Monthly Archives: February 2012

human karyotype

Childs Play

It’s February 29, the birthday of the great pediatrician and medical geneticist Barton Childs. Born in 1916, he would have had 24 candles on his cake today.

Childs was adopted as a baby. An irony for a medical geneticist, he told me, “Because I have no family history,” no pedigree to check for inherited traits. He graduated from Williams College and enrolled at Johns Hopkins medical school in 1938. He served in World War II and then returned to Hopkins, joining the medical faculty in pediatrics.

Pediatrics has a venerable place in the history of medical genetics. Childs was intrigued by young patients with congenital anomalies and began to read up on genetics. A formative moment in his career came in 1952, when he took a fellowship at the Galton Laboratory of Eugenics (later, Human Genetics), at University College London. There he studied under Lionel Penrose and worked with Harry Harris, two pioneers of the field. Penrose was a psychiatrist interested in mental deficiency—his 1938 Colchester Study was a landmark in the understanding of diseases such as phenylketonuria and Down syndrome. Harris was interested in genetic polymorphism. Newly available techniques, such as protein sequencing, electrophoresis, and chromatography enabled him to identify biochemical idiosyncrasies and variations. Both Penrose and Harris were devotees of Archibald Garrod, the English physician who developed the concepts of biochemical individuality and inborn errors of metabolism—two ideas central to genetic medicine today.

Harris and Penrose showed Childs the Garrodian light. He had a scientific temperament, and back in Baltimore he set up a Drosophila laboratory in the hospital to study genetic mechanisms. He contributed to early understanding of numerous genetic diseases, including G6PD deficiency, congenital adrenal hyperplasia and others. He took a particular interest in diseases of the X chromosome, which have a characteristic pattern on a pedigree. In the 1970s he participated in debates over genetic screening and counseling, arguing in favor of proceeding with caution and an eye toward respecting patients’ rights and autonomy.

childs2 300x201 Childs Play

Barton Childs, courtesy Chesney Archives

But his most important contributions were his steady, articulate advocacy of the importance of genetics for medicine. Like his mentor Harris, Childs’s passion was variation. He was not interested in finding “the gene for” a disease; he wanted to understand how our genes contribute to variability in disease. What is it that makes us each biochemically and genetically unique? In particular, he was interested in bringing an understanding of the principles of genetics and evolution into medical education. He was fascinated by the challenge of molding physicians’ minds as the most potent way to improve medical care. By influencing how doctors think, he believed, one could have the largest possible effect on how patients are treated.

His 1999 book Genetic Medicine: A Logic of Disease is his magnum opus. In it, he frames disease as a deviation from the norm of health and asks, How did the normal become the norm? How and why do people vary? Can we identify a set of principles for understanding the mechanisms of disease, and can we develop a structured argument that can be taught to medical students? “To be comprehensible, a logic of disease requires a language common to biology, medicine, and other disciplines. In fact, there is such a language: that of the DNA.” Childs saw molecular genetics as the foundation of the life sciences, the principles on which all life is founded. Drawing on a mechanistic tradition reaching back to Claude Bernard, Childs articulated medicine as an expression of science. Science, in this view, describes the normal, and medicine the pathological, which is a deviation from the norm. Childs was not a simplistic genetic determinist, though. He understood that both health and disease result from the interplay of genetics and environment—an interplay that was unique to the individual and shifted through time. Though his intellect was austere and philosophical, his intent was always to improve medical care for the individual patient.

Childs’s commitment to theory as a guide to practice came from and contributed to a self-effacing personal style. He refused to discuss any personal matters with interviewers, insisting, for example, that nothing about his life was relevant to his ideas. This is a curious stance for a physician, whose first gesture with a new patient is to take a history. He could be gruff and curt, but his curmudgeonly exterior covered a gentle demeanor and a light ego. Seeking a portrait of him to use in my forthcoming book on medical genetics, I scoured the Chesney Medical Archives almost in vain. The only view of his face the archivists and I could find was a three-quarters view image of him talking with colleagues. I settled instead on a silhouette that for me evokes his independence and austerity.

