Race, Medicine, and Public Policy

November 12, 2004

Unedited transcript prepared from a tape recording

Proceedings:
MR. ENTINE:  At the American Enterprise Institute on Race, Medicine, and Public Policy.  I particularly want to thank Chris DeMuth of AEI who makes these opportunities possible.  AEI is very much committed to public discourse on issues that aren’t always aired in the public forum.  And I think although the issues of medicine and race is often discussed, it’s not often--a dialogue does not always accompany such controversial, potentially controversial issues.  And we’re hoping today to have a very constructive discussion about the public policy issues raised by some of the latest research, genetic research on medicine and race.

This, in fact, has been a remarkable week in the medical genetics community.  Four years ago, as the first sketchy map of the human genome came into focus, President Bill Clinton declared all human beings, regardless of race, are more than 99 percent the same.  J, Craig Venter, one of the two key scientists responsible for that crude genetic map, echoed this sentiment, when he said race has no genetic of scientific basis.

Yet, this week, a groundbreaking study, published in the New England Journal of Medicine--it came out yesterday--suggested that when it comes to responsiveness to certain drugs, one’s race may not only be grounded in science; it may have life and death consequences.

The study, which focused on a drug known as BiDil, which is a heart failure pill, developed by the Massachusetts company Nitromed, reports that it is compellingly effective in patients of African ancestry, Black African Americans in this case.

It is now poised to become the first so-called race specific drug approved for use in the United States.  BiDil is now the leading protagonist in the debate over what role race, ethnicity, and ancestry, which is the complicated bouillabaisse of terms that make up the fuzzy notion of genetic population, should play in medicine.  There is now overwhelming evidence that some genetic disorders and behavioral patterns, and there are thousands of them , are associated with racial or ethnic groups.

Only last month, the prestigious journal Nature Genetics reported that at least 29 medicines have so far been identified that are either safer or more effective in certain populations because of genetic differences between those population groups.

This is not a black and white issue, by the way.  It’s the result of evolution’s impact on population groups all around the world.  For example, bone marrow transplants are more successful when the donor and recipient are matched by ancestry; and, therefore, by genetic characteristics.

Differences show up in many population groups that because of geographic barriers, linguistic isolation or cultural practices have retained their distinctiveness.  Descendants of the Amish, gypsies, Icelanders, Fins, and West Africans are among dozens of soft-edged, and that’s important, overlapping, and that’s important, populations that are genetically identifiable in some not all key characteristics.  And are often afflicted by unique diseases as a result of this insularity.

For example, Jews around the world, despite migration and physical separation, are genetically distinct in many key ways.  Subgroups of Jews, Ashkenazim for instance, from Eastern Europe, are the target of dozens of what are known as Jewish genetic disorders.  That’s a term coined innocently by molecular geneticists, many of them Jewish, but which understandably provokes some unease among all of us.

This is prickly stuff.  No question about it.  In less than four years, we’ve moved away from the notion that race has no genetic basis to the recognition that genetic differences may be, in some cases, quite real.  This is a dramatic and provocative shift in conventional wisdom in an extremely compressed time frame, with enormous public policy consequences.

While many geneticists and disease researchers see this exploration of differences as a way to deconstruct diseases that could lead to breakthrough cures, others worry that this renewed emphasis on genes could resurrect discredited notions of racial science that we all believed had been buried in Adolf Hitler’s bunker in Berlin, or in Selma, Alabama, 40 years ago.

The loser in this rebiologizing of race, they warn, could be minority patients, and the consequences could be inferior health care.  Although our speakers today disagree, in some cases significantly, over how closely genetics, race, and medicine are, in fact, linked, they are united in the belief that it’s time to move beyond the taboo that has limited candid discussion of population-based differences, and slowed the kind of research that has led to BiDil, which suggests it will be a remarkable new addition to the arsenal for doctors treating heart disease.

To being today’s dialogue, we are fortunate to have one of the co-authors of heart treatment study released this week,  Keith C. Ferdinand, one of the country’s most prominent cardiologists,.  Now, that study is actually in your package.  You can take a look at it.  It just came out in the New England Journal of medicine yesterday.

Dr. Ferdinand is the Medical Director and Professor of Clinical Pharmacology at Xavier University in New Orleans, where the announcement was made this week at the American Cardiology Association Meetings, I believe.

He’s the former Chairman of the Board of the Association of Black Cardiologists.  Dr. Ferdinand has authored many journal articles on medical issues, and has served on numerous committees examining the nexus of population and medicine.  He is also an investigator and steering committee member on the African American Heart Failure Trial.  It’s the first study designed to examine whether a unique nitric oxide enhanced drug, BiDil, can help African Americans dealing with heart problems.

I am pleased to welcome Dr. Ferdinand to share his views on this very, very important topic.  Thank you, Dr. Ferdinand.
BIDIL HEART DRUG:  THE NEXUS OF RACE AND MEDICINE

DR. FERDINAND:  Thank you very much.

First of all, I would like to thank the organizers for giving me the honor of giving the first presentation in this important forum.  I would also suggest to you that my life’s interest has been in reducing health disparities, specifically as it relates to African Americans and ethnic minorities.  My daily work is as a clinical cardiologist in the ninth ward, New Orleans, Louisiana, a working class neighborhood which is socially disadvantaged.  We see high-risk patients, and I have treated these patients for over 20 years and have been dismayed of trying to put out the fires of cardiovascular disease with a thimble of water.

The report that’s in your packet is published in one of the leading journals, medical journals, the New England Journal of Medicine.  It was presented the plenary session at the American Association.

But I will caution you that while the report does suggest benefit of this new agent in African Americans, it does not conclusively suggest, and we have this in the document--it’s written in the actual formal presentation of the data--it does not conclusively prove that there is a genetic basis for this difference.

So, I will attempt to review some of the literature as it relates to ethnic and racial disparities in cardiovascular disease.  I will not try to say that all of this is genetic-driven.  I will specifically look at the impact of culture, the impact of socio-economic status, the impact of how we as clinicians treat or undertreat patients, and I will try to give you the rationale as to why we did the study and why the results may be what they are.

The handout that you have has most of the key slides.  This is a bar graph of the leading causes of death for African Americans, males in the red, females in the white bar.  And you can see it greatly outdistances other forms of death.

I could show the same bar graph for the majority population, Latino population, Asian Pacific Islander population in the United States, cardiovascular disease is the leading cause of death.

Now, what about African Americans?  Let’s first look at hypertension.  It’s three to seven times more prevalent.  There’s a high-end stage renal disease incidence, up to 20 times more.  This is not just of social interest, and it’s not even just of medical, it actually has a great health care burden, because Medicare pays up to $65,000 per year to maintain someone on dialysis.  And the fact that you have a population which may only 12 percent of the general population, but is 35 of the Medicare dialysis registry, speaks to the economic and social impact of these disparities.

African Americans have a higher risk of stroke.  More mortalities who are dying from stroke.  A higher incidence of left ventricular hypertrophy.  Left ventricular hypertrophy is when the muscle of the heart is enlarged, and it’s marker for early onset and poor control of blood pressure.

And the blood pressure vascular response appears to be somewhat more malignant.

What about congestive heart failure, which is the condition which was the treated condition in the BiDil study.  Up to three percent of the African American population is affected, and, again, this has not only a health, but a socio-economic burden.  Heart failure is the leading cause for hospitalization in the Medicare registry.  So, it’s the leading cause of putting people in the hospital in terms of disease processes.

In terms of African Americans, it has a unique epidemiology.  It’s probably more related to hypertension than it is to epicardial coronary disease.  This means that if you look at the general population of African Americans with heart failure, you see more patients who have heart failure from uncontrolled or poorly controlled hypertension than from heart attacks per se.

Worrisome prognosis.  A higher rate of hospitalization and an increase in mortality, and then the question that we attempted to answer in the African American Heart Failure Trial was altered response to medical therapy.  And I’ll try to into that in some detail, since it is a fairly complex issue.

Regarding coronary heart disease itself in African Americans, older studies have suggested at one point that coronary heart disease was not as prevalent.  The newer data from the National Health and Nutrition Examination Survey suggested that the prevalence rates are somewhat higher in African Americans, but even more important, the mortality rates, dying from heart attacks, is higher.  Those specific numbers are located on this slide:  383 for 100,000 for Black males versus 312 for 100,000 for White males; 284 per 100,000 for Black females versus 208 for White females.

The bottom suggests that this is not just purely genetics; that it’s risk factors, rf, that probably induces these high rates of death, and those include not lipids, or forms of cholesterol, but other things such as an increase in obesity, Type II diabetes, and hypertension.

This diagram dramatically shows what was demonstrated in some of the detailed data that I just covered.  The yellow bars are death rates, hard end points for coronary heart disease in African Americans, women followed by men.  And if you look at the heights of the bars, they’re much more than that seen with the White population.  Specifically, African American women have a death rate from heart disease more similar to that of White men than White women, a very high risk population.

Before I go on to some more studies and to suggest to you that there may be a basis for using different drugs in different populations, let me suggest that how we treat patients remains very important.

Cardiovascular racial and ethnic disparities is a reality.  It’s something that in our society we would think in the year 2004 would have been eliminated.  But the truth is, this is from the Kaiser Family Foundation, in which they reviewed in medical journals studies showing the access and the utilization of high cost and very important cardiovascular interventions.  Eighty-one percent of the--or eighty-four percent of the studies showed a clear racial/ethnic differences in how these particular high-risk, very important cardiovascular interventions were utilized.

