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Eric Lander, D. Phil.

The following is an excerpt from an interview with Eric Lander that took place at the "Winding Your Way through DNA" symposium at the University of California San Francisco in 1992. Eric S. Lander, DPhil is a member of the Whitehead Institute for Biomedical Research and Associate Professor of Biology & Director at the Center for Genome Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.

Excerpted from the symposium transcripts with permission of the University of California, San Francisco.

Q. What is the ultimate goal of your research? What are you trying to accomplish?

EL. What we do in the laboratory is we're trying to study the basis of multi-gene diseases. For a long time people have been studying single gene diseases--diseases caused by a defect in a single gene. And technology has gotten to the point now where for any such disease it is possible to find the genetic cause.

But a lot of the diseases that affect humans are in fact multi-genic in origin, several different genes come together, often in different ways to cause things like hypertension, heart disease, diabetes, immune diseases. The frontier of genetic research in some sense is to be able to dissect out the causes of those diseases. So what we work on are ways to simultaneously map all the chromosomes of the genome at once and see how they are inherited in a family. By analyzing the pattern of inheritance, we try to figure out where the multiple causes may lie.

Q. What's a mathematician doing in this very biological field?

EL. Well, I've been wondering what I, as a mathematician, am doing in this field. It is in a sense very much an accident. But so much of one's scientific career is an accident. Although I trained as a pure mathematician, when I was finishing a set of work in pure mathematics I began casting about for something else to apply my interests to, and a good friend suggested I go study the human brain.

There are lots of great mathematical problems in the human brain. Being hopelessly naive and having a spare summer, I started reading about it. And I came away at the end of the summer realizing I didn't even know enough biology to understand what the problems were. So being even more naive, I started learning biology in my spare time. And you know how these things are--one thing led to another, I began moonlighting in labs, cloning genes late at night, and eventually took a leave of absence for a while to go down to visit at MIT and learn more about this and I guess I got hooked.

I didn't really plan to be working on human genetics, but it just got more and more interesting and then I found, as the human genome project came along, and as it became important to study the whole genome and lots of complex information at once, that there really was a nice marriage between laboratory work and mathematics. And so now I run a genome center in the laboratory that has both wet laboratory work and dry mathematical analysis and they come together very happily. It is a nice accident.

The things about the scientific careers is they are impossible to predict where they are going to go. Science is ever changing, and so all scientists have to be prepared to go with the flow. And it is much more exciting that way, a little unpredictable, and insecure, but very much more exciting.

Q. What was it about genetics and biology that was so intriguing?

EL. Well, as a pure mathematician by training I found genetics to be the most rigorous and the most clear and in a sense the most exciting and logical part of biology, because you could explain the wonderful diversity of inheritance in humans and plants and animals by a simple set of rules. And because of that you could take even really complicated traits and you could try to parse them out into their individual components. And so as a mathematician that appealed to me a lot.

From a biological perspective we were just having the revolution that made it become possible to not just do that in an abstract sense but to translate that abstract understanding to a very concrete set of genes and actors at the molecular level. And so it was just a wonderful wonderful time with this explosion of both knowledge and the ability to turn that knowledge into something useful for society.

Q. Where are we in terms of our understanding of ability to analyze multi-gene diseases?

EL. Well, complex diseases are really a new frontier for genetics. There were a couple of early studies, things like studies of manic depression, and schizophrenia, where people got barely statistically significant results and were so excited that they could see anything that they rushed to publish it. I think a lot of those haven't really stood the test of time terribly well. And it is not shocking, because they were really just on the borderline of being significant.

I think what's happened is that people have found out that it is possible to make some progress, the standards have really risen and folks are really saying, look, just like every other area of science we better build a very firm foundation. And so you see now studies of complex inheritance in animals, in mice and in rats, to try to build a firm foundation about how multiple genes interact and about how we can dissect them. And then that information is spilling out to the human. It is a very hard task. Single gene diseases have been worked on in some sense for the entire century. Multi-gene diseases are very much the work of the last 5 years or so. And so complex inheritance is a frontier for the next century.

