Do you know who you are?
Many of us spend an entire lifetime trying to answer that question.
Physician-scientists like UCSF's Esteban Burchard, MD — who operate more on a genetic than a psychological plane of existence — can't wait that long.
Well, people are different. This is not as simple an answer as it seems.
Our genes help to determine how prone we are to certain diseases. And the environment can be a trigger or a muzzle — or sometimes both.
It's a complex interplay and one that Burchard, a native San Franciscan, has dedicated himself to sorting out, particularly when it comes to asthma and Latinos, whose rates are high and climbing.
The sorting-out also extends to the very term Latino, which encapsulates more than 500 years of history, waves of migration, thousands of miles of geography, and populations that mix European, Native American and African gene pools.
Not knowing who we are can have serious consequences for our health. Some Latinos — Puerto Ricans, for example — are far more likely to get asthma than others, and react differently to the drugs used to treat it. In short, a drug that saves the life of one Latino could be useless in another.
Understanding the genetics behind asthma risk not only helps asthma sufferers; it also validates epidemiological and genetic approaches to other racially concentrated diseases, such as multiple sclerosis, which only strikes Caucasians or non-Caucasians who carry European genes.
Far from daunted by the size of his research task, Burchard is energized by it. Indeed, he calls his work "complex and beautiful." And he credits the career choice that brought him to this moment to the fish in San Francisco Bay.
- Esteban González Burchard, MD
- Latino Populations: A Unique Opportunity for the Study of Race, Genetics and Social Environment in Epidemiological Research
- American Journal of Public Health (2005), 95:2161-2168
Jeff Miller: Hello I’m Jeff Miller and welcome to Science Café. Today I’m with Esteban Burchard, assistant professor of biopaharmaceutical sciences and medicine in the UCSF school of pharmacy and the UCSF school of medicine. Welcome Esteban.
Esteban Burchard: Thank you.
Miller: Can you define what biopharmaceutical sciences are, please?
Burchard: well how I view it is it’s the enterplay with biology and drugs, or, pharmaceutical agents. Our biggest focus is on how drugs differentially effect different populations based upon their genetics, or pharmacogenetics.
Miller: Is this a new field?
Burchard: Pretty much, very new.
Miller: Unique to UCSF?
Burchard: No, but UCSF has a very strong track record and a very deep pool of talent here all focusing on pharmacogenetics.
Miller: I know you were trained as an epidemiologist, but I don’t know why you chose that field. Could you tell me about that?
Burchard: Well, my initial training was as a physician-scientist, and so I’ve always been trained with the interest of what we call translational research – basically, taking basic laboratory findings and applying them to patients or vice versa. And as I got deeper and deeper into the field I recognized that I needed additional training which would allow me to explain why there differences in disease prevalence across populations, or disease severity, and that’s why I went back and got additional training in biostatistics and epidemiology.
Miller: Does it ever work the other way –- people interested in epidemiology, going back to get MD degrees?
Burchard: Yes, but less so than the people going with MD degrees getting epidemiology degrees, and I think it’s because being a physician –scientist, you are exposed to just a vast array of fascinating factoids, differences in disease rates; incidents; prevalence; everything, and for some folks it’s a curiosity, a drive for them to go back to school to get additional training to help explain why they’re seeing what they’re seeing.
Miller: Are physician-scientists a dying breed?
Burchard: Yes, it’s pretty well documented in the U.S. at least, by the National Institutes of Health, that the pool of physician-scientists is markedly going down. And that is due to a variety of reasons; A lot of it is economics, a lot of it is the additional training that is required of physician-scientists, a lot of it is a lack of incentives, one can do much better in private practice than they will in academics pursuing science and medicine.
Miller: So a physician-scientists is clearly a person tied to an academic environment…
Burchard: Yes. However, there’s been the development of several at the biotech companies, like Genentech which is a great example, where they’re doing very much cutting edge research. It’s very much an academic environment, but now in the private sector.
Miller: Was there anyone in your family with a scientific background?
Burchard: No, not at all.
Miller: Where did you grow up?
Burchard: Here in the Mission District, San Francisco. My mother was a migrant farm worker and taught her self English and went to college. My father was a blue-collar person, and got his high-school degree in his late sixties.
Miller: In his late sixties…
Miller: That must have been an inspiration.
Burchard: My Mom was the inspiration. My parents divorced when I was very young, and so I grew up in a single-parent household with five children. I was taught very young to be very independent, very hard-working – I got my first job when I was nine-years-old working at a flea market, and I just have been very independent ever since.
Miller: does that attitude reflect your career choice?
Burchard: My career choice is complicated. I think, to be honest that when I was very young my father would go to the shipyard bars, and in order to go he would have to take me. I’d have to sit there for hours on end, and I developed an interest in fishing. Sitting for hours on end at the beach, and watching the fish come by, that’s how my interest in science initially developed.
