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Medicine's Race Problem

Saturday, December 1, 2001

On june 26, 2000, the White House announced to the world that the human genome had been sequenced (with the final, polished version due perhaps by 2002). Though the precise functions of all our genes have yet to be deciphered — Nobel laureate David Baltimore foresees a “century of work ahead of us” — it is clear that we are on the threshold of knowledge that could revolutionize the way we predict, diagnose, and treat disease.

The momentous discovery was lauded for something else as well: It supposedly laid to rest the idea that race is a biological category. “Researchers have unanimously declared there is only one race — the human race,” said the New York Times in an article headlined “Do Races Differ? Not Really, dna Shows.” Much heralded was the finding that 99.9 percent of the human genome is the same in everyone regardless of race. “The standard labels used to distinguish people by ‘race’ have little or no biological meaning,” claimed the Times. Said Stephen Jay Gould, evolutionary biologist at Harvard: “The social meaning [of race] may finally liberate us from [that] simplistic and harmful idea.”

That point has found its way into the rhetoric of politicians. As former President Clinton has said, “in genetic terms all human beings, regardless of race, are more than 99.9 percent the same. . . . The most important fact of life on this earth is our common human ancestry.” We were reminded by former gop vice presidential candidate Jack Kemp that “the human genome project shows there is no genetic way to tell races apart. For scientific purposes, race doesn’t exist,” he averred. In Hollywood, too, notice was taken. When a television talk show host asked actor Rob Reiner about the sparring his character did with Archie Bunker on the long-running television program “All in the Family,” Reiner (aka “Meathead”) explained that Archie’s signature bigotry stemmed from ignorance. “We are all the same, though,” Reiner said, “the human genome project taught us that.” The human genome project, in the view of many, helped pound the final coffin nail in place: Race was at long last dead.

It is noble, of course, to celebrate spiritual kinship within the family of man, and now even to suggest that race has biological meaning, it seems, can be something close to professional suicide. The mere mention of race and biology together sends many physicians and scientists scrambling to protest (too much) against a possible connection. The facts, however, paint a more complex picture, one with clinical implications: race does have biological dimensions, and if we regard it solely as a social construct, we may forfeit opportunities to enlarge our medical treatment repertoire.

Wanting it both ways

The sentiments fueling the impulse to regard race as an arbitrary biological fiction should be taken seriously, especially given the shameful history of race and biology. People properly shudder at the memory of the Tuskegee Syphilis Experiment, in which hundreds of black sharecroppers were never told they had the disease nor offered penicillin for its treatment. Many now worry that genetic determinism might be used as the sole explanation for social differences between races or, worse, as justification for new eugenics movements and programs of ethnic cleansing.

Nevertheless, the corrective is not obfuscation or outright censorship of inquiry. It is a clear-eyed understanding of the intertwining of race and biology. Denying the relationship flies in the face of clinical reality, and pretending that we are all at equal risk for health problems carries its own dangers.

We were reminded last May of the controversy about the role of race in biomedical research when the New England Journal of Medicine (NEJM) published two papers describing the responses of black and white patients to medications used to treat heart disease. The researchers sought to compare racial groups in light of the well-documented observation that, on average, African Americans with high blood pressure and other cardiovascular conditions do not fare as well as whites when given the same medications. Reaction from the race-is-a-social-artifact school was swift.

“There is a lot of scientific racism that’s accepted as normal, [but] it’s not valid science,” Richard S. Cooper of Loyola University Medical School told the Chronicle of Higher Education. Even J. Craig Venter, the geneticist and entrepreneur whose company played a key role in mapping the human genome, expressed his dismay to the New York Times: “it is disturbing to see reputable scientists and physicians even categorizing things in terms of race . . . there is no basis in the genetic code for race.”

