefits tend to be long-term, while the largest risks are in the short term. It is not paranoid to be worried about such a situation, nor is it inconsistent to enjoy and admire positive results as they come out while maintaining a healthy, grouchy skepticism about the larger project.

I’m actually encouraged by the fact that transhumanism has a significant overlap with the blue-dreads-and-lip-piercing set. I’m more comfortable with tweaking our genes to, say, be able to grow horns or have Mr. Spock ears than to make everyone tall, white, and smart. Sure, it can be trendy and pretentious, like other body modification subcultures such as the “modern primitives,” but at bottom these folks are interested in it as a form of expression, not social control. Anything that breaks down barriers rather than reinforcing them gets my vote.

 

Human Theome Project sets sights on 2012

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Joe and Mary Juke are models of piety. They attend services twice a week, are active in faith-based charity organizations, and their house brims tastefully with Christian iconography and literature. They describe themselves as “fundamentalists,” although Joe is quick to emphasize, “We’re moderate fundamentalists—we don’t bomb clinics or anything.” They are planning to have a family, and they are making sure to create a pious environment for their children. They know that the setting in which a child is raised helps determine the kind of adult he or she becomes.

But for the Jukes, books, icons, and saying “Grace” are not enough. In what is being cited as a milestone in personal genomics, Joe and Mary have taken steps to ensure their baby is religious—by selecting its genes.

Using preimplantation genetic diagnosis (PGD), a combination of genetic screening and in vitro fertilization (IVF), Joe and Mary are loading the genetic dice for their progeny, selecting embryos that carry the traits they want in little Joe Jr. (or mini-Mary). Modern techniques allow them to select for a wide range of qualities, from avoiding hereditary diseases, to selecting eye, hair, and skin color, to shaping aspects of personality. For example, choosing a combination of half a dozen genes allows them to add a cumulative 40 points to their unborn child’s IQ. Many of these tests have been available for years, although they have only recently begun to be available to consumers. But the most striking decision in their family-planning process was to expressly select for embryos that will grow up to be religious, because they carry the allele known colloquially as the “god gene.”

“It kind of gives a whole new meaning to the phrase, “Chosen One,” Mary says.

Sequencing the human theome

The gene, which was identified statistically in twins in a study published in 2005, was recently cloned and sequenced, as reported in the online journal Nature Theology. Dubbed yhwh1, the gene correlates strongly with feelings of religious fervor. Studies show that the gene encodes a protein that is expressed in a part of the brain called Chardin’s area 86, long associated with religious activity and, strangely, anterograde amnesia. One famous patient was Guineas Phage, a virologist who suffered an injury with a pipetteman that resulted in a plastic tube being driven precisely into area 86; he spent the last two decades of his life on a constant pilgrimage along US Route 66 between Kingman and Barstow, accompanied by his wife, Winona, whom he continually left behind at gas stations.

Particular expression of religiosity in a given individual varies according to environment; what is inherited is the capacity for intense religious experience and evangelism. First described in the Amish in a classic study of the 1960s, the trait was described as an autosomal recessive with high penetrance, and was linked to a rare inherited form of dwarfism. Recent analyses have also found the trait occurring at high frequency among charismatic ministers, shamans, and suicide bombers.

The yhwh1 allele is one of the latest findings in the burgeoning field of “theomics,” which aims to identify all genes associated with the practice of preaching, as well as general feelings of spirituality. Researchers plan to complete the Human Theome Project by December 21, 2012, when, according to ABC News, the world as we know it may come to an end. Here are some of the most exciting new findings of the HTP:

▪   Scientists estimate that at least 400 genes are involved with religious feelings or activity.

▪   A related project seeks to uncover the epigenetics of evangelism, which is thought to be caused by methylation of regions of the X chromosome, a reversible process that can profoundly affect gene expression.

▪   A newly discovered kinase, called Bub666, is strongly correlated with atheism. It seems to be responsible for the breakdown of yhwh1, suggesting that biochemists are approaching a mechanistic explanation of religious experience.