I was fascinated by biological life, marine biology in particular, and in college I started off as a marine biology major. Once I got into the science field, I realized that there is a whole candy store, sort of speak, of scientific interests that I was now being exposed to, and as I got deeper and deeper into it I switched majors to molecular biology and subsequently moved to medicine, and I’m STILL fascinated by it.
In fact this past weekend I was at the Exploratorium, and my wife was telling me how the “kid came out of me” – I stayed there for eight hours doing all the little science experiments, and looking up probabilities; looking at all the harmonic synchronization; everything about science came out, and it’s just fascinating to me.
Miller: Do you suppose that first interest in marine biology is what might help explain your interest in the environmental impact and the interplay with genetic factors and disease?
Burchard: Definitely, Definitely. As I got into marine biology I quickly moved to molecular biology and that was the foundation for my exposure to genetics, and as I got deeper and deeper into the field I recognized that it wasn’t all genetic, and I developed a strong appreciation for environmental factors.
But then our own research just opened up my own eyes, and impressed upon me how strong genetic as well as environmental factors were in the development of disease.
Miller: I know it’s hard to sometimes sort out which is which, this interplay between genes and environment, I know that you have a particular interest in asthma, a chronic disease whose prevalence is increasing. I know that it’s most common in Latinos of Puerto Rican dissent, so do we know why that is, and how did that first become known?
Burchard: This is really really cool. Back in 1996 -97 when I was a medical resident, I was working in the laboratory of Jeff Drazen at Harvard med school, and we first were looking for genes related to severity of asthma, and we identified a genetic risk-factor that was associated with asthma severity in Caucasians, and that risk-factor was almost twice as prevalent in African-Americans.
And this is important because African-Americans have a very high asthma-mortality rate – so much more severe asthma than Caucasians, so I postulated that perhaps genetic factors could help to explain some of the differences of severity of asthma.
At the same time, the Centers for Disease Control published a poster demonstrating that Hispanics (and they lumped everyone together), that Hispanics in the north-east had much much higher rates of asthma and much more severe asthma than any other population in the U.S. And they also demonstrated that Hispanics in the west and the Southwest and the Midwest had low rates. And being Hispanic myself, having lived on both coasts, the east coast and the west coast, I quickly hypothesized the difference really was Puerto Ricans versus Mexicans.
So we initiated at that time a study called “The Genetics of Asthma in Latino Americans” to compare those two populations.
Miller: Now had anyone come to that conclusion before, that it was Puerto Ricans versus Mexicans?
Burchard: No. So we were the first to hypothesize it, and we were funded to do the research, and subsequent to that, the Centers for Disease Control published a follow-up study to their initial paper demonstrating that it was indeed Puerto Ricans versus Mexicans. But by that time, we had already begun our study.
Miller: Now, asthma rates are rising among all populations. Do you care to speculate on why that might be?
Burchard: Well, clearly, it has to be environmental factors, but there could also be an element of reporting biases, perhaps we’re reporting it better than we were in the past, but the rate of rise is so fast that it’d be too fast for it to be explained by genetic differences.
But, we know that asthma runs in families; we know that there is a very strong genetic component to asthma. What intrigues me, and what drives the basis of our research, is that there are population-based differences and we believe that genetics in part, not entirely, but in part, may help to explain some of these differences.
It is intriguing that the populations with the highest and lowest prevalence of asthma in the U.S., and almost in the world, are two Hispanic populations, and that is intriguing because -
Miller: And which are those?
Burchard: Puerto Ricans have the highest prevalence and severity and death-rates and Mexicans have the lowest, and everyone else in the United States falls in between there. It’s intriguing because Hispanics are a relatively young population, created in 1492 when Christopher Columbus came to the New World; they’re a combination of three ancestral groups: Caucasian, native American and African, and the rich ancestry of Hispanic populations provides the intrinsic variability necessary to untangle genetic from environmental factors, and that’s one of the main reasons we are focusing on Hispanic populations. And we could do this with other populations, but this is the population we started with.
Miller: So you have to really understand patterns of history as well as science.
Burchard: Yes, and that’s the fascinating thing about what we do. It’s not just working with the test tubes, or just seeing a patient, it’s actually trying to understand different layers of complexity, from environmental factors to historical factors to demographic factors to genetic ancestry, then to understanding how drugs work in different people and different populations and so forth.
Miller: I want to get on the point, the differences in how drugs work. So, in general, I think I read someplace that a lot of mass-market drugs really only work on 30 percent of the population they’re intended for. So already we have a problem. But then there are further problems that you’re elucidating around ethnicity.