The weight of the evidence is that even if a person looks at the genetic basis for disease, how we treat patients remains important.  African Americans versus Whites have less catheterization, which is diagnostic for coronary disease, less angioplasty, once they have disease, less bypass surgery, less use of thrombolytic therapy, which are the clot busters that have been shown to decrease death and disability from heart attacks.

And these racial/ethnic differences in care remain even after adjustment for clinical and socio-economic factors.  So, the hard truth is that there may be bias in the medical system in terms of how we treat African American patients.

There are limited data on Latinos, Asians, and Native Americans, so I will continue to focus most of my report on African Americans.

Before we go on to the medical literature, let me not overlook the importance of culture.  Culture or shared beliefs, [inaudible] and learned behavior--it is not the same as race, but tends to group around race, and also includes language, national heritage, and socio-economic status.  So, culture clearly play a  major part in terms of cardiovascular outcomes.

It expresses itself in how we communicate disease, and it does relate to ethnic and racial disparities.

What about the African American population?  There’s an historical distrust of the health care system, which is why many patients in the African American community often delay going to the doctor.  And this distrust is not just out of ignorance.  In fact, at the turn of the century, in post-Civil War, it was actually the White medical community which was an apologist for the idea that Blacks were inherently inferior.  Their strong folk health beliefs, illness is natural or unnatural, the use of alternative medication and herbs, the importance of religion and kinship, which could be very important in terms of trying to reduce these disparities, and women often as gatekeepers.

Those of you who don’t know, I would like to remind you of the Tuskegee experiment, in which the U.S. Public Health Service had approximately 400 African American diagnosed with syphilis, and even after the discovery of penicillin and the knowledge that penicillin would treat this particular condition, they continued to quote "observe" men in a so-called quote "clinical study."  So, I think some of the distrust of the health care system of the African American community is actually founded on strong historical data.

I’m going to move now on to specifically cardiovascular disease, because that it is the primary area of my training and interest.

Inadequate resources leads to poor lifestyle--poor diet, overweight obesity status, distrust of medical profession, and an adverse view of medications.  These are some of the genetic polymorphisms that may, and I put an emphasis on may, participate in the pathogenesis of cardiovascular disease in African Americans.  Growth Factor B-1 is relate do hypertrophy, endothelium is a vasoconstricting substance, the Glide 389 B-1 receptors means that those patients who have this particular polymorphism may respond less to beta blockers, and there have been some data in monotherapy for hypertensions, beta blocker has not worked as well; and, in some heart failure trials. African Americans have not done as well with beta blockers as the majority population.

Aldosterone synthase is related to salt and water retention.  Nitric oxide is a vasodilating substance, and, in fact, one of the hallmarks of the new drug that is being utilized in the study of A-Hef [sp?] is a combination of isosorbide nitrate and hydralazine, which gives the body nitric oxide and prevents the breakdown of nitric oxide.  This vasodilating substance may be more important in and African American cohort, and I’ll describe some of those data shortly.

The 825 T-allele G protein subunit is relate to production of angiotensinogen, which is related to the renin angiotensin system.  And there are some data that African Americans response differently to Ace inhibitors, a class of drugs used in cardiovascular medicine.

I suggest all of you get a copy of Nature Genetics.  It has much of the data related to some of the differences in response to medications.  It does necessarily prove that all of these differences are genetic driven, but it does suggest that there may be some ways in which we can micromanage patients based on their response to medications.

Before I go on further with the studies, I would also like to quote directly from that journal, and I will take the time, this is from Dr. Collins, who’s the Director of the Human Genome Product, of the National Institute of Health.  He’s speaking directly related to genetics and health.

A true understanding of disease requires a thorough examination of root causes. Race and ethnicity are poorly defined terms that serve as flawed surrogates for multiple environmental and genetic factors in disease causation, including ancestral geographic origins, socio-economic status, education, and access to health.  Research must move beyond these weak and imperfect proxy relationships to define the more proximate factors that influence health.

So, it’s with great caution that we continue to look at differences in how medications respond in different populations, and we must always take into account socio-economic status, access to health care, culture, and perhaps in how we as physicians treat racial and ethnic minorities.

This is a very busy slide, but I think it’s in your handout.  And it’s a review of the randomized clinical trials of African Americans.  What has been done in medicine is that a general population is entered into a clinical trial, then sub-group analyses are done.  We then try to make generalizations about a medication or a response based on these sub-group analyses.  The problem with that approach is that sub-group analyses often give flawed outcomes.  The data are often limited by the size of the sub-group.  It may be related to not controlling for socio-economic status, sodium intake, obesity, financial distress, et cetera.  But large pronouncements are made on the benefit of lack of benefit of a medication based on these sub-group analyses.

The specific point of the AHab trial was to attempt to show the benefit of a specific medication and a sub-group, not to suggest that all of this is genetic driven, but to show that there was a response in a medication in a high-risk, disadvantaged population.

These are some of the trials, specifically in heart failure, looking at the angiotensin inverting enzyme inhibitors, or Ace inhibitors, and you look at the total number of patients in the various trials, and you see the numbers of African Americans are disproportionately low.

The same is true with the use of beta blockers.  African Americans should benefit from these medications, but unfortunately they have not been studied at the levels which would give us great confidence in many instances.

And even lipid therapy, the statin drugs, which we now know are life saving, most of the trials were either done in European populations, and even those trials that had an American cohort have an underrepresentation of African Americans.

I bring your attention to the one trial at the bottom. ALLHAT.  ALLHAT is the Anti-Hypertensive Lipid Lowering Heart Attack Trial.  It was sponsored by the National Institutes of Health, the National Heart, Lung, and Blood Institute. I was on the data and safety monitoring board for ALLHAT, so I’m very familiar with these data.

And ALLHAT suggested that statin drug provostatin benefitted the African American population.  But caution:  the study was provostatin versus usual care.  Some patients were randomized to be given the statin drug provostatin; other patients were randomized to usual care.  What happened?  Well, we’re not really clear, but perhaps the Blacks benefitted from provostatin because usual care was poor or bad care; hence, leading to gap or a difference in outcomes that would suggest some specific benefit of the medicines, but it actually may be a marker for poorer care in the usual care cohort.

I understand these concepts are somewhat complex, and hopefully throughout the panel, we’ll be able to tease out why we see some of these things in clinical studies.

I bring your attention to the yellow in this particular, very busy graph, and this is looking at ethnic differences in the response to the Ace inhibitor Analopril and hospitalization for CHF is patients who were given this drug and were then hospitalized with heart failure.  You’ll note next to the African Americans, NS, meaning not statistically significant.  This suggested that the Ace inhibitors in the African American cohort in this landmark Ace inhibitor trial did not show benefit with the medication.

But this is an example I also think where sub-groups analysis leads us astray.  While, indeed, the outcome shows less benefit with the Ace inhibitors in the African American cohort, there is a statistical significant difference, and this is within the primary paper, and I also think a clinical significant difference in the African American sub-group.  What were those differences?  They had less aspirin use, less use of beta blockers, which is another medication that helps patients with heart failure, more diabetes, which is a powerful risk factor for an increase in cardiovascular events, more socio-economic disadvantaged status, more financial distress.  So, then you have a very complex interaction of culture, socio-economic status, and how the patients were treated even within the clinical trial, with the primary end point of patients who progressed to hospitalization being different with the drug Analopril versus placebo, and the conclusion is then made that the African American population don’t respond to Ace inhibitors.  Life is just no that simple.

Medicine is a complex interaction of both genes, socio-economic status, culture, and environment.

This is an older heart failure trial, using the combination of Isosorbide dinitrate and hydralazine.  It was known as the VHef trial, and this trial was published in 1991, with the reanalysis.  And what it suggests in the African American cohort is that when they were given isosorbide dinitrate with hydralazine versus placebo, there was in improvement in mortality.  At the right hand side of the slide, you see the P-value, which shows statistical and probable clinical significance of less than 0.004.  So, remember we have a high-risk population, increase in hospitalizations, increase in death, and here we have a medication which appears to show benefit.  This sub-group analysis of the VHef trial then led to the hypothesis that perhaps African Americans would benefit from the combination of isosorbide dinitrate and hydralazine.  This was not an effort to show that it was purely genetics, but it was an effort to show perhaps we could use this combination in medication in this population and give benefit.

What is nitric oxide?  Well, this is a very complex diagram.  I’ll try to simplify it as much as I can and as quickly as I can.

The endothelium is the lining of the cells of the body.  EDFR is endothelium relaxation factor.  Nitric oxide is basically a gas that is released by the cells of the body to allow the large vessels to dilate and to allow the blood to flow freely through the body.

In patients with the yellow there, on the right side who have high cholesterol and atherosclerosis, you have a decrease in nitric oxide which is EDRF.  This allows the platelets, the little sticky things in the blood to adhere.  It promotes vasoconstriction, where the blood vessels clamp down.  It increases tearing of the blood vessels, and it increases the progression of hypertension and atherosclerosis.

There are some studies to indicate that perhaps African Americans have less availability of nitric oxide, known as EDRF.  This may lead to higher rates of hypertension and more malignant forms of heart failure.

Hence, the study was designed to try to combat the decrease in nitric oxide bioavailability in African Americans due to the consumption of oxidative stress.