Things like the tools of the Human Genome Project really provide just the beginning infrastructure to do it. So I'm quite optimistic about it. There are also lots of false starts in the beginning of any science. The important thing is to be sure the foundation gets laid very solidly because you can then build upon it, and over time I think begin to dissect these sorts of genetic and medical conditions.

Q. A lot of people have heard about DNA fingerprinting. Could you give me a basic explanation of what it is?

EL. DNA fingerprinting is an incredibly simple idea. It's just based on the notion that each of us has a DNA genome of about 3 billion letters of DNA. And they are almost, but not quite, identical between any two people. Any two people share 99.9% of their DNA identically. There is only about one letter in a thousand variation of DNA. But that translates, given the amount of DNA you have, into 3 million separate differences between any two people. That means everyone's genes, everyone's genome is unique. No two people, except identical twins, have exactly the same DNA.

And so if I find someone's DNA at a particular location I could in principle find out whose DNA it was by comparing its sequence to the sequence of anyone who might have left it. That is the basis of DNA fingerprinting. In fact, we don't do it that way. We don't do it by reading the entire DNA sequence, because that is just too hard technically. It would be a great thing and that is a goal of the human genome project.

But what people do in DNA fingerprinting is they compare particular regions, 3 or 4 highly variable regions, but in fact have a lot of discriminating power. By doing that you can still get a pretty unique, although not perfectly unique, fingerprint in a sense, that identifies an individual who might have left the DNA sample. So it is not hard then to take DNA from the scene of the crime. If you have a specific suspect in mind, then ask does that DNA match at each of 4 or 5 places where DNA varies, does it match your suspect?

It is easy to exclude somebody. If their DNA doesn't match at those places, then that suspect can't be the person who left the material. If they do match, well then you've got to ask how rare is it that you would find such a match? And it is a question of statistics, but people collect data bases on it and have answers to those questions.

Q. How is DNA evidence different from other evidence that might be introduced in court?

EL. Well, DNA fingerprinting evidence, it is important to remember, is primarily a way of excluding someone if they don't match with certainty. And including someone as a possible person who might have left the DNA if they do match. And so it is a probabilistic thing to include somebody, and is a certain thing to exclude somebody. It is a somewhat odd thing about DNA evidence in that sense, it is a kind of statistical thing. But if the statistics can be made quite compelling through a look at many many places where the DNA varies and you always see a match, it becomes quite overwhelming that this DNA really does belong to the person you say it does.

Q. Do you see an increased use of DNA fingerprinting in trials? And if so, does that concern you?

EL. Clearly over the long run there will be a greatly increased use of DNA fingerprinting in trials--DNA typing, as we prefer to call it, instead of DNA fingerprinting.

It is an extraordinarily powerful technology. The single place where it will be most valuable is in rape case, because in rape cases when you find a semen sample from a rape, you can compare that to a suspect and establish really with overwhelming probability--if you do it right and look at enough of the DNA--whether that semen sample belongs to the suspect. That means that a woman doesn't have to testify at a rape trial about the sexual act taking place. You can present scientific evidence instead of putting the victim on the witness stand. In addition, it is very hard to argue about mistaken identity and all the things that used to come into rape trials. I think rape is the one case where there is usually almost always some biological sample left in the form of semen, and in which it is pretty easy to make the connection that if this semen was left that was not an innocent act. Really with DNA fingerprinting I think it reduces a rape case to the only possible remaining defense, which was consent. At most the suspect can say, "This was a consensual act." There is nothing that DNA evidence can say about that, that is something outside the scientific domain of biology, but it does dispose of all the other questions if this is done right. I think it is a wonderful thing, that DNA evidence can do alone.

There will also be applications in murders, but I think somewhat less likely because it is typically the victim that leaves their blood at the scene of a murder, not the murderer who leaves their blood at the scene of a murder. And so what you will be looking for is the blood of a victim on the murderer. Sometimes you will find it, a speck of blood on a shirt or a watch, or something like that, but very often you won't. For example, if it is committed with a gun at some distance you'll never find it that way.