Discrediting the idea of racial distinctiveness is a common strategy. “It has become clear that human populations are not unambiguous, clearly demarcated, biologically defined groups,” states the American Anthropological Association, for example. Well enough, but no serious scholar believes that races or ethnic groups (blacks, Eskimos, Asians, whites) represent genetically discrete, static classifications. To claim as much is to set up a straw man. As early as 1775, Johann Friedrich Blumenbach, who originated the concept of “race,” remarked that “innumerable varieties of mankind run into each other by insensible degrees.” Considered the father of physical anthropology, Blumenbach wrote the landmark treatise “On The Natural Variety of Mankind” (1795) in which he introduced five races (Caucasian, Asiatic, American, Mongolian, and Malay) and saw them as part of a single species, Homo sapiens. Indeed, two centuries later the human genome project confirmed what Blumenbach had first articulated. Robert S. Schwartz, a member of NEJM’s own editorial staff, attacked the straw man in an editorial response entitled “Racial Profiling in Medical Research.” He insisted that, genetically speaking, “humans — all humans — are so similar that to try to divide them up into neat little categories and label them yellow race, white race, black race, and so on, is insupportable.” Instead of investigating biological variables associated with race, Schwartz wrote, “physicians everywhere must teach the immorality of racial discrimination in clinical practice.”

Schwartz wants it both ways. On one hand he warns against the “dangers inherent in practicing race-based medicine,” yet on the other he eagerly encourages the analysis of race as a variable in “research to root out social injustice in medical practice.” Schwartz need not worry. The Department of Health and Human Services as well as numerous non-profits, such as the MacArthur and Robert Wood Johnson Foundations, are dedicating vast resources to investigating social causes of illness in minorities. Many of these causes are valid, among them culture-based habits of diet and lifestyle; attitudes about health and health care; and access to care. But other presumed causes, such as bias within the health care system or the impact of social hierarchy and income inequality on health, are susceptible to politicization. Not surprisingly, the quality of research targeting those factors is often dubious.

Despite the rhetoric about the bankruptcy of the race concept, it is notable that the federal government is pouring millions of dollars into studying racial differences in course-of-disease and in treatment response. In 1993 Congress passed and President Clinton signed a law requiring researchers whose projects are funded by the National Institutes of Health to include subjects of all major races. There are reasonable criticisms of the law as policy — for example, the expense entailed in amassing large enough study samples for valid statistical comparison — but there can be little question that one of its purposes was to illuminate potential differences in treatment response that are mediated by physiology, i.e., racial differences.

The practical clinical implications are real. For example, when doctors transplant kidneys or bone marrow, they have more difficulty finding a tissue match for African Americans because there are more possible antigen (protein) combinations on their cell surfaces than on the cells of white patients; some of those antigens are very rare in the population at large. In treating pain, doctors often give low doses of narcotics to Asian patients, given their tendency toward an acute sensitivity to the effects of those drugs. Or consider the higher mortality rate from breast cancer among African-American women. While obstacles to timely diagnosis and treatment may partly account for this difference, it cannot tell the entire story as African-American women have a 50 percent higher incidence of breast cancer before the age of 35, a greater likelihood of developing more aggressive tumors as well as the highest incidence of pre-menopausal cancer.

Medicine, like society as a whole, seems torn about how to regard race. But a sober look at the relationship between race and genes can clarify the purpose and promise of research based on the notion that vulnerabilities to certain diseases and response to treatment can sometimes vary by race. “Race” is an approximate category, to be sure, but one with undeniable biological significance.

Small differences loom large

One of the most heralded (and misunderstood) findings to emerge from the human genome project is that fact about the 99.9 percent genetic similarity between races. This is technically true. Then again, we share a very high percentage of our genetic makeup, about 98 percent, with chimpanzees, our closest primate relative, and we are clearly distinct from mice despite the fact that only 300 of the 40,000 genes in man appear to have no counterpart in the mouse. The resemblances extend into the plant kingdom, where mustard weed has 26,000 genes, about two thirds of the gene count of human beings. Even a one-celled organism — the yeast — has about 6,200 genes. No surprise is it, then, that there is quite enough room within that 0.1 percent of variation among humans for the existence of gene patterns, or frequencies, that cluster by group, or race.

The best way to appreciate how even tiny dna changes can translate into big differences is to consider the single-gene diseases. Within a single human gene there are hundreds to thousands of irreducible building blocks called nucleotides. The order of a gene’s nucleotides forms the recipe for a protein, each gene coding for a unique protein — for example, an enzyme that breaks down a target substance or forms a structural element of a cell or tissue.

