This is the piece I was writing when the brick hit my deck, inspiring this earlier post, which is now a finalist for the 3QuarksDaily science blog prize. For a more detailed and absolutely deadpan look at Wade, see Dick Dorkins’s review.
BAM! A sharp thud on our little back deck about a yard from me the other day. I looked and saw a brick, lobbed over the fence by three kids in the alley. I yelled an obscenity and dashed for the gate. The kids took off and I gave chase, barefoot, indifferent to the shards of back-alley glass. The boys were young—between 9 and 12—brown-skinned. They outran me easily after a couple of blocks. But I got close enough to get a good look. They were clean and well-groomed. Nice-looking kids. They probably had moms who would give them a licking if they knew what their boys had done. Fortunately, no damage was done. I didn’t get a concussion or a bone bruise. It didn’t total my laptop. It didn’t shatter a window. The event was not serious in the wider scheme of city crime. But it was an invasion, a violation. It pissed me off and I thought about it the rest of the day. I weighed their crime as racially motivated. They were black and I am white and they probably wouldn’t have thrown that brick into a black family’s yard. Then I thought about it as motivated by class. Houses in our neighborhood are modest, but probably by those boys’ standards we are wealthy. I thought about how much violence lay behind the gesture. The beefy white cop who took my statement told me to dispose of the brick safely (lest it explode?) and suggested I work in a safer place than my back deck. The brick remains, as a reminder, and I continue to write in the garden. I will not be cowed by a nine-year-old. In the end, I concluded that class was more important than race—and mischief more important than class. The incident was the more troubling because two days earlier, I had also been writing outside when helicopters began circling. We live near a hospital with a Medevac, and traffic copters occasionally make a few passes when there’s a jam or an accident on a nearby artery, so a couple of minutes of their drone is normal. But these persisted, and then I saw that they were black police choppers. A few minutes later, a woman ran up our small one-way street screaming and wailing into her cell phone. We thought we heard her scream, “My baby!”
I checked the Baltimore PD Twitter feed and my heart sank:
Shooting. 3600 block Old York Road. Adult female and juvenile reported to be shot.
It was about five blocks from my house, across the busy thoroughfare marking my neighborhood from the friendly but sketchier one to the east. It’s not “The Wire” sketchy. Just a lower-middle-class neighborhood, mostly black, higher-than-average unemployment rate, lots of families and low-budget hipsters. Shootings are rare there, and broad-daylight gunplay is rare anywhere. But this particular afternoon, three-year-old MacKenzie Elliot was playing on the porch. Caught a stray bullet. Was dead by sundown. The piece I was trying to write that weekend was a review of several books, on genetic and cultural theories of race. One is Nicolas Wade’s A Troublesome Inheritance, which received a satirical review on these pages. It is a pernicious book, a defense of white privilege on biological grounds, cloaked in the same phony tone of reason that eugenicists and anti-evolutionists have evoked for decades: I just want to talk about this issue. Science has to be able to investigate any question, no matter how unpopular. Help help, the Political Correctness Police are trying to silence me. Blah blah blah.
In the early 1980s, I learned that the nature/nurture controversy was officially over. The Victorian polymath Francis Galton had coined the phrase “nature vs. nurture” a century before.
Everyone knows now that it’s a false dichotomy. Everything interesting is shaped by both genes and environment, and moreover, genes and environment mold one another. The relative influence of genetics on a trait is not fixed; the trait may be primarily genetic under some conditions, primarily environmental under others. Scientists know this. Science journalists know it. Scholars of science know it. We have moved past it. Twenty-first century biology is about the interplay among heredity and environment: gene–gene, gene–environment, and environment-environment interactions.
Except it isn’t. Why else do we still have books like Wade’s? If anyone ought to be up on the latest findings in genetics it ought to be him, a long-time reporter on the genetics beat for the New York Times. Yet instead of providing a fair survey of the field as he was trained, he chose to be persuaded by a narrow slice of work that continues a long-discredited scientific tradition. One focusing on the biological race concept and its supposed connections with intelligence, sexuality and other tinderbox issues. As Sussman shows, much of this research is sponsored by the blatantly white-supremacist Pioneer Fund. When it comes to those qualities we think of as quintessentially human, the basic question of nature or nurture seems independent of the state of scientific knowledge. The question returns with force whenever the trait is morally charged. Sexuality. Violence. Intelligence. Race.