Burchard: Well, we know that drugs work differently in different populations and the classic one that everyone knows about is alcohol. In some populations, particularly Asian populations who drink alcohol, a lot of individuals of Asian background will turn red, have facial flushing, it’s an uncomfortable feeling, and in other populations that won’t happen, and so if you equate alcohol to the drug, you’re having a differential effect in different populations.
We know the same is true for some anti-hypertensive medications, where they might work better in some Caucasians and work less effectively in African Americans and some drugs work better in African-Americans versus Caucasians.
Now, there were even in the past, in the recent past, guidelines created to guide physicians on which drugs to use in which populations based on ethnic background. Well, race is a complex construct, and is probably a proxy for a variety of factors: social factors, environmental factors, but also genetic differences between populations. And we believe some of these genetic differences may help to explain differences in drug response, and that’s what has been coined “Pharmacogenetics”.
And in our own research we’ve demonstrated that when subjects of Puerto Rican background were compared to subjects of Mexican background, Puerto Ricans by and large had much lower response to the most commonly prescribed asthma medication in the world, which is Abuterol, than Mexican children, and that has significant implications because, here you have a population that has the highest asthma prevalence, they have the highest asthma death rates, yet when Puerto Rican children reach for their inhaler they don’t get the same bang for their buck as any other child. And that, in our view, merits further exploration.
And to date, what we have subsequently identified is that there are genetic factors that helped explain some of the differences we saw, in differences in drug response between these two populations.
Miller: And are there drugs that now exist that actually work better based on what you’ve learned?
Burchard: Yes, from the GALA study we demonstrated that, in Puerto Ricans there are drugs, leuketrines For example, work better in Puerto Ricans than Mexicans, whereas inhaled coricol steroids and regular Albuterol work fine in Mexicans but not are as efficacious in Puerto Ricans.
Miller: You mentioned the GALA study which stands for Genetics of Asthma in Latino Americans, so how long has it been going on, and in addition to what you just mentioned, what other things have you learned?
Burchard: The GALA study started in 1997, when I was a medical resident at the Brigham women’s hospital in Boston, and subsequent to that I brought it to San Francisco, I initiated it with the help of several people during that time, Jeff Drazen, Scott Weissman, Ed Silverman, and then I brought it to UCSF where we solicited the help of a variety of folks not only here at UCSF, but at several of the other clinical centers where the GALA study was taking place: Harlem, Puerto Rico and Mexico city.
Since coming to UCSF we’ve also initiated a study called SAGE, a study of African Americans, asthma, genes and environments, and that’s a case-controlled study of African American children with asthma here in the Bay Area.
Miller: So how many patients have you studied so far in the GALA study?
Burchard: It was a family-based study, so in that study we recruited mom, dad, and asthmatic child. We had a total of about 700 families so that’s at least 2,100 individuals, and we also had healthy controls from two of the sites. So in total GALA consisted of about 2,800 individuals. And the SAGE study has 500 people. We have started recruitment for GALA 2, and we’ve changed the name somewhat, but it’s called: Genes, Environments and Admixture in Latino Asthmatics, and the purpose of that study is to better characterize environmental factors as well as social factors which we believe may play a role in causing asthma, or modifying asthma severity.
Miller: Is the GALA 2 study a multi site study as well?
Burchard: Yes it is.
Miller: And what other sites are involved?
Burchard: Two sites in Puerto Rico, on site in Harlem New York, a site in Chicago, a site in Houston Texas, and the San Francisco Bay Area. The GALA 2 has five sites, and also have SAGE 2 going on, which involves Kaiser of Northern California.
Miller: So the first GALA study is now complete, so in addition to what you mentioned about the differential effect of drugs, were there any other key findings?
Burchard: We’ve identified several genetic risk factors that were present in one population and absent in another population, we’ve identified gene environment interactions, and that’s fascinating because clearly the environment’s changing but now everyone develops asthma, so what we demonstrated was that individuals who had a genetic risk factor, and who were exposed to the right environmental challenge, develop more severe asthma than individuals who either just had the environmental risk factor or the genetic risk factor.
So really, it’s a gene/environment interaction, almost like a two-hit phenomenon. It requires two risk factors to develop more severe disease than if you just had one alone.
Miller: Were there any surprises along the way, maybe in some of the patients who self-identify as a different ethnicity and the genetics showed otherwise?
Burchard: Yeah, that’s fascinating, and that’s one of the fascinating things about what we call admix populations, populations that are a mixture of two or more ancestral groups. In the U.S. the classic groups are Hispanics or African-Americans, even Europeans to some extent have varying ancestral proportions from different European groups, but Hispanics have been classified as almost a homogenous group, or a monolithic group, and a lot of our work has demonstrated, using what we call forensic markers or ancestry informative markers, that we can calculate the percentage of an individual’s racial background, and really categorize them based upon that.
