Jewish World Review June 12, 2001 / 23 Elul, 5761
Jon Entine & Sally Satel
the stem cell debate
http://www.jewishworldreview.com -- Science and politics do not mix very well, particularly when it comes to such hot-button issues as diversity. That's certainly the case with the stem cell debate. Although this effect is surely unintended, if federally funded research is limited to the 64 stem cell lines approved by the Bush administration, potential cures could end upbeing most useful toa narrow sliver of the world's population: whites of mostly European ancestry and some Asians. Much of the rest of the world will find that some promising therapies developed from these lines do not work very well.
The problem lies in the lack of genetic and "racial" diversity of the 64 lines. Most of them were harvested from embryos at U.S., Swedish and Israeli fertility clinics, where patients are overwhelmingly white. Based on discussions with most of the 10 laboratories with approved cell lines, we have concluded that as many as 49 of the lines are from white couples. As Alan Robins, chief science officer for one of the labs, BresaGen Inc. in Athens, Ga., told us, "Although we do not know for certain the racial background of our donors, it is reasonable to assume they are from white couples." About 15 of the lines, harvested at clinics in Singapore and India, are of South and East Asian parentage, we believe, based on those discussions. Even if all of these stem cell lines are shown to be viable for research, that's a very narrow segment of the world's population and a tiny fraction of what is necessary to ensure genetic diversity in therapies eventually developed from the cells.
And that's a problem because, as with whole organ transplants, therapies and tissues derived from stem cells will likely share the body's tendency to reject as foreign those that come from different populations. Patients with stem cell transplants will have to take drugs that suppress the immune system -- drugs that can cause substantial problems themselves. A menu of far more than 64 lines of embryonic stem cellswould be necessary to accommodate the vast immunological variety of human beings.
Scientists have alluded to the problem, but only indirectly. Harold Varmus, former director of the National Institutes of Health and now head of Memorial Sloan-Kettering Cancer Center in New York, and noted Harvard molecular and cellular biologist Douglas Melton warned in a recent Wall Street Journal commentary that "Even 100 good lines will likely be inadequate to treat our genetically diverse population without encountering immune rejection." But while they addressed the theoretical issue of genetic diversity, Varmus and Melton avoided the practical issue of its implications. A non-scientist would hardly have understood that adding hundreds more cell lines would not necessarily result in that much more genetic diversity. To ensure that, researchers need embryos from a wide range of populations and ethnic groups.
Although genetic diversity does not equate with ethnic and racial diversity, they are not unrelated. "If research is limited primarily to the announced stem cell lines," says Arizona State evolutionary biologist Joseph Graves Jr., "then you may develop drugs for, say, Alzheimer's or Parkinson's that work best only in those populations. There are many genetic variants that are only found in certain Asian populations [or] only found in sub-populations in Africa [or] only found in certain European populations."
What does that mean? After all, the fact that medically significant differences exist between populations would seem to conflict with a spate of declarations in recent months proclaiming that "humans are 99.9 percent the same" and "race is biologically meaningless." The paradox revolves around a common misunderstanding about the notion of "race" -- in particular, the popular notion thatraces are discrete groups, each with distinct genetic profiles.
In fact, modern humans are made up of overlapping, soft-edged genetic clusters. Although humans share most of their estimated 40,000 genes, there are as many as 500,000 gene components, or single nucleotide polymorphisms, many of which are more common among people from one geographical region than from another.
This is not a "black" and "white" issue. Genetic factors help explain the prevalence of any number of population-specific diseases and physiological responses to drugs. These differences are rooted in the different variations of genes, known as alleles. Some populations have a higher frequency of a specific allele. That has huge medical consequences. Tay-Sachs is a neurological disease more common among European Jews and their descendants. Northern Europeans are more susceptible to cystic fibrosis. A specific allele is a potent risk factor of Alzheimer's in whites but not for most blacks. Different ethnic and racial populations metabolize common drugs such as codeine, beta-blockers and antidepressants differently. African, Mediterranean and some Asian populations are far more likely than whites to develop a toxic reaction from Primaquine, a drug used to treat malaria and pneumonia. Genetic variants are associated with Type 1 diabetes, asthma and thrombophilia, a bleeding disorder -- as well as with sensitivity to certain foods.These are all "racial" differences of a kind, although the interaction of genes and environmental factors is extremely complex.