His principal legacy is as he would have wanted it: in the medical curriculum. When Johns Hopkins reformed its curriculum in the 1990s, they grounded it on Childs’s biological approach to medical individuality. Administrators and faculty consulted with Childs, tooling up on his erudite and rich framing of medical education in genetic terms. The course “Genes to Society” is the keystone of the new curriculum, and is explicitly based on Childs’s “logic of disease.” In it, Garrodian individuality, polymorphism, and personalized medicine find pedagogical expression. They put molecular principles up front, using them to then characterize higher organ systems and environmental interactions. In contrast to traditional curricula, in which basic science is taught in the first two years and clinical exposure is in the last two years, the Genes to Society program introduces students to the clinic from the beginning, in an effort to convey the dynamic relationship between the normal and the pathological.

So raise a glass to Barton Childs on his twenty-fourth birthday—a fitting day for one so interested in human idiosyncrasy.

 

Selected bibliography:

Childs, Barton, and James B. Sidbury, Jr. “A Survey of Genetics as It Applies to Problems in Medicine.” Pediatrics 20, no. 1 (1957): 177-216.

Childs, Barton, and William J. Young. “Genetic Variations in Man.” American Journal of Medicine 34, no. May, 1963 (1963): 663-73.

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

Childs, B., C. Scriver, and et al. Genetic Screening: Programs, Principles and Research.  Washington, DC: National Academy of Sciences, 1975.

Childs, B. “Genetics in Medical Education.” Am J Hum Genet 52, no. 1 (1993): 225-7.

———. “A Logic of Disease.” Lipids 31 Suppl (1996): S3-6.

Childs, B., and R. S. Spielman. “Harry Harris (1919-94): In Memoriam.” Am J Hum Genet 58, no. 4 (1996): 896-8.

Childs, Barton. Genetic Medicine: A Logic of Disease.  Baltimore: Johns Hopkins University Press, 1999.

Childs, B., C. Wiener, and D. Valle. “A Science of the Individual: Implications for a Medical School Curriculum.” Annu Rev Genomics Hum Genet 6 (2005): 313-30.

 

The genetic medicine bubble

“The medical world is holding its breath, waiting for the revolution. It will be here any minute. Definitely by the end of the decade. Or perhaps it will take a little longer than that, but seriously, it’s right around the corner. More or less.”

So begins Abigail Zuger’s review of three new pop genome books in yesterday’s New York Times. Zuger raises an interesting point about genetic medicine. The panting, bug-eyed enthusiasm for genetic medicine is ever-increasing, uncorrelated with therapeutic advance, and as obscurantist as a political speech. Which, if you believe economics and politics to be different teams playing the same game, it is.

Genetic medicine whips up support not for its results, but for its promise. It sells a vision of a medical future: one in which I will live forever, my doctor will know me personally, medical care will be tailored to me individually, and my diseases will be identified before they start—with treatment begun accordingly.

The promise is not without substance. Science and medical headlines are indeed full of examples of genomic data improving outcomes for one therapy or another and of cases of personalized high-tech medical care. Revolutions are built of many small steps, and it may well be that some time in the future we will understand ourselves sufficiently well at the DNA level to control much illness that currently confounds us and causes suffering. The scientific, mechanistic approach to human health and disease produces astonishing results that are indeed worth celebrating. Medicine is changing. It’s just that, as the doctor said to the achondroplastic dwarf, you’ll just have to be a little patient.

The hype over genomics and personalized medicine has little bearing on the real results coming out of real labs. The glare of the sunny future blasting from the headlines blinds one to the threats lurking in the shadows—the elitism of expensive, high-tech therapies for rare diseases, the risks of side effects from the increasing number of pharmaceuticals we ingest, the prospect of having our health managed from cradle to grave by a privatized, profit-driven medical establishment.

In both these promises and these threats, genomic medicine exposes its roots in biotechnology. In the 1970s and 1980s, recombinant DNA technology transformed biology—but it also transformed the stock market. Investors bought on the rumor and sold on the news, and so rumor became the most valued currency. Today’s genomic medicine grew out of those techniques of manipulating DNA—and it is driven by the same economic forces. The beauty of hype, from an investment standpoint, is that it fans optimism and masks risk. It is a dangerous model for healthcare.