▪   Rocker Ozzy Osborne has had his genome sequenced. Preliminary results show 85% homology with a Presbyterian minister from Des Moines.

“It’s tremendously exciting research,” said Mary Magdalene-Gohdtsdottir, a senior researcher in the University of Utah’s Department of Omics. “Just think of it: the genes for God! Isn’t that cool?” Indeed, the federal government thinks so. NIH Director Francis Collins, a molecular biologist and born-again Christian, has recently created a National Institute of the Molecular Biology of Yahweh (NIMBY), with an annual research budget of $400/year, as part of the government’s effort to support faith-based initiatives in biomedicine.

 

But is it science?

Some critics have called the Jukes’ actions a step toward eugenics, described in the 1920s as the “self-direction of human evolution.” They see religiosity as a gift, not something that can be ordered from a catalog. “This is an outrage,” said the Reverend Reginald S. Inkblot, of Southboro Baptist Church in Onan, Kansas. “Religion can’t be in your genes. Science can’t explain it. It’s just a part of who…you…um, are. It’s just in your…uh, yea.” He brightened momentarily and added, “If God had wanted us to be religious, he would have….oh, wait. Damn!”

Others are appalled that religion would receive scientific consideration from scientific foundations at all. Dick Dorkins, President of the atheistic Society for the Prevention of Intelligent design, Theology, Or Other Nonsense (SPITOON), calls the entire effort a “travesty.” “If I must check my brain at the church-house door,” he said in a Skype interview, “then you must check your soul at the laboratory door. Come on—be fair.”

Dorkins worries that should the procedure become widespread, it could lead to nonreligious persecution. If those chosen by PGD tend to express genes such as yhwh1, scientists predict, it could lead to changes in gene frequency across the population. Dorkins envisions a dystopian scenario in which an atheistic underclass washes the wineglasses and polishes the pews for their genetic spiritual superiors. “It will be GATTACA crossed with The Ten Commandments,” Dorkins said, an audible quiver in his voice.

Evolution in religious hands

Some theologians have condemned in vitro fertilization because it normally results in the destruction of unused embryos. However, new gene therapy techniques make it possible to link a “suicide gene” to alternative forms of the desired genes in Joe’s sperm samples; thus, only sperm that carry the traits they want survive to fertilize Mary’s eggs. No embryos are destroyed in the process. This makes in vitro fertilization acceptable to many pro-life Christians.

Joe and Mary dismiss critics who say they are taking evolution into their own hands. “That’s just your theory,” says Joe. They view their decision to choose the religiosity of their unborn child as a command from above. “WWJC?,” Mary asks. “Who would Jesus clone?”

Ironically, as Biblical literalists, the Jukes dismiss Darwinian evolution as “unproven.” To them, the earth is 4,000 years old, and all the types of animals in the world today were on Noah’s Ark. They see themselves as spearheading a Crusade of believers into biomedicine.

His eye acquiring that spark of evangelism that is a tell-tale sign of heavy methylation at Xq66, Joe’s voice deepened and he intoned, “The heresy of modern science will only be righted when human evolution is safely in the hands of people who do not believe in it.”

 

 

Anti-determinism on the march!

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Nice piece today from SciCurious, guest blogging over at Scientific American. The post is an analysis of a recent article in Nature claiming that by knocking out serotonin in two different ways (both neurotransmitter production and receptors), they abolished sexual preference. The mice apparently mounted either sex with equal frequency.

SciCurious does a beautiful job dissecting the assumptions in the Nature article, analyzing the data, presenting alternative hypotheses, and looking at the history of the research. For example, the authors might have merely lowered the threshold of sexual activity–an extension of “all girls get prettier at closing time”. Or perhaps the researchers influenced the perception of other cues, for example olfactory cues. “So does this paper prove that there are drastic increases in sexual behavior associated with low serotonin?,” SciCurious writes. “Absolutely. Does it show that low levels of serotonin change sexual PREFERENCE? Well, that’s difficult to say.”