The potential consequences of ignoring population factors were underscored last Monday with the announcement by researchers at the University of Wisconsin that they had turned human embryonic stem cells into blood cells needed for bone marrow transplants for patients with leukemia or other cancers.
However, not all populations would benefit equally from such research. Bone marrow transplant registries, like the newly released stem cell registry, are drawn primarily from white populations. But people with lots of sub-Saharan African ancestry show greater variety than Europeans in their HLA, the complex of genes that effect whether the body rejects a tissue or organ. The combination of these factors means that white Americans are five times more likely than blacks to get a bone marrow match from an unrelated donor.
It is well documented that populations in Africa, where modern humans likely originated, are the most genetically diverse in the world. A stem cell policy that does not guarantee a significant percentage of cell lines from various African sub-populations will limit human biodiversity -- and could limit the effectiveness of drug therapies on those and other populations not adequately represented in the current cell lines.
Health and Human Services Secretary Tommy Thompson offered assurances last Wednesday that "the private sector will fill any voids if there are any voids" in the quality and diversity of the stem cell lines. But researchers are extremely doubtful, as are we, that this will happen. Because minority populations would be generally less able to afford expensive therapies tailored to their genetic profiles, private companies would have little economic incentive to spend the kind of money necessary to ensure therapies would work in genetically distinct sub-populations, including those of African ancestry.
"The fact that monolithic racial categories do not show up in the genotype does not mean there are no group differences between pockets of populations," states Graves, who is African American. "There are some group differences. We see it in diseases. But that's a long way from reconstructing century-old racial science."
Misinformation about racial differences and justifiable concerns about resurrecting "race science" has so far hampered an open discussion on these critical issues. We found that many scientists are afraid to discuss the link between stem cells and race in an already politicized issue.
"We need to look at the causes of differences in diseases between the various races," warns geneticist Claude Bouchard, director of the Pennington Biomedical Research Center at Louisiana State University. "Only by confronting these enormous issues head-on, and not by circumventing them in the guise of political correctness, do we stand a chance to evaluate the discriminating agendas and devise appropriate interventions."
How did we get into thisquandary and what can be done about it? Much of the responsibility falls on the shoulders of scientists who haveinsisted that there are no patterned genetic differences among various populations. In May, a firestorm ensued after the New England Journal of Medicine published a paper seeking to explain why blacks with high blood pressure and other cardiovascular conditions do not fare as well as whites when given the same medications, in part because of genetically based sensitivities to certain drugs.
J. Craig Venter, a geneticist and entrepreneur whose company, Celera Genomics, has played a key role in mapping the human genome, sharply criticized race-based research, although he did not challenge the science. "It is disturbing to see reputable scientists and physicians even categorizing things in terms of race," he told the New York Times. (Intriguingly, Celera's research is based on the DNA from only five people, an absurdly small fraction of the world's genetic variability.)
Certainly, classic notions of race based on skin color can be scientifically simplistic. But past mistakes should not be invoked to censor research and harm potential patients.
In the case of ovarian cancer, for example, Jewish women of East European ancestry are as much as 40 times more likely to contract the disease than other women because of their increased likelihood of having the gene BRCA1. Could such a dramatic pattern exist for the effectiveness of drugs that might be developed from a limited number of cell lines? Scientists do not know yet, but some critical differences are certain to emerge.
Stem cell researchers are discussing among themselves establishing international cell banks or launching a long-shot effort to genetically engineer "universal donor cells" stripped of rejection problems, but those efforts would require government funding, from the United States and other wealthy nations.
Barring that, it's important to keep in mind that while polemical demands to exclude population-based differences as a factor in biomedical research may play to understandable concerns about past misuse of race in science, they do so at a high price: They perpetuate the historical tendency to exploit simplistic notions of race in the name of science and medicine. Ironically, in leaving race out of the current stem cell debate, history may be repeating