The publication is in your packet.  I suggest those of you who are not physicians will read it with caution and look to the conclusions and within the conclusions, again, I reiterate, it doesn’t necessarily prove that this is all genetic based, but it does show that there is a benefit with the combination of isosorbide dinitrate and hydralazine in this population.  There are also some editorials that accompany the primary article on race-based therapeutics and tries to describe in more detail, the nitric oxide theory.

One of the reasons we continued to do this study was that if you looked at the benefit of African Americans with the combination of isosorbide dinitrate and hydralazine, that benefit was even more profound than seen in non-African Americans, suggesting that this particular sub-group would benefit from this medicine.  Here are the AHef results that were reported at the American Heart Association in New Orleans two days ago.  One-hundred and seventy sites.  One thousand fifty randomized patients.  Five hundred and eighteen took the fixed dose of isosorbide dinitrate and hydralazine, which has been or will be marketed as BiDil, versus 532 on placebo.  Those of you who are concerned about the ethics of this trial, let me first state very clearly that all patients were treated with modern medications for heart failure, including Ace inhibitors, beta blockers, diuretics, if needed, and other medications. This was placebo, meaning added to conventional modern therapy, versus BiDil, or isosorbide dinitrate added to conventional modern therapy.  It was not a Tuskegee redux 2004.  All patients were treated with modern cardiovascular medications.

Eighteen months follow up.  No patients were lost to follow up.  This is really unusual in a study to follow 1,050 patients and to be able to find out who died or who had hospitalizations, and one of the reasons it was done so well is that the study was supported with some coordination of the Association of Black Cardiologists.

So that particular organization, which is a non-profit medical association, was able to assist in identifying patients and identifying researchers and make sure that we had appropriate follow up.

There was a 43 percent decrease in mortality versus placebo, added to conventional modern therapy with isosorbide dinitrate and hydralazine.  The P-value is significant:  0.01.  This means that patients who were given this particular medication added to conventional therapy who were self-described as African American showed less death.

Certainly, our particular concerns with the abnormal responses of a medicine in a population remain, but this was a positive response, in that adding this medication appeared to help people live longer.

The design of the study is in the paper, and I will not bore you with all the details.  But I would bring your attention to the fact that if you look at ejection fraction, in the middle of the slide, 24 percent plus or minus seven, both in the isosorbide dinitrate group and the placebo group is very low.  Ejection fraction is how well the heart pumps.  Usually, with each beat, you empty about 55 to 60 percent of the blood that’s in your heart--diastole versus systole.  An ejection fraction of 24 percent indicates that these were very high-risk patients with a high incidence of the possibility of being hospitalized with heart failure or death.

And, again, to suggest that this was not a Tuskegee redux, you can look at the number of patients who were on life saving medicines which have been used in the general population, including Ace inhibitors, angiotensin receptor blocker, or ARBs, beta blockers, spironolactone, which blocks Aldosterone, a neurohormone, which has been shown to be deleterious in heart failure, the Digoxin, which is an older drug, and diuretics which are fluid pills, if needed, for congestion.  And there was no difference between those patients who were on isosorbide dinitrate versus placebo.

These are bar graphs which describe very simply the differences in death, first hospitalization for heart failure, and changes in quality of life.  Placebo is in the white.  BiDil or isosorbide dinitrate hydralazine in combination is in the blue.  There is statistically less death.  There is statistically less first hospitalization for heart failure, and the bars are going down.  It’s counter intuitive, but going down in this particular case is good.  There as an improvement in quality of life.

This is the mortality curve, which I demonstrated earlier.  One of the reasons this may have worked is that the isosorbide dinitrate gives nitrate oxide, which is the vasodilating substance.  The hydralazine, which is also a vasodilator, is also an anti-oxidant, and may help the body maintain the nitric oxide, which was donated by the nitrate.

I’m going to conclude with a few studies to bring it back to the point of how we treat patients remains very, very important.  The medication used in AHef showed benefit in this population.  It does give us a window of opportunity and away of trying decrease death and disability in this very high-risk population but how we, as clinicians, treat our patients remains very important.

This is the HERS trial.  Most of you have heard of HERS.  It was the trial that showed that if you gave estrogen to post-menopausal women, it did not protect against heart attacks.  In fact, it may have been a deleterious effect on cardiovascular outcomes using estrogen.  Hence, no longer physicians recommend estrogen for post-menopausal females for reducing heart attacks or strokes.

Within the HERS trial, now this is a controlled clinical trial, national trial, sponsored by the Government--cardiovascular mortality was higher among Black women within the trial.  This is not the general population.  There was a two-time increased risk in coronary heart disease events, Blacks versus Whites.  Why is that?

Well, if you look within the trial itself, the Black cohort had more hypertension, more diabetes, more higher cholesterol, but were less likely, even within the trials, to receive aspirins or statins.

So, the trial was randomized to show benefit or lack of benefit of estrogen, and did not control for these other factors, but clearly there was a difference.

The Black women in the trial had less optimal blood pressure control, control of the LDL cholesterol, which is the bad cholesterol, and, at the last bullet, the Black women often received less appropriate preventive therapy and adequate risk factor control, despite, as I’ve shown in national data, a higher coronary heart disease event rate.

The authors of that trial said because of their higher risks and lower rates of some treatments in risk factor control, this treatment of Black women, even within the controlled trial is troubling.

In New Orleans, for many years, we’ve had the Healthy Heart Community Prevention Project.  The citation is there.  I believe that community-based programs induce favorable changes.  Prevention, prevention, prevention is most important for coronary heart disease and stroke, and that will lead to further declines hopefully in heart disease, stroke, death rates, and disability.  There are differences in morbidity and mortality, which is illness and death from cardiovascular disease, with higher rates in African Americans.  However, the African American community and other minority communities often have low socio-economic status that leads to these higher rates of cardiovascular disease, disability, and death.

In conclusion, there are disparities in health care.  There’s an excessive risk factor burden specifically in African Americans, and very high in Black women.  Patients often delay seeking medical care because of a lack of insurance status and cost considerations, and, of course, culture plays a part.

There remains, even within the practicing clinicians, an underrecognition and the undertreatment of high-risk individuals and a lack of access to cardiac, medical, and procedural care.

Regarding the art of healing, which is why we who are physicians, nurse practitioners, physicians’ assistants, and other professionals in the health care industry do what we do, it’s simply to make money.  In terms of the art of healing, essence of the modern physician will be to continue to include humanistic direct patient care.  No matter what scientific breakthroughs are noted in the future and despite increasing complexities of the health care delivery system, there will remain a need for men and women who are willing to undergo the rigorous sacrifice of delivering one-on-one patient care.

Thank you very much.

[Applause.]

MR. ENTINE:  Dr. Ferdinand, thank you very much.  I think you added significant layers of nuance to what is already a pretty complicated issue.  But I think it’s important that people recognize one of the key points that Dr. Ferdinand underscores is that anyone who sees issues of health or the larger issue of race as a genetic debate misunderstands how complex this is.  This is many issues--culture, environment, popular perceptions, and other things that are very much entwined with this, and I think what we’re dedicated here today is to try to figure out how we can tease out some of these elements, discuss them, and then put the whole back together, so we can figure out public policy protocols for funding research in this area, government oversight of some of these things.  These are all very much on the table now, and I think even more so because of the popular reaction to the BiDil research.

Let me just quickly lay out how we’re going to proceed from here.  We have a number of panelists, each of whom has a different area of expertise; all of whom have written and spoken to some degree on this issue, and so we’re going to bring a whole range of expertise.  We’re going to hold any questions for Dr. Ferdinand until after each of the panelists have also had a chance to make their presentations, which will not be quite as long as Dr. Ferdinand’s.  I will give everyone a mercy break at the bathroom midway in that, so for those of you who loaded up on coffee earlier this morning, we’ll have a chance to take a few minutes off.  But what we’re going to do is proceed right off with the panel.  Get it going.  I’m not going to go into long introductions of all the individuals.  You have long introductions in you packet of information, so I’ll briefly introduce each person as they begin.  We’re going to begin actually with Sally Satel from the American Enterprise Institute, who has written on this issue in many venues and will bring both her intellectual and scholarship interests to this, but also her personal experiences as a psychiatrist at the Oasis Clinic in Washington, D.C., and in other aspects of her clinical practice.  Dr. Satel.
RACE AND CLINICAL PRACTICE
"Why I Racially Profile"

DR. SATEL:  Thanks, John.  What I’m going to talk about today is how these concepts play out in clinical life.

But I first want to mention how I did get interested in this, and I can almost date it--it’s kind of a flashbulb memory--to May 2001, when there were two articles in the New England Journal of Medicine, perfectly standard articles. One was looking at beta blockers for heart condition, hypertension, and the other was looking at the Ace inhibitors.  And they were looking at the response by race.  And the Ace inhibitor study actually found some difference.

That’s not surprising.  Doctors have known for a long time that there are differences in response to cardiovascular medications by race.  But what was striking to me was the editorial that accompanied it.  It was written by one of the editors at the New England Journal of Medicine, and it was very indignantly titled Racial Profiling in Medicine.

And actually now, four years later, we can say, well, yes, some kind of racial profiling in medicine certainly makes some sense.  Disease is not color blind, and doctors shouldn’t be either.

But that’s what got me interested because I thought this issue was, from a medical perspective, was fairly resolved, not that we had all the answers, by any means, but the notion that there might be differences certainly in disease prevalence and also in the way folks respond to certain therapies based on ethnicity and race was just not that novel a concept.  So, I found that very interesting.