And so I don't want to be Pollyanna-ish that DNA will solve all sorts of crimes. It's not Sherlock Holmes. But for certain classes of crimes, and rape is right up there as the most prominent example, I think DNA will play a major role in shifting the way that courts proceed. It will really leave a presumption of guilt if the DNA does match that has be rebutted almost by a defendant. And that changes the way the courts work. In a way I worry about that. I don't worry about it when it is done right. When it is done right I'm very much in favor of seeing guilty people convicted and innocent people let go.

But of course if DNA evidence becomes an absolute determiner, an irrebuttable piece of evidence in the courts, it certainly had better be done right. Because if it were done sloppily, if people could mislabel samples, if people could contaminate samples, it is easy to concoct a scenario where an innocent person could be falsely accused and falsely convicted on the basis of DNA evidence. So the Faustian bargain we have is that when we use an ultimately powerful technology like DNA, we must practice it with ultimate care. As long as that bargain goes together, I'm not worried about the use of DNA in the courts. But it requires constant vigilance, and I think that's something we will have to work very hard to make sure continues.

Q. How can you ensure that sort of vigilance?

EL. I think it is crucial to have mandatory proficiency testing and regulation of laboratories. This is not a situation where the free market is going to take care of it. We really need the government, in the form of the federal government, to step in and set standards for proficiency testing, so that every examiner who does DNA testing who is going to go court is tested on a regular basis, perhaps an annual basis, to be sure that they can do this carefully, that they don't mislabel samples. You need to have blind testing. This is done in all sorts of medical specialties. It is taken as routine that people have to continue to demonstrate their proficiency at an activity.

It seems to me crazy that higher standards of proficiency should be demanded for those who test for Strep throat than, say, forensic examiners who test DNA that might lead someone to go to Death Row.

Q. What is the difference between genotype and phenotype and why is it so important?

EL. Genotype and phenotype are the most important words a geneticist can use. Phenotype is the appearance of an organisms. For a person it might be being tall is a phenotype, being blue-eyed, blond-haired. Those are all external descriptions. Genotype is the description of the underlying genes, the particular spellings of the genes that contribute to that phenotype. Genotype is instructions, phenotype is the result of carrying out those instructions.

Q. The interplay then, in terms of the phenotype that we see, is it solely determined by the genotype or are there environmental factors?

EL. It is very important to remember that genotype is only one of the contributors to phenotype. When you look at a person, whether they are tall or short depends in part on genes, but in part on diet. If you give kids who previously didn't have a good diet lots of milk and lots of calcium in their diet, they'll grow much taller. And so it tells us that genes play only part of the story. As a geneticist I'm extremely interested in the part of the story played by genes. But it is very important to recognize that is not the only relevant thing. The most common misconception, I think, is that genes determine your personality and your intelligence. I think that's a terrible idea for people to think that way. Yes, I'm sure genes play some role in that. But we know that parenting, and good schools and good environment have such dramatic effects on people's intelligence, on their possibilities in life, on their happiness, that to go completely to a notion of humans being genetically determined is to ignore so much of what we know about the role of environment.

The real geneticist knows that genes and environment together produce phenotype, and we can't ignore either half of that equation. As long as we keep that in mind it is fine to study the role of genes. When we start forgetting it, we lapse into a sterile kind of genetic determinism that does no one any good.

Q. Given that the media, of which I'm a member, like to report findings, and findings often involve quantitative results--and the environment is hard to quantify--are you concerned that because of the Human Genome Project we are going to tilt away from environmental factors?

EL. I'm very worried that with all the tremendous successes in genetics the press is going to ignore the other causes that are important to human beings, ignore the environmental components. Just because we are making all these wonderful discoveries in genetics doesn't mean environment has become any less important.

It is just that we geneticists who are undergoing the scientific revolution can do so much more than we ever did before. We don't study environment. We're looking "where the light is good" as in the famous story of the drunk who is looking for his keys in a parking lot where he lost them. He is looking under the street lamp, and someone comes along and asks, "Why are you looking for your keys here? Did you lose them over here?" He says, "No, no, I think I lost them over there in the dark, but the light is good here so I'm looking here." Scientists look where the light is good. We make tremendous progress by doing it. Society can't forget that that is all we're doing, looking where the light is good. If the keys aren't lost there, then we are not going to be finding the keys to society's problems.