And so, despite our best practice, which was to only include subjects who self-identified themselves, their biological parents, their biological grandparents as being 100 percent pure either Mexican or Puerto Rican, we saw a striking variation in the true racial composition of those individuals, so we had Puerto Rican individuals who were 100 percent European, we had some that were 100 percent African, some that were a third European, a third Native American and a third African. Yet they all self-identified as being Puerto Rican.
And the same was true for Hispanics. Clearly, Puerto Ricans have more African ancestry than Mexicans do, and Mexicans have more Native American ancestry than Puerto Ricans do, yet their all classified as being Hispanic, and we believe that it’s this intrinsic variability, (genetic variability), that we can use to help disentangle genetic from environmental risk factors that may be generalizable to all populations.
Miller: So do you suppose an off-shoot of this will be to actually be able to identify what a native Puerto Rican actually looks like genetically? Is it possible to do that, or is it even worthwhile?
Burchard: Well, each of those individuals that were put in our study will tell you they are native Puerto Ricans, and so, that’s part of being Puerto Rican. You’re a mixture of three ancestral groups by and large, and there have been subsequent waves of migration that probably led to the increasing complexity where there are individuals who probably have Indian or East Asian ancestry and ancestors from all over the world that are Puerto Ricans.
That’s the complexity, but it’s also the beauty of it, it’s hard to put down what it means to be truly Hispanic. Clearly, there’s a social component but as well, there’s a genetic or biological component.
Miller: Do you suppose there’s some general principles you will have learned that might help explain for example why Scottish people have the highest rates of MS in the world?
Burchard: We’re still on the hunt for genetic risk factors that help to explain differences in multiple sclerosis or MS, but what is fascinating is that one can use racially mixed populations to help identify new genetic risk factors, and one of the best examples of this is done here at UCSF, by Steve Hauser’s group and Jorge Oxenburg, and they initiated a study based on the premise that it’s well known that only Caucasians develop multiple sclerosis, it happens in no other group than Caucasians. However, in the U.S. it does happen in African Americans.
Also, in the U.S., African Americans are on average, 80 percent African and 20 percent European, so if you go on the presumption that it’s due to a European genetic risk factor, all those African Americans who have MS presumably inherited the European genetic risk factor. So they paired up with Montel Williams and got on the Montel Williams talk show, Steve Hauser did, and made a plea to the African America community that if you have Multiple Sclerosis send your DNA to UCSF.
And by using these genetic risk markers that can differentiate African from European, they were able to exploit the variation within the African American population to identify novel, never discovered before genetic risk factors for multiple sclerosis that will be a benefit to all populations whether Caucasian or African American populations that suffer from Multiple Sclerosis. So that is a perfect example of how one can use the rich variation in genetic ancestry or the history of a population to uncover novel risk factors that are generalizable to all populations.
Miller: Let’s get back to environmental containments for a moment. Let’s say just say that we were able to identify that there’s some increase in particulate matter that was related to the increased prevalence of asthma among all populations. Would we be able to do anything about it? How do we take that information and move it into the policy arena?
Burchard: Well, clearly, if we determine that there are environmental factors such as second-hand smoke that differentially effect some populations more severely than other populations, we can use that information to set environmental thresholds on where we set the bar for allowing either second-hand smoke, or places where we allow second-hand smoke, or, acceptable levels for a given population.
One of my graduate students by the name of Max Seibold has demonstrated that there are genetic variants in a gene that metabolizes one of the most common environmental challenges which is called chitin. He demonstrated that individuals that had a genetic variation in this gene that had a hyperactive enzyme, were better able at metabolizing or chewing up the environmental chitin, versus those individuals that didn’t have this mutation.
What’s interesting is that the new surge in antimicrobial soaps, or antibiotics, has basically depleted one of the best metabolizers of chitin which is bacteria. And so this sort of research may put a break, sort of speak, on what we determine as being acceptable behavior, spraying everything with antimicrobials before we touch it, may actually be causing or contributing to the increased development of asthma, so we may have a second thought before we apply the antimicrobials…
Miller: This is the so called hygiene hypothesis: we don’t play in the dirt anymore.
Burchard: That’s right. As physicians we’ve already changed our practices, whereas before we might have been very quick to prescribe antibiotics to children who had upper respiratory tract infections or URI’s, we now have a second thought, because we know that URIs down the road actually confer some sort of protection against the development of not only asthma, but other immunologic disorders.
So we recognize that it’s a clear symbiotic relationship between us and our ambient environment and the ambient microbes that exists within our environment.
Miller: Estaban, thank you so much, you’ve given us so much to think about.
Burchard: Thank you, it’s been an honor to be here.