Then I heard from a colleague--I should say one of my interests here at AEI is on the intersection of culture and medicine, and I had written a book called PCMD:  How Political Correctness of Corrupting Medicine, so you can get a sense of my orientation.  And someone had told me that the standard way that medical students and residents present cases to their attendings, which is usually--this is a 35-year-old single Asian male, or this is a 50-year-old married Black female, along with occupation, that even that standard intro as to how we summarize clinical information, even that was coming under some assault and some of the students were being told, well, don’t mention the race.  And, again, I thought that was odd, just as odd as it would be not to mention the sex of the patient, the occupation of the patient, and the age.  I mean, these all are information laden variables that we have to know about.

But meanwhile, there was another realm in which race, or what I guess I might call social race, the race that anthropologists talk about, the socially constructed aspect of race, was of tremendous importance in health and remained so in the form the genre we now call health disparities that Dr. Ferdinand was referring to.

Basically, this is about the social determinants of differences in health status, referring to access to care, quality of care, socio-economic characteristics, health literacy, diet, stress--it goes on and on.  There is enormous emphasis on this in health care, at HHS, the health care philanthropies, in medical schools.  This is a major emphasis, and as it should be, no question about that.  And there’s a great emphasis on what’s been called cultural competence, which sometimes seems like a bit of a buzz phrase, but it takes into account linguistic differences, miscommunications that can happen between doctors and patients [inaudible] health literacy problems, cultural attitudes toward health.  The point being we are very race conscious and in a good way in terms of our pursuing these health disparities.

But somehow the idea that race has biological significance sometimes is, as John said, a prickly topic.  And I thought that became even more dangerous to talk about when, I think it was in June of 2000, I believe, the human genome project,some of the results had come forth, and we heard repeatedly how 99.9 percent all people in the world share a common genome; that there’s a .1 percent difference, only .1 percent.  And that’s a true fact.  And subsequent lecturers will talk more about what’s packed into that .1 percent, because there’s a lot of genetic information to that .1 percent, and that can easily account for some of the patterns that Dr. Ferdinand mentioned in terms of which kinds of enzymes or enzyme deficiencies might be more prevalent in certain groups.

But that fact, the 99.9 percent, which was everywhere, became kind of a rallying cry for the perception that there is no such as race; that race has no biological significance at all.  And I think, as you’ve already gotten a little preview so far, and we’ll hear much more detail about population genetics later, that that’s not quite accurate.

Even so, I was very pleased.  I thought the coverage of BiDil this week, which was really extensive was really quite fair and quite accurate and tinged with a lot of optimism in the media coverage.  That was a good sign.

But certainly there are still some things to clarify, such as what are other ways in which this might play out in day to day clinical life.  Again, Dr. Ferdinand gave the BiDil as a classic example we’ve all been focusing on.

But let me just give you two examples from my work.  John mentioned I work at a methadone clinic in Washington, D.C., so obviously that’s a population of folks who’ve had heroin problems.  And a lot of those folks have used needles.  And so, unfortunately, a lot of them are Hepatitis-C positive.  And for reasons we don’t quite understand, African American patients, on average, and I hope that should be embedded in every statement I make, on average, in terms of these response to medications--when Dr. Ferdinand was talking about BiDil, on average African Americans have a better response, but some Whites will respond, too.  Again, on average.  And on average, patients with Hepatitis-C, who are African American, unfortunately don’t respond that well to the standard therapy for Hep-C, which is Interferon mixed with Ribavirin.  Unfortunately, for example, in an average White patient, the amount of virus in the blood will be reduced by over 90 percent after six months of this treatment, but in African Americans only 50 percent.  No one quite understands why, and I know that actually many trials are going on now with other antivirals to see if they can change those percentages and close that gap.

Also, I see some folks who are not surprisingly struggling with depression, so we may use Prozac or an anti-depressant.  And, on average again, we know that folks with African American ancestry tend to be slower metabolizers of those kind of medications, so you just start at a lower dose.  And some people might argue you should start at lower dose for everyone just because you never know what kind of side effects you’re going to get.  Fair enough.  But make sure I start with a lower dose for my Black patients, and then we work up slowly, because, you know, you can’t risk.  Side effects are not good when you’re dealing with someone who’s depressed and already demoralized and now they feel worse because of the medication or they feel it’s not working.  The chances they’re just going to flush it down the toilet are pretty high, so you want to minimize that as much you can, so you go slow to minimize side effects.  That’s pretty standard.

I’ve seen this concept of--I don’t know what’s a comfortable way to phrase it--ethnic medicine.  That doesn’t feel quite right, but this notion that we take race into account.  I’ve seen it parodied in various ways.  I saw one epidemiologist, in fact, say, oh this is great.  So, now, what are we going to do?  Look at the person who walks in the door and see that he’s Black and immediately give him the Black pill or something like that.  Well, of course, not.  That’s not how doctors decide what’s wrong or what they’re going to do.  In fact, skin color, in and of itself, is nothing but more than a proxy here for ancestry.  And, as you’ll see, the subsequent who will talk about population genetics, that’s essentially what we mean by biological race.  It’s just distant ancestry.  The only way I think skin color is important--I can think of one example--is Vitamin D metabolism, which interestingly is in Black skin and dark skin, Vitamin D metabolism is slowed and especially important for folks to have enough exposure to sunlight.

[END OF TAPE 1, SIDE A; FLIP TO SIDE B]

DR. SATEL:  Sunlight.  So a colleague was telling me that he treated some African folks who lived in Minnesota. Their young babies were actually starting to suffer from Vitamin D deficiency, which manifests as bone problems, because they weren’t getting enough exposure to sunlight up there.  It’s too cold.  Kids don’t go out and play, and, anyway, so that had some discrete meaning, the skin color itself.

But generally, when we’re talking about BiDil and things like that, it’s skin color as a marker for the genetic heritage.

And what other folks have pointed out, and very rightly so, is that there’s just so much you can infer from looking at someone.  Fair enough.  For example, take sickle cell anemia, people understandably and rightly correlate that as having a higher likelihood of occurring in people of African ancestry, but actually it’s a risk that people in the entire Mediterranean area face.  And it’s basically a form of a protection against malaria, but this becomes maladaptive in certain other environments.

So, if you had a patient who was White, and they had symptoms that seemed consistent with sickle cell, you ask them about their heritage.  You ask them about their ancestry.  Do you have any Greek blood in their family?  Because they well could have sickle cell anemia, and that’s really technically the right way to do this, not for every problem, certainly.  I mean, a broken bone.  I mean, there are so many problems in medicine that are just treated the same.  But there are some where these subtleties can matter, and the really proper way to do it is to think in terms of ancestry and ask.  You know, where are your great-great-great-grandparents from if people know that.  And that can give you some clues when certain conditions are resistant to first-line therapies and to obvious diagnoses.

Just as I said, you ask about age and sex and occupation because all these things influence as well.  And in medicine, you know, we’re almost always talking about probabilities.  Practically everything in medicine is couched that way.  Will I respond to a medication?  Will you have this chance of this responding?  You know, will I live this long with cancer treatment?  All that kinds of things, not to mention, as Dr. Ferdinand was saying, diet and adherence to medication and making sure that your diabetes is already well controlled and smoking and alcohol use--all those things are key.

Just going to sum up, though, by mentioning what I think are a few objections or the areas of discomfort when it comes to talking about this area?

The first--they’re four that I’ve identified.  But the first is the idea that--notion--that race has any biological significance; that that’s a bankrupt concept.  It is not a bankrupt concept.  It relates to that .1 percent that’s left after the 99.9 percent similarity is taken care of.  You will hear more about that, so I’m going to go to number two right now.

And that John mentioned, secondly, that virtually any mention of race in a medical context will propel us down a slippery slope to abuses; implies defectiveness, which, when John talks about Jewish genes, we’ll see that this is not about Blacks; this is a not a black and white issue.  It’s about all different groups that have predispositions to certain diseases.

Third, and I believe Dr. Sankar is going to talk about this, and I guess we see this a little differently, she is concerned that focusing on the genetic aspect is going to distract us from doing something about the social determinants of health; that we’ll just focus now on the biology and the genes, and we’re going to forget about access to care and socio-economic dimensions.  And have no concern firstly that that’s going to happen.  As I said before, between HHS, the AAMC, the AMA, all our health care philanthropies, this is a huge topic, a high priority, as it should be.  So, I don’t see that going anywhere soon.

And finally, I’ll sum up, you know, the ideal that our society is color blind so medicine should be color blind is just not right.  We can’t really confuse the notion of equality, which is something we hold dear, with the reality that we’re just not all the same.  And if we don’t pay attention to some of the ways in which we’re different, I think we’re actually going to harm our chances for making more medical advances and for helping more people and for reducing the health disparities.  Thank you very much.

[Applause.]
"Jewish Diseases"

MR. ENTINE:  Thank you very much, Sally.  Again, we’re going to hold the questions until the panelists are finished, ‘cause I’m sure you’ll have a lot of them and that will all precede a general discussion among all the panelists on some of the issues that we raise.  So, thank you very much.

I’m going to do a very brief talk.  I’m going to move over to the PowerPoint area--just about Ashkenazi Jewry, Jews in general, and genetic issues.  Again, to underscore the point that this is about population genetics and the issues of race, which are caricatured to some degree in our country because of our sad history about race relations, as black and white issues, and really that’s not the way population genetics really frames this issue.  And I think that’s important.