I don't think genetics holds the key to our problems of education, and schools, and possibilities for children. I think in fact we as a society hold those keys. We have a lot to contribute to medical advances. I don't think we have a lot to contribute through genetics to solving the problems of education and homelessness and we better not forget that. So as the barrage of headlines continues to come out about genes play a role in this and genes play a role in that, I don't want to see the media expecting that the geneticists can solve those social problems. We can't.

Q. Jumping back a bit, you started in math. When did your interest in science start? What traits do you think are important for scientists to have?

EL. What traits does a scientist have to have? I think the single most important trait of a scientist is playfulness and curiosity. People think about scientists as being very erudite, very detached people. In fact, almost all scientists start with playfulness and excitement and curiosity about the world. Scientists are just big kids. They want to know how things work. They are curious about the world. They love to ask questions. There is a giddy delight in getting back answers. It is even fun to be wrong sometimes. It is a lot of fun to be wrong sometimes in interesting ways.

Scientists I think do so well when they keep the playfulness of childhood and of children. I've got young kids and I observe their absolute wonder and fascination with the world, and they ask all sort of wonderful and outrageous questions. That's what scientists have to do to keep productive, is to ask wonderful and outrageous and innocent questions about the world. Then they have to be trained to get answers in very rigorous, very cut-and-dried sorts of ways. But the part that the public sees there, the scientists in the white coat carefully working on something, it is a very small part of the picture. The scientist is very much more a free spirit, wondering and playing, and that I think is what drives a good scientist. Beyond that, lots of training, lots of years, but without it there is none of the excitement that makes it worth doing and none of the drive that leads to really novel answers.

Q. What would be your advice to a high school student who might be thinking about science as a career?

EL. My advice to a high school student interested in science as a career would be to forget all the stuff they tell you in the textbooks about the answers. My advice to a high school sophomore or junior considering a career in science would be to close the science textbook for a minute and forget all the answers that their texts purport to be telling them.

What you should steep yourself in is the ignorance, in what we don't know.

What is fascinating about science is to define the questions.

When we teach science in the high schools we try to teach people all the answers. Well, that's the answers to old dusty questions.

What we should be teaching people is how to ask good new questions. It is a tremendous art to ask good questions. To look at a situation and see that there is something going on and articulate clearly what is it that you want to know about that. To be willing to risk and to explore.

I'm sorry in a way that we don't capture it in the high school textbooks, high school curriculum, because we have to impart knowledge. But in fact it is ignorance that drives us. If we had knowledge about everything there would be no point in going into science.

And so what we have to do is convey our tremendous excitement about our ignorance, the wonderful potential of ignorance, and then we have to teach people how it is that you take raw ignorance and turn it into processed ignorance, and processed ignorance, well-defined ignorance, well-asked questions that we don't know the answer to, that's the root of experiment. It is processed ignorance, carefully constructed ignorance, and apply it to the situations.

I think kids interested in science should look around the world and start asking questions. And don't worry so much about all the facts that are in the books. Ask questions.

Q. Given that all of us can be identified by DNA, and we could identify predispositions to diseases we might get in the future, do you have concerns about the privacy?

EL. I've been worried about keeping the DNA information that we are going to learn about people private. It is really important to be able to look at someone's genome and know that because they've inherited a particular type of a gene they might be at risk for diabetes, because it means that you might be able to intervene early and prevent that disease from having the ravages it usually has.

Unfortunately, if you get that information, your insurance company is going to want to know. They'll ask, and if you don't tell them, then God forbid you develop the disease. They'll cancel your policy because you withheld important information that you were aware of. I think it is a real tension.

We need to know our own genetic make-ups in order to seek medical care, but the notion that we'll have to turn that over to insurance companies will discourage people from getting that information. What a terrible situation for a parent to be in! To be asked, "Would you like to know whether your child will be at risk for Type I diabetes?" But if you find out that your child is at risk, you will have to tell the insurance company and you will lose the medical coverage. What a terrible choice to be put in.