Since the 1970s, the brilliant Marxist population geneticist Richard Lewontin has been arguing that the essence of using genetics as a social weapon is equating “genetic” with “unchangeable.” For decades, Lewontin has been pointing out examples of how that’s not true. It’s even less true now, with biotechnology such as prenatal genetic diagnosis and genome editing. Increasingly, the eugenicists’ dream—the control of human evolution—seems to be coming within our grasp. The new eugenicists want to give individuals the opportunity to make the best baby money can buy. No government control, they insist, no problem: if the free market takes care of it, the ethical problems disappear. Adam Smith’s invisible hand will guide us toward the light. As we take control of our own children’s genomes, the rich white people may have rich white babies, but, once we equalize access to whole genome sequencing, IVF, and prenatal genetic diagnosis, then poor black couples can have,…um…the smartest little black babies they can. And so can the Hispanics! And the Catholics who believe procreation shouldn’t require intervention, well they can produce “love children,” just like in GATTACA. It’ll all be fair and market-driven, once we socialize it a little bit.
So why are we even still talking about race and IQ? To Wade and others who say that it is a reasonable scientific question, that proper science has no politics and that the Morality Police have no business blocking scientific progress, I respond: What progress? What benefit? In order to frame this as a scientific question one has to define race, and any definition of race has a moral dimension. There is no way to ask whether racial associations with IQ are “real” without an agenda. The association of race and IQ is a legitimate historical question, but it must be acknowledged that even the most objective historian can only be interested in that question for moral reasons. If the scholarship is good, the agenda will be transparent, evaluable, debatable. But not absent. A good scholar (or reporter) will seriously investigate other viewpoints, present all sides. But he or she will not make pretense to absolute objectivity. The great danger of scientific investigations of questions such as race and IQ is just that pretense.
Science has immense cultural authority—it is the dominant intellectual enterprise of our time. Consider the state of funding or education for “STEM” (science, technology, engineering, mathematics) fields versus that for the humanities, social sciences, or arts. A good deal of science’s cultural authority stems from its claims to objectivity. Thus when a scientist investigates race and IQ, or a science journalist writes about it, they can invoke a cultural myth of science as having privileged access to The Truth. Not all do it—those with historical sensitivity recognize and teach the fallibility of science. But it’s common enough, even among experienced science educators and reporters, to be a crucial justification for the scholarly study of science as a social process. Science has a potent Congressional lobby. Like any industry, it needs watchdogs. Science is not just any industry. Aspects of it remain curiosity-driven, independent of the profit motive. It has an aesthetic side that unites it with the arts. And yet, for many types of questions, it provides a pleasingly rigorous set of methods for cutting through bias and pre-expectation. When scientific methods are pitted against superstition, belief, and prejudice, I side with science every time.
But when you study a lot of science; when you examine it over broad swaths of geography and time, rather than focusing on one particular tiny corner of it; when you study the trajectories of science; when you study the impact of science; when you examine the relationship of science to other cultural enterprises; you find that scientific truth is always contextual. The science of any given day is always superseded by the science of tomorrow. Despite popular myth, science does not find absolute Truth. “Science erases what was formerly true,” wrote the author John McPhee. When I was in college, brain-cell formation stopped shortly after birth. The inheritance of acquired characteristics was debunked nonsense. Genes were fixed and static. Humans had about 100,000 of them. IQ did not change over one’s lifetime. There were nine planets in our solar system. All of that was scientifically proven. None of it is true any more. Only a scientist ignorant of history can be confident that what she knows now will still be true a generation hence.
Which brings me back to the murder and the brick. On one level, the shootings a few blocks away were another incident of violence, probably drug-related, in a poor, predominantly black neighborhood. When they catch the bastard that shot that little girl, if they do a DNA test they might find genetic variants that occur with higher frequency in black males than in the population as a whole. If I catch the little punk who nearly beaned me with that brick, should he spit on my clothes and were I to have it analyzed, the lab might find SNPs in his DNA associated with a predisposition to violence. Whether those differences exist are legitimate scientific questions. But they are moot. The only reason to ask them is to prove an innate predisposition that, historically, has tended to foster racism and hinder social change. They may be legitimate scientific questions, but they’re stupid questions, and the motives of anyone who asks them are suspect. It’s not censorship to declare certain inquiries out-of-bounds. And people knowledgeable about science but outside the elite ought to be part of the process. Scholars. Journalists. Technicians. Students. Research funding should be less of a plutocracy, more of a representative democracy, so we can make better decisions about what questions are worth asking. In my case, the right questions are not “What biological differences account for that brick or that murder?” They are, Who is that brick-throwing kid’s mom? Can I, a “rich” white male, win her trust enough for her to let me into her house, to tell her my story in a way she can hear, so that she can discipline her child and get him back on a more positive path? What can we do to take our neighborhoods back, to make them not shooting galleries but communities again? How can we get people to get to know their neighbors, to keep their eyes open, to watch out for each other?