I’m going to talk about Jews, genetics, and disease.  And this is an issue which is not only of academic interest to me--I have a book coming out called Abraham’s Children next year, which talks about the genetic ancestry of Jews and the issues of the nexus of genetic identity and social identity--but it actually has a very personal meaning to me, and frankly I just became aware of this in the past month or so.  I am Jewish.  My sister contracted breast cancer about three years ago, which we thought was environmental, we weren’t really sure, so if my quavers a little bit, excuse me.

Excuse me.  But she recently, after a reoccurrence of it, she went in for genetic testing about a month and a half ago, and found out that she carries one of the mutations, the classic Jewish mutations, BRCA-2, that marks her as someone of Ashkenazi Jewish ancestry.  Ashkenazi is the German word--I mean is the Hebrew word for German.  So, I’ll explain that a little bit in a few minutes.

So, it came home very clearly to me.  I’ve since been genetically tested.  I do not yet know my results, ‘cause it takes about 30 days before Myriad Genetics in Atlanta gets this information.  But I’m rightly concerned not myself, but my daughter.  My mom died of ovarian cancer.  My aunt died of breast cancer.  And my sister has this as well.  So, it’s clearly in the maternal side of our family, so these are very real issues, and this is a mutation that is basically not found in any populations other than those of Jewish populations.  It’s a mutation that appeared some time during the formation of the Ashkenazi Jewish population, sometime between the 9th and 16th centuries is pretty much what we understand at this point.

But I’ll discuss this a little bit more.

Jews are one of the population groups that’s come under a lot of scrutiny for the issue of so-called genetic disorders and frankly the issue of so-called race-based differences, everything from questions about so-called Jewish IQ, which you’ve heard about, to issues of proclivity of Jewish diseases to even behavioral patterns among Jews.  Some people say that these are all social and cultural.  And frankly, other people, and this is very observable in the literature--people are discussing that many of the things that we’ve always ascribed to culture and environment may have a genetic component.  How much, how to tease these things out are not only not known, they may never fully be knowable; but they’re on the table right now.  So, we all are going to have to get used to discussing issues that we always had felt were outside of normal debate because science is concerned about these things.  They want to develop therapies for that.  So, it’s very, very important to understand that.

Many of you may not know that Jews are an ancient population; been around for quite some millennia, but when you go back to the 11th and 12th centuries, the world Jewish population, which had been five million at the time of Christ had really dwindled to somewhere between five and 50,000.  There was a Jewish population obviously in Spain at that point.  A Sephardic Jewish population.  But the Jewish population of Europe was incredibly tiny, literally.  Some people say as few as 20,000 people.  And, over the years, frankly, beginning around the 17th, 18th centuries, the number of Jews grew dramatically.

But because Jews were such a small population, for many, many centuries, a millennia [sic] ago, any genetic mutation that developed, any disorder that developed, was [inaudible] within that population.  That’s how population genetics work.  When you have an insular population because of cultural reasons, because of geographical barriers, for any reason--linguistic cohesiveness.  If that group sticks together, and interbreeds, whatever mutation, positive or negative, is likely to stay within that population.  So, the fact that Jews have been--were genetically insular at that time, and frankly remain so until the 20th century.

Now, Jews out marry out of the group.  About 50 percent of Jews out marry.  But up until the early part of the 20th century, less than one-half of one percent of Jews had married outside of their religion, an incredible measure of cultural homogeneity and which resulted in an incredible measure of genetic homogeneity, which is why we have these kinds of patterns.

As you see, again, contemporary Jewish populations is spread all over the world, but, again, up until the last 20 or 30 years, pretty much, despite the fact that Jews were all over the world, did not mean that they had culturally--I mean, excuse me--genetically intermixed.  They maintained that cohesiveness, so a lot of the genetic markers that distinguish Jews from other populations have remained very much intact, including disease markers.

Who are Ashkenazi Jews?  The Jews that you meet in the United States are mostly Ashkenazi Jews.  That’s of central European, eastern European ancestry.  The core population formed around in the beginning around the 9th century.  And they came from the Middle East.  Jews and Palestinians and Middle Easterners share an ancient genetic heritage, so many diseases that might have mutations that might have first appeared let’s say 2,000 years ago that are in Jews will also be found in let’s say Yemenites or Palestinians, whatever.  But many of the mutations that first appeared in Jews when Jews moved to eastern and central Europe are unique to Jewish populations and unique frankly to a division of Jewish populations, Ashkenazi Jews.

Jews lived in stettels and the population increased from 50,000 to 5,000,000 from 1500 to 1900.  In genetic terms, it’s called going through a population bottleneck.

When you look at the genetic evidence across a number of genetic markers, you see that, and you also compare it to other populations, you see sub-Saharan Africans, on the far left, very much a genetic similarity . Of course, there’s been a lot of intermixing in the United States over the past 200 years and in other cultures because of slavery and other things, but many of the genetic markers that are observable suggest that sub-Saharan Africans are very much a genetic population that is quite distinct.  You cannot find this.  I mean, you cannot look at a genetics textbook and not see the distinctiveness of sub-Saharan Africans.

But you look at Jews, and you can see--that’s the pink area--you see A-S-H--that’s Ashkenazi Jewry, Kurds, Yemenites, and a few other groups.  They’re very, very similar when you look at a lot of the markers, and they’re very distinct from Europeans.  So you can have German Jews who actually look a lot more like Yemenites than they look like the Germans who they’ve lived next to for 500 years, because they maintain that genetic similarity.

And there’s a lot of complexity to these issues.  I’m just trying to give you a quick overview of population genetics so you can understand how relevant and why population geneticists feel these issues are very important.

Now, Jews--there’s at least 30 what are called Mendelian diseases.  Mendelian diseases are diseases that can be linked to one gene.  For instance, Tay-Sachs or sickle cell anemia are linked to one gene.  Most disorders, genetic disorders, are a combination of and a reaction of a number of genes with the environment.  But there are a number of disorders that are clearly what are called Mendelian; it’s from Gregor Mendel who in the early stages of genetic research thought that each trait was linked to one gene or one version of a gene.  We now know that that’s not necessarily true.  But these are all diseases that are far more common among Jews than among any other population.  They are what goes under the rubric Jewish genetic disorders.  You can put that in Google, and you’ll find many, many universities that use the term Jewish genetic disorders with all the problems and associations that we discussed today bring up.  But yet, it’s a way to distinguish the fact that although these diseases show up in other populations because of inbreeding--I’m married to a Christian woman, who does not have the BRAC-2 line--it’s likely that some of my Jewish genes, so to speak, Jewish genetic disorders and other things that may mark me distinctly from my Ashkenazi background will be watered down so to speak as my family trees expands out.

But over time, you see that there’s many diseases that are very distinct and overemphasized, overrepresented among Jews.

As I mentioned, some of these diseases, mutations appeared during the ancient period of history, in Palestine, so you can find them, and a lot of these are also found in Sephardic Jewish populations, which trace their roots there.  Sephardic Jews--Sephardic is--it means Spanish Jews.  Sephad is Hebrew for Spanish.  And at one point, Sephardic Jews dominated Jewry. They were the largest part.  But that changed with the Inquisition and the conversion of many Jews from Judaism to Christianity.  In fact, in my book, I talk about an amazingly high incidence of BRCA-1, one of the breast cancer mutations, among Christian Hispanics in the San Luis Valley in Colorado.  And they’ve now done ancestral tree investigations and found out these very fervent Catholics are almost all Sephardic Jews who were forced to convert to Catholicism or willingly converted to Catholicism.  I think a lot of people don’t understand the history, because a lot of Jews willingly converted.  But they’re actually of Jewish ancestry, and a lot of them, some of them, now wear Stars of David.  I know one Catholic priest who I talk about in my book wears a Cross and a Star of David.  He says I’m Jewish by ancestry and Catholic by belief.

So, it’s very interesting what this means in terms of identity as well as genetic issues.  But you see some of these mutations appeared during the Palestinian era of Jewish history.  Some, like Tay-Sachs disease, which is very much a killer disease in the Jewish community, the mutation appeared much more recently, during the Ashkenazi period.  So, you don’t find it in Sephardic Jews, and you don’t find it, or at least you almost rarely find it in any other populations, particularly Palestinian or Middle Eastern populations.

Again, many of the Ashkenazi Jewish diseases appear between the year of 900, when the Ashkenazi population began to found, and today, they’ve--you’re actually--geneticists can actually find out within a reasonable band of time when those actual mutations appeared.  And they are kept.  They are not passed out.  Usually bad genetic mutations that are harmful are passed out of the gene pool, because they end up killing people.  They don’t confer genetic advantage.  But we’re doing a lot of investigations of this. Geneticists are starting to find out that some of these very deleterious genes may actually confer a hidden advantage as well.  Very controversial.  I don’t have time to go into it now, but there’s some reason why some deleterious genes, including maybe the breast cancer gene, may not be passed out of the gene pool, why it may be kept in.  It may offer a disadvantage and kill people, but it may offer a survival advantage as well.  That’s how genetics works.  I think Sally referred to malaria, which continues to confer a benefit, though less so in this modern technological age, but the reason the gene was preserved for so many years ‘cause it had a benefit to it as well.

Why are so many diseases found in populations like Jews, sub-Saharan Africans, and others, and I briefly discussed it.  It’s because of population bottlenecks.  When you have a population of 5,000, 10,000, 8,000 a mutation appears very quickly. In a population like that a disease will pass through that population and then ultimately if elements of that population move to other places, they’ll carry it with them.  That’s why geneticists like to study Iceland.  That’s why they like to study populations in Costa Rica, where a disease mutation appeared, and it stayed within that family.  It’s a very clear marker to understand why there are genetic differences at the disease, in terms of diseases, between various populations.