Medical genetics has greatly advanced diagnosis but it has always struggled with therapeutics. Today’s genomic medicine claims to be at last breaking through the therapeutic wall: through understanding the molecular mechanisms of disease, the claim runs, researchers will develop new drugs. Personalized medicine, then, is pharmaceutical medicine. Every drug ever created has side effects, and they tend to be as potent as the main effects. Drug-based medicine treats side effects with more drugs—an antidepressant leads to weight gain, which is treated with an appetite-reducer, which leads to sleeplessness and high blood pressure,… This works out well for the pharmaceutical industry but turns the patient into a passive, chemically managed being. Medicine so dominated by drugs reduces patient autonomy— an ironic and dispiriting side effect of “personalized” medicine.

The books Zuger reviews are contributing to a healthcare bubble. Whatever the benefits that accrue to patients from genomic technology, they cannot possibly live up to the hype.

 

Dorkins DNA may reveal slaveholder gene

Prominent atheist and genome advocate Dick Dorkins is genetically hardwired to treat human beings as chattel, according to some interpretations of preliminary results from the amateur analysis of his genome.

The findings come from Project Dick, the widely publicized effort to sequence and analyze the Dorkins DNA. After initial setbacks, Project Dick has become one of the most over-hyped genomics efforts, which is saying something. While Project Dick started as a conventional private sequencing effort, in recent months it has become a group project. Dorkins approved the posting of DNA data online and solicited analyses from the online community—a type of public science made possible by “open-source” genome analysis programs. Like the popular online encyclopedia, content may be contributed by anyone, although it is subject to editorial approval before it goes live. So-called “genome bloggers” have contributed markedly to the analysis of the Dorkins genome. “It’s a Dorkipedia,” said one Project Dick spokesman.

A recent Dorkipedia post, contributed by the genome blogger “SnipDaddy” compared Dorkins’s DNA to that of 5 antebellum plantation owners and found a common set of single-nucleotide polymorphisms, or SNPs. SnipDaddy’s three roommates, none of whom own slaves, do not have the mutations. SnipDaddy concludes that the SNPs constitute a genetic signature for slaveholding. SnipDaddy concludes, “Dorkin grate grate grandad like wippin ppl—he lik wippin em 2. Its inz jeans.” Analysis of the post suggests that SnipDaddy is implying the existence of a slaveholding gene that is correlated with sadism.

The findings could be related to the recent discovery of a genetic predisposition to violent crime. Attention will be focused on finding any basis whatsoever to the claims.

The Master-of-the-Universe Gene

Jonah Lehrer has a new post in the Wall St. Journal on the applications of genetics to finance. For several years, two neuroscientists at Claremont Graduate University have been studying genetics, neurophysiology, and investor behavior. Their latest paper suggests that in the ever-elusive search to balance risk and reward, the sweet spot of maximum investor longevity (i.e., not going bankrupt) was predicted by their dopamine levels.

The paper is a masterpiece of handwaving. It illustrates beautifully how behavior genetics embraces the correlation-suggests-causation approach we like to condemn in those silly, bad old eugenicists from the Progressive Era. Kids, you couldn’t ask for a better example of genetic determinism. Here’s their abstract:

What determines success on Wall Street? This study examined if genes affecting dopamine levels of professional traders were associated with their career tenure. Sixty professional Wall Street traders were genotyped and compared to a control group who did not trade stocks. We found that distinct alleles of the dopamine receptor 4 promoter (DRD4P) and catecholamine-O-methyltransferase (COMT) that affect synaptic dopamine were predominant in traders. These alleles are associated with moderate, rather than very high or very low, levels of synaptic dopamine. The activity of these alleles correlated positively with years spent trading stocks on Wall Street. Differences in personality and trading behavior were also correlated with allelic variants. This evidence suggests there may be a genetic basis for the traits that make one a successful trader.

Of course there’s a genetic basis for it. The trick in finding it is in defining “trait” such that there is a genetic basis for it, and then you find it.

In a typical rhetorical move for overhyped scientistic explanations of fantastically complex behavior, both the scientists and Lehrer suggest a deterministic future by denying it. Let’s take the last three sentences one by one and translate them:

Dr. Zak notes that it’s far too soon to use his genetic assay as a hiring tool—the results still need to be replicated.

I.e., “We have no basis whatsoever for saying this, but…”

Still, it’s possible to imagine a future in which the financial sector requires less oversight because firms have found a way to hire more prudent employees.

“…Wall St. could hire people based on their DNA! If it works–and why shouldn’t it?–we could save so much money! And MAKE so much money!”

Given the massive amounts of money at stake, spending a few hundred dollars on a DNA kit might strike Wall Street as a particularly wise investment.