Also, Ed Yong looked at the article from a different but equally skeptical point of view. He points out how difficult it is to translate these kinds of behavioral findings from mice to humans. Further, he writes, “serotonin isn’t all about sex.” When I was a teaching assistant for the Neural Systems and Behavior course at Cornell back in the late 1980s, we used to drill in to the students’ heads the idea that neurotransmitters do not have behaviors. They act in many regions of the brain and influence all sorts of behaviors in ways that are very far from straightforward.

Yong worries (rightly) that anti-gay groups will use findings like this to argue for a simple biological basis for homosexuality, perhaps even proposing serotonin therapy as part of their effort to “cure” it. And SciCurious links to news stories soon appeared suggesting that the researchers had “turned mice gay.”

Such stories illustrate a fundamental fallacy that is one of the gravest dangers of popularizing science. For the sake of argument, let’s say the researchers did in fact eliminate sexual preference. In what sense is “no sexual preference” the same as “gay”? Ans: only in a world so normative that strict, unwavering heterosexuality is the only behavior considered normal. Of course, there are lots of people like that–I read about them all the time. But it is blinkered, naive, and deeply chauvinistic.

Biological and especially genetic explanations of behavior are a double-edged sword. The gay community has oscillated in its support for research to find “gay genes” and other traces of the biological basis of homosexuality. If homosexuality is innate, the reasoning goes, then it is cruel and pointless to try to “cure” gays, in the same way it was cruel to “cure” left-handed people.

But “gay” is a cultural construct. There were no “gays” in Ancient Rome or in 19th century Paris, and there are no gays in the Foré of Papua New Guinea. Here and now, in our culture, we need the term in order to protect human rights that are trampled on by people unreflectively absorbing an outdated cultural taboo on homosexual activity. But in the long run, the ideal should be to get rid of the concept–for us all, in short, to be “gay-blind.”

Good skeptical science writing helps that cause, because it exposes fallacies in the ways we think about science. I’m fine with describing a physiological mechanisms for a behavior, but we need to be careful not to equate mechanism with cause. I’m wary of science writing that talks about the “roots” or the “basis” of complex behavior or disease. It implies a hierarchy that blinds us to many biological mechanisms that work in the other direction. In biology, cause and effect go both directions: behavior changes gene activity as much as gene activity changes behavior. Studies purporting to examine the biological “basis” of behavior rely on cross-species analogies and make unsupportable assumptions about motivation.

In short, a “gay” mouse is a ludicrous concept.

 

 

Thalassophilia unmasked

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There is no gene for thalassophilia—yet, anyway.

My satirical post last week about scientists finding a gene for love of the sea was intended to make a point about how we view genomics today—and a historical point about how we smugly congratulate ourselves on being so much more sophisticated than early human geneticists and eugenicists. Most people got that it was a spoof, but I thought it would be worthwhile to discuss some of the deeper issues at stake.

Charles Davenport was a real scientist, and the quotes from him are real. Davenport was a geneticist in the first half of the 20th century and the leader of the American Eugenics movement during the Progressive Era. He is often demonized as wrong-headed, misguided, and simple-minded. Indeed, he could be all of these things. Davenport really did believe there was a recessive, male-linked trait for the love of the sea. Thalassophilia has become a classic example of how eugenicists could ignore obvious environmental explanations in favor of the hereditary. When I told my 11-year-old daughter about Davenport’s thalassophilia, she immediately saw the fallacy: the sons of ship captains learn their love of the sea, they don’t inherit it.

My larger point is that simplistic analyses like Davenport’s can be masked by numbers and fancy technology.

For years, medical genetics involved the search for genes underlying genetic disease. Diseases that were caused by a defective gene, and not, say, by a germ or some other environmental factor. But that distinction has been erased. We used to think of genetic traits and non-genetic traits. Now, non-genetic traits are called “complex”—i.e., partly genetic and partly environmental. In other words, all diseases, and indeed all traits are understood as partially genetic.