There is no solution to that other than legislation to protect privacy. The insurance companies are doing nothing evil in this. They are trying to collect information as best they can to assess risks. And if any one insurance company didn't collect this information to protect people's privacy, their competitors who did collect the information would do better in an economic sense. So if all the insurance companies are barred from doing this, then none of them suffers. That is the reason why this is a quintessential problem for us to address at a societal level by legislation.

Q. Are we all created equal, and if not, then what does that mean in this society?

EL. Genetics sometimes makes people wonder about the phrase, "All people are created equal." We are all created equal in the sense that we all have the same wonderful rights, the same entitlements to enjoy ourselves, fulfill ourselves. When we say all people are equal that is a statement about all people's ambitions and aspirations and the right to fulfill those. In no sense are we all equal if you look at height, weight, skin color, hair color. In fact we are riotously different, and that is the wonderful thing about the human species. We are spectacularly different. We revel in our differences. The fact that we are different though at the level of phenotype, the level of appearance, doesn't mean that we're not equal as people. And that is the distinction. Sometimes people forget that because genetics points out many differences amongst us, it somehow erodes our fundamental belief that we are all equal. Those are two very different concepts.

Q. One can make the argument that if we have limited resources that we would spend our resources on those people who would benefit most by them--a kind of triage. Would that concern you?

EL. I don't know enough about rationing--medical economics--to give a sensible answer. I'd really like to, but I don't have a really clearly thought out position I'm going to defend. It's hard. Resources are finite and how you allocate them is a mighty hard one. I wish I had some wisdom to offer on that, but I don't.

Q. Some people may want to use genetic information to try to rank people on a kind of intelligence scale. Is that very useful?

A. I'm concerned that people may try and use genetics to rank people on an intelligence scale. Americans have a real fondness for putting everything on some linear scale when it comes to intelligence, saying whose the smartest, and the second smartest, and ranking everyone in a class like this, instead of appreciating that intelligence is a pretty diverse thing. There are many different kinds of intelligences.

I don't understand how Americans can buy the notion of a single linear IQ when in fact no American would buy the notion of an AQ, an athletic quotient. If I tried to get two red-blooded Americans together and argue over who was the best athlete of all time--we could take Bo Jackson, we could take Larry Bird. They would start saying, "Well, you can't compare them, they're different in different ways, they're each excellent in their own way." ...You can't rank athletes on some linear scale. I think everybody would say that.

And yet we buy the notion that you can rank people according to a linear scale of IQ. I think there is altogether too much fuss in trying to rank people in some order. And a little bit too little attention to enjoying the many different diverse talents people have. I hope genetics is not used as a way to try to rank order everybody, to say who is better and who is worse. Genetics certainly has nothing to say about that.

Geneticists know that the strength of a species comes from its diversity, from the fact that the population as a whole can respond in many different ways to many different situations. No one wants a monomorphic, an identical population where everyone is the same. There is no best human trait, best human appearance, best human phenotype that we should strive for. It is the diversity and the appreciation of that diversity that we should strive for. I hope we remember that that is what genetics tells us about, those are the lessons of genetics, and not try to pervert genetics to some social cause of making us all live up to some unique standard on some scale.

Q. Other periods of time have seen tremendous explosions in ideas and technologies. In that vein how do you see these items?

EL. These are one of the most exciting times to live through for science. There are brief periods, 50 years or so, in the history of a science where everything explodes, when there is revolution upon revolution upon revolution.

These are the most exciting times for biologists. Starting really with the discovery of the structure of DNA and its role as the gene, up to the present, there has been an uninterrupted series of revolutions occurring every five or eight years, each revolution having the seeds of the next revolution within it, each creating the technologies and posing the questions that get addressed in the next revolution. And every one of those revolutions within the last 40 years has been followed by people saying, "Well, this has got to be the end, clearly we've reached the pinnacle." And yet the breakthroughs come again. I don't see any stopping in sight for the next 20 or 30 years, well into the next century, with the Human Genome Project, with technologies of transgenic constructions. It seems to me that we'll be continuing to get answers and posing new problems and creating new technologies just as far out as the eye can see.

What an exciting time for scientists to live in, where all assumptions have a half life of 4 or 5 years. And where the impossible takes just a little longer.


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