This is a very, very important for public policy issues, because we know the genetics of Tay-Sachs disease, we’ve essentially been able to wipe it out in the Ashkenazi Jewish community.  You can see what the mortality rate was as recently as 1980.  There’s a lot of intermarriage among Jews in tightly-knit Orthodox Jewish communities, particularly in the New York, or the Orthodox Jewish community is very resistant to genetic issues; have been resistant to genetic testing.  When they first found out that Jews had a high proclivity of this, they figured out a biblical way around it.  They committed themselves to it, and they’ve essentially wiped out Tay-Sachs disease in Jewish community in New York.  And the model for that has been rolled out around the world, not only for the Jewish community and other places, but to deal with other population-specific diseases.  It’s a way, through using genetic information that population genetics that distinguishes racial groups, population groups, however you want to call it, can lead to huge, huge public value and save lives, which is really ultimately I hope what we’re talking about here.

In summary, the Jews are a people of Middle Eastern origin who have retained their religious and genetic identity over 2,000 years of the Diaspora.  Jewish groups have many Mendelian, single gene, conditions with [inaudible] mutations whose allele frequencies exceed one to 200, which is an extraordinary high number for disease.  These mutations have arisen over the entire course of Jewish history, sometimes limited to certain subgroups of Jews, like Ashkenazi Jews.  The presence of so many founding mutations facilitates genetic testing, so in groups like African Americans, in Jews, in the Amish, and gypsies and others, where you do see this, you can get huge benefit in saving lives by doing genetic testing of racial groups, population groups, ethnic groups.  It suggests that SNPMS, single nuclear polymorphisms or microsattelite association studies, using genetic markers and linkage disequilibrium--this is probably something I shouldn’t talk about--it’s too complicated--may facilitate discovery for new disease genes.

So, I just wanted to give you taste of the fact that this, again, please we’re not framing this is simplistic notions of race, though, as Sally mentioned, our simplistic notions of race are not without some value.  They have some--they are markers.  They’re crude markers.  They can be wrong in some cases, but the reason they haven’t disappeared besides the obvious reason that there’s facial characteristics that might distinguish Jews from other groups might.  There are skin color characteristics that might distinguish people of African ancestry from other groups because there’s examples where this doesn’t hold true.

They are a crude proxy that we use in the science world, in the medical community--sometimes has negative social consequences that we have to factor in, but it is of importance.  Thank you.

What we’ll do now is take a five-minute break.  Five minutes, ‘cause we really want to--some interesting things ahead.  And we’ll convene in a few minutes with our next panelist.  Thanks.

[Recess.]

MR.          :  Oh.  Paul Goodman.  I could call Goodman, too.

DR. ENTINE:  We would like to get started in another 30 seconds or so.  If everyone can take their seats, please.

Thank you very much.  We’re now going to continue with two more panelists.  We actually had three scheduled.  Dr. Lawson, who’s the Professor and Chairman of the Department of Psychiatry at Howard University School of Medicine, was scheduled to be here.  He warned us he would be late.  And he’s late.  So, I’m sure he’s doing something much more important than this.  If he comes, he will participate in this.  If not, we clearly have enough background speakers with an interesting with an interesting background to shed light on these issues that it’s important to go forward.

Our next speaker is Vincent Sarich, who’s Professor Emeritus of Anthropology at the University of California, Berkeley; as a faculty member at Berkeley from 1996 throuhg 1994, when he took over emeritus; when he took emeritus status.

He is a Professor of Molecular Phylogenetics.  It was for his doctoral dissertation that Mr. Sarich worked out the details of human origins that were to bring him into conflict with the fossil experts of the time.  This was in the 1960s, relying, in part, on proteins and the differences among that provided a new frame work of relationships among the species involved.  He showed that the human line went through various stages on the way to bipedalism.  I’ve written about Dr. Sarich’s work for many, many years.  Many consider him one of the founders of molecular biology and the so-called molecular clock theory that was ultimately utilized to find mitochondrial Eve, a genetic Eve.  So, he’s really here with one of the most renowned geneticists in the United States.  And so, we’ll very much welcome him, and you have the floor now.
"The Reality of Race"

DR. SARICH:  Thanks, John.  I’ll just read a definition.  Races are populations or groups of populations within a species that are separated geographically from other such populations or groups of populations, inseparable from them on the basis of heritable features.

And operationally, races exist to the extent that you can take individuals and on the basis of their visible characteristics and, of course, these days their DNA characteristics, put them into the area of their origin or the origin of their recent ancestors, to the extent that you can do this, races exist.  To the extent that populations fulfill that definition I gave you, races exist.

Now, let’s take some of the things that you might believe about races, which aren’t true, and let’s try to deal with a couple of those on the way.

First, people have a way of saying these days race is only skin deep.  Well, in a way, it’s not even that deep, because obviously dark-skinned populations.  There are three groups of dark-skinned populations who have nothing to do with one another except that they’re human beings.  We have those in sub-Saharan African.  We have them in southern Indian, and we have them in the island, in Melanesia and Australia.

Those three groups are--their separations among them must go back practically to the origin of homo sapiens so that dark skin--I mean, it’s difficult to believe--is not a racial character by global standards, because having dark skin means that you belong to one of those three populations, which is not very defining.

Another question people might ask--and they got unhappy with this--all right, how many races are there?  Let’s classify them.

Well, that’s what I used to call a non-question.  You know, your question doesn’t have a productive answer.

The number of races depends on how sharply you want to discriminate among them. That could be a fairly small number.  It could be a very large number, but in any sense, it’s not a terribly productive avenue to go toward.

And the other one is--belongs to the same track--what about continuity.  Races merge into one another.  They are not discrete so, therefore, they don’t exist.

Well, we have to get past this business that categories have to be discrete.  Human beings would be in a terrible fix if they only could talk about discrete categories.  In fact, they’d have real, real problems.

There’s continuity among races because they’re not species.  If races were discrete, they’d be species.  Well, they’re obviously not discrete and you get areas of mixing.  A classic one is in the Middle East, where you had contact between African and quote "European" unquote populations.

Now, what about functional significance?  People will argue, well, races exist.  No.  They don’t exist.  Even if they do exist, it doesn’t make any difference because race has no biological significance.  I have to beg to disagree again.

If we look at human beings, we can take an old style look in terms of cranial and facial characteristics, and look at the differences in those compared to the differences we see in non-human primates.  For example, let’s take chimpanzees as a clean example.  There are two species of chimpanzees:  pygmy chimps and common chimps.

And we have a fair amount of measurement data, the classical kind of anthrometric data that anthropologists worked with for more than a hundred years.  We have such data on chimpanzees, and we have data, of course, on human beings.  And we can ask the question:  how different are human races, morphologically, that’s cranially and facially, compared to the two chimps?

Well, the percent difference, I’m not going to spend any time going into how we calculate these. I’d be happy to talk to anybody who’d like to listen about it.  But in any case, we can look at chimpanzees, and the difference between pygmy chimp and ordinary chimp depends on which ordinary chimp or common chimp you’re looking at.  But it runs somewhere between 10 and 15 percent between pygmy chimpanzees and the other species.

Now, when human beings, if we look at the same characteristics and used the same metric for measuring the differences, 10 to 15 percent is a fairly small number.  In other words, fairly closely related human racial populations differ from one another by on the order of 10 to 15 percent.

If we take a more, a larger difference, like if we compare, let’s say, Australians and Europeans, the difference is more like 25 percent, which is a more common intercontinental percentage.  And the differences can go up well into the 30 percent if we just compare sub-Saharan Africans and, let’s say, American Indians.

So, with respect to cranial and facial characteristics, human beings are much more differentiated from one another than chimpanzee species are from one another, number one.

Number two, we have to put a temporal consideration in here.  The two chimpanzees diverged more than a million years ago.  Somewhere around one, one and half million years ago into their ancestral lineages.

Human races certainly have not been separate from one another for more than 50,000 years, and most of them probably less than 25,000 years.  So that we have differentiated much more than the two chimpanzees have in a much, much shorter period of time.  So, we can get significant differences in very short periods of time.

This very much suggests that these are adaptive in some fashion.  They aren’t just sort of along for the ride.

Another of these comparisons, and this is one that John and I have sort of collaborate on over the years.  John wrote a book on it.  I’ve written just a couple of articles.  On our bipedal adaptation.  There is a notion out there that if you look at characteristics which are very important, have been very important in human evolution, there have been very strong selection against variation.

So, if we look at those characteristics, we should expect them to be highly non-variant.  Well, one of those characteristics which is evident is running.  And we know that there are differences in how well people run obviously within populations, and we’re finding out more between populations.

What sort of relative difference do we find?  Well, if you look at the east African rest of the world difference, which is the one that stands out most clearly, we can say that--again, there is not time to go into how the calculations are done--I’ll be happy to talk to anyone about how I’ve done the calculations--but we can estimate that the average for east African populations is about one and half standard deviations from the average for the rest of the world.  That is, the east African populations are one and half standard deviations on the average--

MR. ENTINE:  And this is in long distance running, you’re saying?

DR. SARICH:  In middle to long distance.

MR. ENTINE:  Middle to long distance, right.  And these are like Kenyans and Ethiopians and--

DR. SARICH:  Yeah.  I’m not going to go into the west African business, too, but that’s even more evident.