There are sound reasons for thinking this way. I’m not arguing that those genes don’t exist. I don’t question the data—I’m happy to believe that there really is a genetic association with all of these traits. Indeed, I think it’s becoming possible to find a real, verifiable genetic basis for almost anything you like.

The advent of genome-wide association studies (GWAS) has made it vastly easier to examine traits with smaller and smaller genetic contributions. In essence, you can pick your trait, sample the DNA of a large group of people, and scan their genomes for bits of shared sequence.

As a consequence, we have the recent bloom of studies describing the genetic component of all sorts of “complex” traits, from religiosity to getting drunk and beating people up. We’re only limited by our imaginations, and by the kinds of traits we’re interested in today.

Thinking about these recent studies, it occurred to me that these traits were not fundamentally different from Davenport’s old favorite, thalassophilia. I bet, I said to myself, that if sailing were as culturally important today as it was in 1919, people would be doing GWAS to find the genetic basis of sea-lust. And I bet they’d find it.

Of course, there are big differences between human genetics in 2011 and human genetics in 1919. Davenport advocated sterilization laws and immigration laws to manage and shrink what he saw as the swelling populations of the “unfit.” That would be inconceivable today. I don’t think we’re returning to a “new eugenics” in any meaningful sense.

But cutting across the cultural differences are some continuities. One of them is the desire to believe there is a simple genetic explanation for our tastes and talents. That I think is a dangerous view. So on the one hand, I think we should be careful to evaluate 1920s science by the standards of the day, rather than by those of the 21st century. And on the other, we must not delude ourselves that modern science is completely objective. Mechanistic explanations are not proof against cultural bias.

My spoof was intended as a word of caution, a way to inject a note of skepticism about genetic explanations of human nature. C.M (“Call Me) Ishmael, the journal Genetic Determinism Today, MysticGene, the 4C (“for sea”) variant, the salt-stained polo shirts and the sailing widows—all that was pure balderdash. As the motto of this site goes, “Here lies truth”— in roughly equal measure.

So, keep your heads up, folks—and watch for the keyword “Satire” in the Categories section of this blog. Thanks for reading.

Scientists find gene for love of the sea

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What did Thor Heyerdahl, Captain Ahab, and Odysseus have in common? They all may have shared a common variant of a gene for love of the sea.

Researchers at Mystic University in Connecticut have identified a gene associated with seafaringness, according to an article to be published tomorrow in the journal Genetic Determinism Today. Patterns of inheritance of the long-sought gene offers hope for “sailing widows,” and could help explain why the sailing life has tended to run in families and why certain towns and geographical regions tend historically to have disproportionate numbers of sea-going citizens.

The gene is a form of the MAOA-L gene, previously associated with high-risk behavior and thrill-seeking; another form of the gene, found last year, made news as the “warrior gene.” The current variant, dubbed 4C, was found by a genome-wide association study (GWAS) on 290 individuals from Mystic, CT, New Bedford, MA, and Cold Spring Harbor, NY—all traditional nineteenth-century whaling villages. Residents showed the presence of the 4C variant at a frequency more than 20 times above background in neighboring landlocked towns.

C. M. Ishmael, the lead researcher on the study, said the findings could be a boon to medicine. Although the International Whaling Commission outlawed commercial whaling in 1986, the research could benefit literally hundreds of “sailing widows” left alone for Wednesday-evening sailboat races up and down the East Coast. Each year, an average of 11 salt-stained Polo shirts wash up on the New England and Mid-Atlantic coasts, the only remains of lantern-jawed investment bankers and their half-million-dollar boats. Ishmael said he is trying to have the irrational urge to sail entered into the Diagnostic and Statistical Manual, standard reference for psychiatric diseases, in the next, fifth, edition.

“This receptor is an exciting potential target for new drug therapies,” Ishmael said in a phone interview. “We hope lots of companies will be interested in it. And venture capital, too.” Ishmael is himself CEO of a company, MysticGene, formed to develop such therapies. When asked about potential conflict of interest, he replied cryptically, “Well, duh.” Shares of MysticGene closed higher on Monday following the announcement.