The other night, my wife took me along to an impromptu wake for the murdered girl, a five-minute bike ride away, near where the shootings occurred. In conventional racial terms, the crowd looked like Baltimore: about two-thirds black, one-third white (the latter mostly young), a sprinkling of Asians. But culturally, it was a black event, run by black women. The MC was the head of the neighborhood community association, a black woman. Words were said by the mayor, a state senator, a city councilwoman—all black women—and the governor, a white man. There was a prayer led by Sister Tina, a holy-rolling preacher who could make a middle-aged, over-educated, white atheist’s eyes well with her furious message of love and community. After the prayers and speeches, one young man threw down a Michael Jackson imitation, lip-synching and doing every move in Michael’s bag—full splits, knee-drops, and skids—on the coarse, hot Baltimore asphalt. The crowd whooped its approval. But the power that evening was held by the women. As we got ready to leave, I walked up and introduced myself to a few of those formidable, warm women. I threw my arms around Sister Tina and told her I thought she was amazing. She beamed and said she could see that the light of God was in me, she could see that I understood. And maybe I did. I know too much about evolution to believe in a literal god, but our mutual warmth and shared ideals are real. It may have been a culturally black event, but all were welcome. I understood in a new way how race matters in exactly the ways, to precisely the extent, that we want it to. Searching for the SNPs that make “them” and “us” different, seeking differences in test scores between the mixture of genes and culture Americans call “black” with those we call “white,” divides us. But here in this corner of this city, we have opportunities to celebrate each other’s cultures, and we have opportunities to share each other’s grief. The more I take those opportunities, the less value I see in the sciences of human racial difference.
A student* linked me to The Postnational Monitor, which features composite photographs of different racial, ethnic, and cultural groups. By superimposing many images (selected by unstated criteria) and centering them on the eyes and other key facial features, they produce visual “averages”. Here’s an average German male:
And here’s an average Irish female:
Some of the distinctions are pretty subtle. I had to look back and forth several times to make sure the Belgian and Dutch woman were not the same image. Can you tell which is which?
Statistics can be witty. Here’s “Ras’ average ex-girlfriend:
This lovely individual is the average South African female:
And the average Han Chinese man:
This fascinates me because in the 19th century, Francis Galton (Charles Darwin’s cousin and the inventor of eugenics and linear regression) invented this technique to uncover the “true” underlying features of different groups. His methods were cruder, of course, but the technique was basically the same. Here’s the essential Boston physician:
But for Galton, this was more than just visual play. He thought you could identify fundamental features of physiognomy, letting one get at the structural qualities of health and behavior. Composite photography could reveal the facial features of predisposition to disease (diathesis):
It could also be useful in crime prevention. Here are portraits of the kind of man who commits larceny (without violence):
Right! If you see any of these men, look for the nearest Bobbie.
Today, more sophisticated image-processing could be easily combined with DNA sampling and whole-genome analysis to find genetic correlates of these facial features. The Human Genome Project was, of course, a “composite” of a sequential sort—it comprised consensus sequences of numerous individuals to provide an image of “the” human genome. Today, much of personalized medicine relies on genomic composites of “Europeans,” “Africans,” and “Han Chinese.” Someday, similarly blurry visual portraits might even be made from genome data.
Think of the possibilities for preventive medicine and crime prevention! With sufficient data, it would be straightforward to produce “Wanted”-style posters of people predisposed toward illness or indiscretion, enabling the appropriate authorities to step in and save both the public and the individuals themselves from suffering.
There is a long-standing dialectic between the belief that individuality most faithfully expresses the real world and the belief that truth lies in averages–that variation is noise. Personalized medicine, which relies on “big data,” inches forward by the pushes and pulls of that dialectic, alternately claiming to tailor treatment to the individual and relying on racial categories considerably less differentiated than the composites above to parse disease and behavior.
The patron saint of this style of research is (or ought to be) a hybrid of Galton and Archibald Garrod, whose inborn errors of metabolism are often cited as the origin of the kind of individualized, biochemical-genetic approach so much in favor today. So we close with a portrait of that patron saint, Sir Francibald Galrod:
*h/t Dmitry Pavluk
- “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.
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.” 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.
It was a losing battle, though. The germ theorists were winning: diathesis and constitutionalism were already becoming outdated.
“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.
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.
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.
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.
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. 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.
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. 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. 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.
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. 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.
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.”  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.” 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.
Since then, the genome’s supposed refutation of a biological race concept has become a standard trope among scientists, journalists, and historians. 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.
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.” 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.” 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.” 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. Deep Background 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.