These single-gene (monogenic) diseases — among them Tay Sachs, muscular dystrophy, and cystic fibrosis — show that alteration of a handful of nucleotides, or sometimes only a single one, can have profound physiological effects. In cystic fibrosis, the critical abnormality is in the protein that helps move ions and fluid along their normal travel routes in and out of cells. As a result, that movement is disrupted and the patient’s organs become packed with thick mucus. Death before adulthood is common. The most common specific defect that causes cystic fibrosis? Three out of the 250,000 nucleotides of the gene that codes for the protein are missing: three out of thousands of nucleotides in that gene and out of three billion in the entire genome.

Single-gene diseases are relatively rare, accounting for about 2 percent of all diseases that afflict humans (most human conditions, such as heart disease, diabetes, or high blood pressure are likely caused by several variant genes acting together) but they clearly illustrate how very small genetic variations can translate into palpable differences, sometimes between individuals and sometimes between racial or ethnic groups. This is not to say that every nucleotide variation spells disaster. Often it means that the enzyme produced by the gene will be less efficient at its job, for example, in b
reaking down other chemicals that are made by the body or are taken into the body, like medications. The clinical manifestations of this can vary, ranging from nonexistent to subtle to striking.

Consider the Canadian tuberculosis epidemic of the 1950s. All tb patients received the standard treatment: many months of triple-drug therapy, including a medication called isoniazid. It turned out that a sizeable fraction of Canadian Eskimos had a variant form of a liver enzyme that metabolized isoniazid so quickly that the drug was effectively used up before it could attack the tuberculosis bacteria. Many of the Eskimos metabolized isoniazid much faster than the general population and thus fared poorly under what was an inadvertent two-drug regimen. Many succumbed to tb and the partly treated, still-living tuberculosis bacteria themselves mutated into drug-resistant forms that went on to infect others in the general Canadian population. The significance of these results is that to ignore race under such circumstances is practically akin to withholding treatment.

The investigation of medication effects in black and white patients was published in that recent NEJM issue. The patients under study all had chronic heart failure, a condition in which the heart muscle is weak and cannot pump blood efficiently. The researchers were interested in improving treatment for heart failure and noted that while a class of medication called ace-inhibitors was generally considered a standard treatment for heart failure, accumulating evidence suggested that black patients, on average, did not derive as much benefit as whites. The study, in which black and white patients were randomized to treatment with an ace-inhibitor drug or placebo, found that black and white patients taking placebo fared no worse than black patients taking an ace-inhibitor with regard to blood pressure control and hospitalization for worsening heart failure.

How to explain the results? The working theory revolves around a molecule called nitric oxide (no), a gas that is normally produced by the cells that line our blood vessels. The no gas rapidly spreads through the lining cells to the underlying muscle cells that surround blood vessels and regulate their constriction, an important dynamic in the control of blood pressure. Specifically, no dampens contraction of the muscle cells, thus relaxing the vessels and lowering blood pressure. For unexplained reasons, black individuals are more likely to have nitric oxide insufficiency arising from either reduced production by the lining cells, enhanced inactivation, or both. Since ace-inhibitor drugs appear to exert their blood pressure-lowering effect by interacting with no, patients with deficits (innate or acquired) will not have as vigorous a response to the medication as those with higher no levels.

To be sure, not all black patients have low nitric oxide activity. But it is helpful for physicians to be aware of the likelihood, so that they can make better judgments about risk-benefit ratios of particular treatments. One group of scientists has taken the relationship between race and nitric oxide to its logical end: producing a medication specifically for African-American patients. Jay N. Cohn, a professor of medicine at the University of Minnesota School of Medicine, holds the patent on BiDil, a combination diuretic and vessel dilator that is believed to replenish stores of no. Last March, the Food and Drug Administration authorized the testing of BiDil and the clinical trials will enroll only black patients with heart failure. The Association of Black Cardiologists is helping recruit patients for the trials in the hope that doctors will be able to offer another treatment option for black patients. Their rationale is obvious: Black patients suffer heart failure at twice the rate of whites, and those afflicted are twice as likely to die. “It is in the name of science that we participate,” says B. Waine Kong, of the association. The Congressional Black Caucus voiced support as well.