MR. ENTINE:  These people don’t have a background in sports, so they [inaudible]-

DR. SARICH:  Oh.

MR. ENTINE:  You’re bring to this, so you have to give a little bit more background.

DR. SARICH:  It’s the most important feature of our existence.

[Laughter.]

Okay  Yeah.  Talking about east Africans.  And so, in other words, about one and half standard deviations difference. This is a huge difference.  And one of my other friends, Steve Sailor [sp?], when I appraised him of this, nicknamed it RQ, running quotient.  So the running quotient would be about 122 to put it in context, up in the top five percent or so of the world.

Now. All right.  Now, another comment that people make about races is--well, John mentioned it already.  99.9 percent.  Yes.  Absolutely.  We differ from one another by on the order of one-tenth of one percent.

However, there is a comparison that is present, but never explicitly made in this realm, because--spurred first by Richard Owanton [sp?] in 1972, he put out the idea, put out this conclusion, valid conclusion, that the amount of inter-population difference it’s only about 15 percent of the total amount of human variation.  In other words, 85 percent of the variation is within populational, and 15 percent is between.

Now, let me reiterate, that conclusion--the calculations and conclusion are correct--okay--as far as they go.  However, they ignore a very important realm of variation; that is, in--not intra-populational, but intra-individual.  Okay.  In other words, you carry, each one of us carries, two genes in their bodies, two genomes.  The parental--sorry, the father’s genome; mother’s genome.

So, you differ--how do you want to put this--among yourselves with respect to this variation, and of that 85 percent that’s intra-populational, about half of it is intra-individual.  So, instead of it being 15 percent of the inter-populational differences that become--sorry, let’s try this over again.  It gets confusing.

Instead of it being 85/15, what it really is like 45/45 and 15 or 40; 42 and a half and fifteen.

So that instead of the amount of inter-populational being 15 percent, it’s more like 26 percent, because you have to take off the part that’s intra-individual.  That obviously has nothing to do with inter-individual variation.  If you take that off, then the two things that are left, split about 70, 30.  That is, inter-individual differences and inter-populational differences.

This is something which, as far I know, does not exist as a discussion in any of the literature I’ve seen.  Okay.

Now, all right.  So, we have very large--going to have very large morphological differences.  We have very significant levels of inter-populational variation.  We also have evidence, before we’ve gotten into the more modern, we’ve known about one very important area of inter-populational variation, and this alcoholism.  People have known as individuals, or course, that some of them can hold their liquor a lot better than others.  What was not clear until fairly recently is that certain human populations have great difficulty handling alcohol at all, and these are northeast Europeans, sorry, northeast Asians and American Indians.  The alcohol is fire water among American Indians may have been stereotyping, but it was also true.  And this was something that Europeans noticed very early in their contact with American Indians.  And they didn’t particularly like--it’s not as if they fed American Indians alcohol to knock them out.  For better or for worse, they wanted the American Indians to collaborate and work with the Europeans, and if you--they were perpetually out on alcohol, that wasn’t--and Europeans would be complaining about this.  So, the business of alcohol as a racial variant, susceptibility to alcohol as a racial variant, is something which was--has been evident for a long time.  Only recently has it become clear what the--and this is again a one locus, a one Mendelian characteristic.  There is a build up of acetaldehyde in these people, and acetaldehyde is a toxic substance.

Now, another one, which again goes back to early days of this sort of thing was just after World War II, when the first drug, which was useful in treating tuberculosis was developed, and this was Isoniacid.  However, it was found that Eskimos who had a real problem with tuberculosis, in fact, didn’t react to Isoniacid as Europeans did.  In other words, they reacted much more rapidly, they metabolized the Isoniacid, and, therefore, people started figuring out that they have to give them a larger dose so that it would, in fact, do its proper thing as far as tuberculosis is concerned.

Now, I’ve just mentioned here a few racial matters, and I’ll mention one racial behavioral one.  And it won’t be IQ and brain size.  Okay.  About almost 40 years ago now, a physician at the University of California at San Francisco was interested in neonatal development, and he was also interested in racial variation.  He had a Chinese and he wrote, in these more innocent days, that looking at the two of us, you’d almost think we were different species.

And an extension of this observation, he got a little study going at the hospital in San Francisco with newborns.  And they looked at the reaction of newborn humans of different races to being annoyed, if you wish.  The classic one was covering their head with a blanket or something along those lines.

And they observed a very striking difference between European babies and African American babies on the one hand, and the Chinese and Japanese babies on the other.

The former complained mightily when they were annoyed in that way.  The Asian babies didn’t care.  They sort of took it in stride.  And Friedman, Dr. Friedman, who was the person who ran this study, said once that looking at the films, which I never had the opportunity to do, it is really striking.  The audience has really found it particularly striking that you could find these differences in neonates who have had no cultural exposure of any sort.

So, what I’ve tried to do here is to bring in some notions that people have about race which just aren’t true, and other notions, which it’s important if we would, in fact, get them straightened out.

And the last go home lesson [inaudible] published in 1963 by [inaudible] Myer, who just celebrated his 100th birthday.
     [END OF TAPE 1 SIDE B; BEGIN TAPE 2, SIDE A.]

DR. SARICH:  [Inaudible].  Concept, and requires the moral [inaudible] of [inaudible] would be incapable.

Equality in spite of evident non-identity is a somewhat sophisticated concept and requires a moral stature, of which many individuals seem to be incapable.  Think about.  Thank you.

[Applause.]

MR. ENTINE:  Thank you very much, Dr. Sarich.  I had a minor accident, so if you see me with glasses with one glass missing, my glass popped out.  So, but I need it to read.  So, if I look a little weird here, you’ll understand when I squint.

We have Dr. Lawson who was held up a bit this morning; has come.  And so, we very much want to have Dr. Lawson as part of the panel.  So, Dr. Lawson, if you could come up and be there--and I’ll try to read what I have, if I can read it, considering my blindness.

Dr. Lawson, we actually had a wonderful presentation by Dr. Ferdinand about BiDil and African Americans and heart disease issues, both the social cultural, genetic entwined debate and then a number of us have presented various aspects of this debate as well, and I’m sure you will share your own experiences on the nexus of so-called race and health.  You all have Dr. Lawson’s bio in your packets, but I’ll just briefly say that he’s Professor and Chairman of the Department of Psychiatry at Howard University School of Medicine, and he’s also authored more than 85 publications on severe mental illness and its relationship to psychopharmacology, substance abuse, and racial and ethnic issues.  Dr. Lawson, thank you very much for coming.  We are setting up your PowerPoint as we speak.

Are we close on this or should we--okay.  Recognize that there’s technological limitations on these things.  Great.
"Psychiatry and Race"

DR. LAWSON:  Let’s change things.  Well, if this group probably is aware, this is a very diverse country these days.  It’s getting more diverse.  Not only that people are now choosing multiple identities, which I think drives genetic researchers up the wall.  And in a recent, in a paper back in ‘85, it was demonstrated that African Americans showed a disproportionate morbidity, mortality, including access deaths that they related to the lack of access, lifestyle.  A few brave souls even tried to say there was some genetic issues as well.

More recently, Dr. Satcher, the Surgeon General, did a very similar approach in terms of looking at mental disorders.  And there are a couple of points that came out that was surprise to the public, but well known to those of us in the field.

One is that mental disorders are common.  About 20 percent of the population.  They’re treatable.  The whole of idea of an irreversible schizophrenia, I think, has gone by the wayside.

But we find that there are many groups that do not have sufficient access.  That led to a subsequent report called the Surgeon General’s Report on Mental Health of Minorities, and one of the key points that came out of that, and it’s still a source of debate, is that there are not substantial differences in prevalence.  There may be some small differences, and we’re still investigating it, related to problems of diagnosis, misdiagnosis, but generally around the world, irrespective of culture, irrespective of ethnicity, we find that most severe mental disorders, the prevalence of it is pretty much the same irrespective of group.

But there are vast differences in terms of illness burden and there are big problems in terms of lack of access.

Now, how does this tie into the Human Genome Project and other attempts?

Well, one of the points that came out very quickly is that a least in terms of mental health and in terms of mental illness, because of this tie-in to the whole aspect of who we are, there’s been a significant concern in the African American community.

The Tuskegee story has ironically had a big impact in terms of mental disorders.  Often, when we try to encourage people to come into treatment, we are told, well, are you going to treat us like the guinea pigs that were done in the Tuskegee syphilis study?

So, there’s a good deal of fear in terms of many studies involving mental disorders related to that experience.

The other one is that there’s a good deal of concern that African Americans may be exposed inappropriately to certain kinds of procedures, such as psychosurgery and electroconvulsive therapy.  Actually, just the opposite is true.  African Americans are much less likely to get these kinds of procedures.

But there is a concern that because the African Americans are perceived of being genetically inferior, based on two important observations.  One is the eugenics movement, and most importantly the whole issue of IQ and race.  Very early on, in the debate, the issue of why should African Americans not go to the same schools as Whites.  We’re now involved in the Brown versus School of Education’s anniversary.  This had a profound impact in terms of looking at the role of genetics in African Americans, and basically one of the arguments that has been persistently presented as to why segregation should persist had been the argument that African Americans were somehow intellectually inferior.

And, in fact, the end of Brown versus Board of Education, the reason that school desegregation was actually implemented really wasn’t a legal argument at all.  It was a demonstration by Kenneth Clark and other psychologists that school segregation had negative attitudinal effects on African Americans.