The gene for seafaringness has long been an object of study for human geneticists. The trait was first described in 1919 by Charles Davenport, director of Cold Spring Harbor Laboratory, who named it “thalassophilia.” Using pedigree analysis and anecdotal correlation, Davenport identified thalassophilia as a sex-linked recessive gene and distinguished it clinically from wanderlust, or love of adventure. Although one might think naively that people living in towns with good harbors would tend to go to sea, Davenport suggested the reverse: those with the thalassophilia trait have tended to migrate toward regions with good harbors and found settlements there. The current study does nothing to refute Davenport’s analysis.

Further, a tentative expansion of the GWAS analysis to various racial groups largely confirms Davenport’s observations that thalassophilia is more prevalent in Scandinavians and the English, and less common in people of German ancestry.

Thalassophilia joins a rapidly growing list of complex behavioral traits that have been shown to have a genetic basis, thanks to GWAS. Besides the warrior gene, recent studies have found genetic links to promiscuity, aggressive behavior, especially while drinking, religiosity, and bipolar disorder, or manic depression—all traits that Davenport and other early human geneticists were deeply interested in. The difference is that modern science better understands the mechanisms involved.

“Seamen know very well that their cravings for the sea are racial,” Davenport wrote in 1919. “’It is in the blood,’ they say.” Today we know it’s not in the blood—it’s in the genes.

The true bits:

Garland E. Allen, “Is a New Eugenics Afoot?,” Science 294, no. 5540 (October 5, 2001): 59 -61. (http://www.sciencemag.org/content/294/5540/59.short)

Charles Benedict Davenport and Mary Theresa Scudder, Naval officers: their heredity and development (Carnegie Institution of Washington, 1919),http://books.google.com/books?id=EWESAAAAYAAJ&dq=naval%20officers%3A%20their%20heredity%20and%20development&pg=PP1#v=onepage&q&f=false.

Richard Alleyne, “A gene that could explain why the red mist descends,” Telegraph.co.uk,http://www.telegraph.co.uk/science/science-news/8219521/A-gene-that-could-explain-why-the-red-mist-descends.html.

Jeremy Taylor, “Violent-drunk gene discovered,”http://www.asylum.com/2010/12/23/bad-drunk-gene-discovered/.

Justin R. Garcia et al., “Associations between Dopamine D4 Receptor Gene Variation with Both Infidelity and Sexual Promiscuity,” ed. Jan Lauwereyns, PLoS ONE 5, no. 11 (11, 2010): e14162.

C. Frydman et al., “MAOA-L carriers are better at making optimal financial decisions under risk,” Proceedings of the Royal Society B: Biological Sciences (12, 2010),http://www.newscientist.com/article/dn19830-people-with-warrior-gene-better-at-risky-decisions.html.

 

 

First post

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Hello and welcome!

I’m glad to be the newest member of the ScienceBlog team. I am going to be writing mainly on genes,  genomes, heredity, and health. Subjects in the news today such as personal genomics, pharmacogenomics, and genetic screening and counseling all have strong historical roots. Examining them can really cut through the hype and illuminate the headlines. I’m going to try to add some depth and perspective–and hopefully some humor–to biomedical questions that affect us all.

Factlets: I’m on the faculty of Johns Hopkins University, where I teach courses on 20th century biomedicine, the history of genetics, and oral history. I have two degrees in biology and one in history. I’ve written a book on the geneticist Barbara McClintock and edited one on the Intelligent Design controversy. My current book project is a history of medical genetics. The working title is The Science of Human Perfection and it will be published by the good folks at Yale University Press.

I also like to write for wider audiences. I’ve published in the New York Times Book Review, Natural History, Science, New Scientist, and The Believer, and have been on National Public Radio.

I also blog over at the Philadelphia Area Center for History of Science, where I’m planning to focus on more historical, probably somewhat more scholarly material. I tweet @nccomfort and you can find some of my writings on academia.edu.

Okay, enough preamble. Let’s get started!

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