That BiDil’s therapeutic strategy relies on a crude predictor of drug response (race) is something its developers readily acknowledge. Some critics, however, are offended by the very idea. “I challenge any member of our species to show where this kind of analysis has come up with something useful,” Richard Cooper says. It has “no proven value” according to Schwartz, who hopes the elucidation of the human genome “will force an end to medical research that is arbitrarily based on race.” Arbitrary? No proven value? These protestations crumble in the face of one simple fact: In large-scale clinical trials BiDil provided a selective benefit to black patients with heart failure; white patients who took the drug had the same results as those on placebo.

Much as it might offend — “Skin Deep: Shouldn’t a Pill Be Colorblind?” asks the headline in the New York Times coverage of BiDil — skin color can sometimes be a surrogate for genetic differences that influence disease and the response to treatment. “Right now we have only skin color to identify populations,” Cohn explained, “you’d have to blindfold yourself to say we are not going to pay attention to obvious differences.”

Pharmacogenomics

The ultimate purpose of work like Cohn’s and other biological realists is to identify factors that may be genetic in origin. First, researchers hope that identifying particular genetic markers within certain ethnic groups will yield insight into the genetic basis of disease and reveal why certain conditions are more prevalent in some groups. Second, the ultimate goal is to understand differences between individuals, not between races or ethnic groups. Pharmacologists talk enthusiastically of one day being able to customize medications to individuals based on their unique genetic profiles. While there is debate about the technical and commercial feasibility of this practice (dubbed pharmacogenomics), the ability to map an individual’s genome efficiently is at least several decades away.

Until then, researchers can reasonably use race or ethnicity to direct them in identifying genetic markers that may predispose some patients to greater vulnerability to illness or to less robust treatment response. Dr. Cohn’s work makes a persuasive case that there is a clinical imperative to do so. Knowing that a particular illness is more likely to afflict a certain group allows scientists to focus their attention on specific defects or the constellation of abnormalities that produce it. As far as treatment is concerned, “racial differences in response to drugs should alert physicians to the important underlying genetic determinants of drug response,” explains Alastair J.J. Wood, a pharmacologist at the Vanderbilt University School of Medicine. And why not? The entities we call “racial groups” essentially represent individuals united by a common descent — a huge extended family, as evolutionary biologists like to say. Blacks, for example, are a racial group defined by their possessing some degree of recent African ancestry (recent because, after all, everyone of us is out of Africa, the origin of Homo sapiens).

In a sense, then, the purpose of examining race as a variable in biological research is to be able to transcend the use of race, to perfect a bottom-up kind of genetic analysis that is routinely performed in other arenas, such as forensic medicine. Its specialists can use tissue, hair, blood, or other fluids remaining at a crime scene to look for “population-specific genetic markers” in the dna to help determine the race or ethnicity of a victim or suspect from his traces. Anthropologists can calculate, with startling precision, a person’s ancestry from different parts of the world by analyzing the dna from a few cells. Renowned population geneticist Luigi Luca Cavalli-Sforza has reconstructed human migration out of Africa within and between the continents in his landmark book, The History and Geography of Human Genes (Princeton, 1994).

Forensic and anthropological uses of genetic analysis show that race is not built on any particular trait. It is built on ancestry. Every present-day population harbors clues to its ancient roots. Members of a group would have more genes in common than members of the population at large. This is called, not so mysteriously, population genetics — the field of inquiry that examines changes in frequencies of particular genes within a population over time. And its legitimacy actually seems to be a point of agreement for both social constructionists and those who comfortably examine race in biomedical research.

Indeed, members of the “social construct” camp do not deny the basic observation that certain illnesses cluster by race. They recognize that among Americans, sickle cell anemia, for example, is most common among African Americans. They are quick to point out, however, that other people whose ancestors come from the Mediterranean region are at risk as well, albeit less so than those of African heritage. This doesn’t change the fact that African-American descendants are vulnerable, but it seems to reduce the anxiety that blacks alone will be saddled in the public imagination as having a “defective” trait. (Ironically, depending upon the environment, the sickle cell condition — another condition in which a single nucleotide has undergone mutation — is less a defect than it is a genetic protection against malaria. When the malaria protozoan infects the red blood cell, the sickle shape makes the cell collapse and die, preventing the multiplication of the protozoan.)