“What the hell? Go for it, data or no!”

Why so conservative? Since we already have one study–no one likes to do those boring “replication” studies anyway–why not just do away with resumes and job interviews and have would-be stockbrokers simply submit their genome profiles to potential employers? With minimum genetic standards for their mates, in a few generations we could have a race of genetically superior investors who would lead the market ever skyward!

Diseases as verbs

Last week I reread Owsei Temkin’s classic essay from 1963, “The scientific approach to disease: specific entity and individual illness,” for a course I am co-teaching on individuality and medicine. (I have not found the Temkin essay online. If you would like a copy of it, put a request in the comments section.) In it, Temkin distinguishes between the “ontological” and the “physiological” concepts of disease. An ontological approach treats diseases as specific entities—“things” that exist out in nature and befall humans and other creatures. The best example of an ontological approach to disease is the germ theory: the notion, developed by Pasteur, Koch, and others in the late 19th century, that many common diseases are caused by microbes. An ontological approach treats diseases as static; curing disease entails getting rid of the thing that causes it. An ontological approach gave us some of the greatest triumphs of twentieth century medicine: penicillin, the polio vaccine, the triple-drug AIDS therapy.

In contrast, a physiological disease concept treats illness as a process. Temkin also calls this a “biographical” or “historical” concept of disease. A physiological approach is individualized; it treats disease as a unique constellation of disease agent, heredity, experience, and local conditions. In its extreme form, it treats every case as different, because no two individuals have the exact same circumstances. Temkin shows how this approach characterized ancient Greek and Roman medicine, and illustrates how the two, ontological and physiological, have been in dynamic interplay down through the centuries.

Thinking about how to explain this distinction to my students, it occurred to me that ontological diseases are nouns, while physiological diseases are verbs. Objects versus processes; things versus actions. This is a little bit crude, but as a mnemonic it works well to remind one of the fundamental distinction Temkin makes. It’s important to remember that these are not properties of the diseases, but of one’s approach to disease.

Catching up on The Daily Show last night I saw an interview with USC professor David Agus, author of the new book, The End of Illness. Near the beginning of the interview, Agus uses exactly this concept. He says,

We look at diseases as one little factor…You have cancer. You have heart disease. Well to me, those diseases are verbs. You are cancering. You are heart diseasing. And I want to take you from a disease state, the other direction.

After a long and successful run in the twentieth century, the ontological approach to disease has recently ceded the limelight to the physiological disease concept. Genomic medicine is all about individualized or personalized medicine. It promises to end “one size fits all” medicine and treat patients as individuals once again. Individualized medicine is also about prevention—about identifying and stopping disease before it starts. Indeed, Agus segues immediately from diseases-as-verbs to prevention: “And I want to prevent illness.” The physiological approach to disease, individualized medicine, is intimately bound to this notion of disease prevention.

Prevention seems an unassailably benevolent goal; however, in this age of intensive medical management and a potent biochemical, pharmaceutical therapeutic style, prevention also means the erosion of the patient as a medical actor. We all become patients. Your health needs to be managed from birth to death, probably with an armamentarium of drugs designed to forestall a battery of diseases for which you have risk factors.

Agus seems to say that everyone should take a physiological approach, that all cancer and all heart disease, and perhaps even all diseases are verbs. But Temkin concludes his essay by insisting that neither the physiological nor the ontological approach is “correct.” Rather, one must treat a given disease ontologically or physiologically (or perhaps in some combination), depending on whether one is a patient, a doctor, a researcher, a public health worker, or what have you.

It is a marvelous example of how a historical approach to biomedicine—even from an essay half a century old—can deepen our understanding of current events in science, health, and disease.

References

Temkin, Owsei. “The Scientific Approach to Disease: Specific Entity and Individual Illness.” In Scientific Change: Historical Studies in the Intellectual, Social and Technical Conditions for Scientific Discovery and Technical Invention from Antiquity to the Present, edited by AC Crombie. 629-47. NY: Basic Books, 1963. Reprinted in The Double Face of Janus, Johns Hopkins, 1977.

See also Rosenberg, C. E. “What Is Disease? In Memory of Owsei Temkin.” Bull Hist Med 77, no. 3 (Fall 2003): 491-505

Interview with David B. Agus by Jon Stewart, http://www.thedailyshow.com/watch/thu-february-2-2012/david-agus