So, in terms of the whole issue of genetics and behavior, I think a key part has been played out in terms of looking at the whole issue of education.

And what does that have to do with mental illness?  Quite a bit.  Because we’re now finding that there’s a good deal of suspiciousness of providing mental health services in the African American community, and that’s a whole issue in and of itself.  In brief, African Americans are much less likely to see mental health services or mental health providers because of this issue.

Now, concurrent with this, the observation I mentioned earlier that mental disorders are treatable.  But we’re finding huge ethnic differences in terms of prescribing practices of people who treat different populations.

We find that Asian providers are much more likely to give lower doses to their patients.  On the other hand, African Americans end up getting high dosages.

When we look at some of the clinical findings, we find that Asians attend at the same--given the same dose of medication.  Caucasians tend to give some side effects, such as movement disorder symptoms.  We find that there’s more of a persisting mood disorder, called Tardive Dyskinesia in African Americans.  African Americans have a lower side effects.

We already know from some of the basic research that many of the medications are metabolized through the liver, through a specific enzyme system, TYP2D6.  We find that people of African ancestry tend to be what we call slow metabolizers, and this is a simple graph showing that Caucasians tend to be on this side in terms of the number of functional [inaudible], which means that they can grind up the medication a little bit faster; and if you go on the other side, African Americans, Asians, some Latino populations, the medications are metabolized a little bit slower.

That means if you give African Americans and Asians the same dose of medication as your Caucasian, there’s more or many of the older psychotropic medications that end up in the body.

Now what as to implications?  Well, if you have higher blood levels of the medication, you think that you should give lower doses of medication to African Americans.  What we find is that African Americans get more medications from the nurses, higher doses of medications, more different medications, and more injections of medication,  and more likely to receive Depo medications.  The point is that in contrast to the genetic data, we’re finding that in reality African Americans end up on more medications, especially anti-psychotic medications.

Why is this?  Well, it partly has to do with misdiagnosis.  African Americans are more likely to be diagnosed as having less optimistic disorders, such as schizophrenia rather than depression or bipolar disorders.  This is just showing that you African Americans who don’t have psychosis are much more likely to end up on anti-psychotic medications.  This is an important cultural/social factor.

Also, it has to do with attitudes.  The less medication is prescribed.  And lower doses of medications.  So, on one hand, we have some very nice genetic data suggesting less medication is required, but then we have the practical issue that often the physician tends not to have a good relationship, especially with African American patients--different income, different ethnicity, different educational level--and consequently end up giving more medication.  Generally, and in another study, it showed that African American males in particular are perceived of to be more hostile than they actually are; end up on substantial doses of medications in different settings.

The case of lithium.  A different issue, but the same result.  We find this African Americans, and this is consistently shown, tend to have a different RBC to plasma ratio, which means that lithium which we depend heavily in terms of blood levels to see if it’s at the right dose to treat manic depressive illness; we find that African Americans given the same blood levels will end up with more side effects and poorer compliance.  So, here’s a clear cut example of a [inaudible] ethnic difference that results in the usual dose of the medication being inappropriate.

Then we also are running into a new issue in terms of health care disparities.  We already know that African Americans tend to have high rates of diabetes and their associated complications, and what we find, then, is that when [inaudible]--this is just showing you again that African Americans tend to have more obesity, leads to more diabetes and higher mortality rate, and yet two of the most popular anti-psychotic medications tend to produce more risk for obesity and diabetes for African Americans.  So, again, here’s the important implication in terms of genetic factors.

Overall, African Americans and Hispanics don’t receive evidence-based psychotherapy.  A lot people on medication don’t need to be [inaudible] psychotherapy; do not receive [inaudible] a second generation, the newer medications, and tend to receive the older medications, which are associated with the side effects that we’ve already recognize are more likely to occur in African Americans.

Part of it has to do with the fact that African Americans are [inaudible] in most studies in terms of pharmacotherapy.  And, as you know, much of the work that comes out of the National Institute of Mental Health involves research, investigator-initiated research, and a large percentage of it is not done by African Americans or Latinos; however, [inaudible] of ethnic minorities, who you often direction--direction of the research.

So, here’s an issue in which we have a public perception that there’s some bad things going on when you look at genetics, but yet we have very good data suggesting that, at least in terms of the broad cut of race, and we can get into a discussion about whether race is relevant.  For example, we find that people of Ethiopian ancestry tend to be what we call ultra fast metabolizers and may require more medication.

Broad cuts of race in which genetic factors may be important in terms of determining what doses of medications it involved; and a larger issue in which these kinds of genetic factors not only are not taken into account, but because of the way in which we provide services to ethnic minorities, we’re actually getting services in contrast to what the scientific data suggest.

MR. ENTINE:  Thank you very, very much.

[Applause.]

Our final speaker, Dr. Pamela Sankar; is that again, is that how you pronounce it?  I’m sure I’ll continue to botch it one way or another.  Is actually she--I want to discuss in context actually she came to be at this conference because she was not originally on the agenda.  In fact, we had two other people who were participating in this who pulled out this week.  And I think it’s important to discuss this, ‘cause it indicates why this is such controversial terrain.  Among the people who was supposed to be here is a Dr. Richard Cooper, Richard C. Cooper, from Loyola University Medical School in Chicago, who wrote the article that was referred to by a number of speakers in the New England Journal of Medicine three years ago, lambasting the use of race as a concept in analyzing and in talking about health disparities, raising serious questions that it was blurring social categories and [inaudible] categories.  I think he’s written some things caricaturing and parodying the issue of race and genetics.  I was convinced when I read his work, although I don’t agree with all of it, that it was a voice that needed to be heard in a discussion like this because this is important.  This is highly contested ground in some ways.  People bring agendas of various kinds.  And he had a very specific perspective on this, and I think brought some light to some of the issues that are being discussed.  And Dr. Cooper was invited about two months ago, and on Friday of last week, I got an e-mail saying that he didn’t want to participate because he was now convinced, because he had read over the agenda for the first time since he was sent it eight weeks before, that he was now convinced that this was going to be a demagogic conference on the issues of race and medicine.  I think we can all agree that that’s not what this conference was about or is about.  I did my best to try to dissuade him.  I think Dr. Ferdinand talked to him as well.  I think we were all sensitive to the potential problems when you talk about race.  This is a very prickly issue, as I said.  But he was determined to not come, and he actually lobbied Dr. Ferdinand and also one other participant, Allister Wood, who interestingly enough had written--he’ a pharmacogeneticist, Assistant Dean at Vanderbilt University, who had written an article, a letter to the New England Journal of Medicine, criticizing Dr. Cooper’s position.  So, you have people from different perspectives.  It’s not just one ideological or personal perspective.

Dr. Wood was up for, I think, to be head of NIH a few years ago.  I think he, based on my--I’m sorry.  At the FDA--and based on my discussions with Dr. Wood and his secretary and others, I think that he just felt that this could be controversial.  I think he still has ambitions to being part of the government in some form.  And he didn’t want to have any part of it.  I’m very disappointed that people would be willing to put political issues ahead of what I think is an open discourse on this issue.

But one thing, I was earlier this week and over the weekend figuring out what are we going to do?  How do we keep a conference that’s this important, that’s this timely, on track?  What should we do?  And I was very familiar with Dr. Sankar’s work, partly because she raises many of the issues that Dr. Cooper raises.  Are we rebiologizing race?  Are we essentially going down a slippery slope, however well meaning, and I think you get the sense that people here are well meaning on this issue.  But what are the problems that this issue causes?  And I felt that without that voice here, we would not be doing justice to a complex and evolving issue.

She brings other perspectives on this as well.  I don’t want to limit what she’s going to talk about or what her views on this are.  But I know that we needed someone like a bioethicist and I think this conference itself and how it evolved underscores the need for a rich range of voices when discussing something like this.  Thank you.
"Are We Rebiologizing Race?"

DR. SANKAR:  Thank you very much.  I welcome the opportunity to be here.  I think these are extremely important issues that need to be discussed in as many fora as possible.

What I want to talk about today is a slightly broader context for looking at BiDil and Nitromed, and I want to talk about the problem of language in this debate and how confusing it can be.  And then I want to look more closely at BiDil and the research design, and these are linked theoretically, how they designed the research.  And then, finally, at issues of conflict of interest and how it is that certain research is promoted and other research is not.  And, again, tying that back into the broader social context here.

Let met state from the outset that I do think a drug like BiDil is conceivable; that there surely could be a drug that benefits one group of people based on common ancestry more than another group of people, and I don’t question that based on the history of the world population migration, which maps to continents, which maps to popular notions of race.  I think that that is certainly a conceivable idea.

But I also don’t think that BiDil is that drug, and, at least, let’s say it hasn’t proven itself to be that drug.

So, what I want to talk about is not the question of is it politically correct to talk about race and genetics and pharmacogenetics.  It’s the broader question in this setting is how does a drug like this proceed and what kinds of questions should we be asking about it?

So, what I want to start out with is a series of slides that I usually put together slightly differently, but they’re a series of slides of polar opposite conclusions from data.  And usually, I line them all up with those people who say there is race and then those people who say there isn’t.  And today, I just sort of mixed them up, and the point being to emphasize that people are overstating things often the amount of certainty that they attribute to findings, and throughout the literature, race and ethnicity are not defined.  They’re changed within sentences, let alone within paragraphs, let alone within articles.

So, we started out with Alan Goodman who is the incoming president of the American Anthropology Association, and he makes it clear that race as an explanation for human biological variation is dead.  He’s got no truck with that.