The rancor surrounding the use of race as a variable in biomedical research was captured by the Chronicle of Higher Education in its exploration of the question: “How much emphasis should doctors and biomedical researchers place on the role of race as they evaluate health problems and potential treatments?” In “Shades of Doubt and Fears of Bias in the Doctor’s Office,” Jay S. Kaufman, an epidemiologist at the University of North Carolina at Chapel Hill, registers dismay over the study of race in biomedical research. “We live in a society in which race is the primary axis of social discrimination,” he told the reporter. Referring to the New England Journal of Medicine articles, he opined, “An article that shows that there is some scientific foundation for the distinction is very comforting to people.” As far as doctors’ behavior is concerned, Kaufman says that these types of studies engender needless focus on race. “A patient walks in the room, the first thing the physician notices is, ‘Oh, it’s a black person’ . . . a [journal] article says, ‘oh, yeah, that’s good, you should notice that, it makes a big difference.’ ”

Indeed, government-funded research in health is becoming extremely race conscious, but not in the way Kaufman criticizes. Efforts to uncover the social explanations for differences in health status between minorities and the general population are blossoming, including millions spent on — in the words of NEJM’s Schwartz — “research to root out social injustice in medicine.” This is a popular theme. The U.S. Commission on Civil Rights, in its 1999 annual report to Congress and the White House, concluded that “racism continues to infect our health care system.” The commission’s assessment derived mainly from the fact that health outcomes were often poorer in minorities, especially African Americans. As is increasingly common, the commission inferred that bias in the system must be the underlying reason accounting for disparate health.

In academia, combating inequities has become a mission. According to Harvey V. Fineberg, former dean of the Harvard School of Public Health, “a school of public health is like a school of justice.” In 1996 the theme of the American Public Health Association’s annual meeting was “Empowering the Disadvantaged: Social Justice in Public Health.” One of the association’s proposed solutions is affirmative action in medical schools, believing as it does that “institutional racism has been an important contributor to racial disparities in health and economic status as well as a barrier to their elimination.” The Centers for Disease Control and the National Institutes of Health give grants and sponsor workshops to assess the impact of “racism,” “classism,” “powerlessness,” and income inequality on health. Unfortunately, politics — not rigorous methodology — often fuels these investigative forays.

Not all efforts, thankfully, are grounded in victim politics. Many simply want to close the health disparity gap in the service of improving the nation’s health. Every 10 years, the Department of Health and Human Services announces its health agenda; this year the blueprint is called Healthy People 2010 and is devoted to the “elimination of racial and ethnic health disparities.” Narrowing the gap between health outcomes in minorities and whites is a worthwhile effort. hhs is targeting six important areas for improvement: infant mortality, cancer screening and management, cardiovascular disease, diabetes, hiv infection/aids, and child and adult immunizations. Last year, Congress allocated over $100 million to fund a new agency within nih called the Center for Minority Health and Health Disparities.

It should come as little surprise that the anxieties plaguing critics tend to follow the ideological fault lines of the culture war. Take the notion of inborn differences. If we acknowledge that risk for particular illnesses or physiological features clusters by race or ethnicity, the critics worry, we are essentially erecting the scaffolding for social hierarchies. As University of Pennsylvania bioethicist Arthur Caplan put it, there is worry that the human genome would be used “to bolster racial and ethnic prejudice and other exclusivity groupings they believe in.”

Also distressing to critics is the notion that intrinsic traits of individuals or groups will lead to unequal outcomes, in this case, in health status. The irony here, of course, is that the very purpose of researching race-related differences in physiology is to develop treatments that can help level the clinical playing field by improving health in people who are at risk. Critics also fret that by paying attention to patterns of biological differences, practitioners and researchers will underestimate or even ignore outright the considerable contributions that environment makes to health. This is an unlikely development given the vast interest, generous research funding, and public prevention campaigns devoted to the role of nonbiological factors such as diet, stress, environmental toxins, attitudes about health care, and access to it.

To acknowledge a biological dimension to race is to risk inflammatory and often groundless accusations of racism. The public’s health is best served by a balanced portfolio that employs race as a variable in both biomedical and social health research. In the debate over the proper place of race in scientific inquiry, the meaning of the human genome project has become a powerful Rorschach test. Deliberately ignoring race in biomedical research can lead to inferior or improper treatment. The fact of a tainted history of race and medicine need not prefigure irresponsible activity now or in the future.