The Einsteins of the 21st Century

The revolution in physics in the 20th century rested disproportionately on the accomplishments of a handful of scientists (Albert Einstein comes to mind) who supplied key insights at just the right moments. The current explosion of discoveries in the biological sciences is no different. NEWSWEEK ASKED 10 of the most esteemed biologists where they think the revolution is taking us. Which among them will turn out to be the Einsteins of the 21st century? You decide.

NEWSWEEK: How did you get two of the most competitive research universities to team up?
[Laughs] We're not really competing against each other. We're competing against cancer, diabetes and heart disease. There's a fantastic opportunity to tackle disease, but only if we work together and bring together biologists, chemists, mathematicians and engineers. If there really is a chance to cure cancer, wouldn't you rather be part of the team to pull that off than to work on your own and not pull it off?

One of the most important recent observations is that disease-causing sequences of DNA are present in most of the population, but cause disease only when they're present in quantities that top a certain threshold. How is this understanding going to lead to treatments?
When we talk about why people get a disease, there are multiple components. There are inherent risks, and there are environmental exposures—and it's about a combination of those. We know that certain diseases are becoming more prevalent these days—asthma, for example. It's not because genes have changed; it's because environmental triggers have changed. So when we say we're looking for the genetic risk factors, we're mindful that genetics is only part of the story, but it happens to be the part of the story that we can understand today, and it's going to point us to the cellular mechanism that's wrong. For most diseases, we don't know the underlying molecular mechanism that's gone awry. Genetics is a very good way to pin down the system that has gone awry—to figure out which genes and which biological pathways [are behind disease]. But it doesn't mean that you're going to treat it by genetics. It might be that, once genetics lets you understand what pathway has gone awry, the best treatment might be a drug or a diet.

You've developed technology that has allowed geneticists to focus on pieces of DNA all over the genome, not just in specific genes. But how do you know where to look?
You don't. The tremendous power of the human-genome era is that you don't [have to] target specific sites. In fact, it's not possible to follow the entire genome. So if you're studying cancer, you can look for mutations anywhere in the chromosomes. If you're studying inherited diseases like diabetes, you can look for inherited genetic variations anywhere. In the past, you had to guess a couple of locations and just look there. You had to roll the dice. What the human-genome era is about is being systematic and doing the entire genome in an unbiased fashion.

What's your next big innovation?
We can now do most of the things we want to do to systemically track the whole genome, but the costs are still dropping. We are entering into a period over the next five years where all of the technologies that have been proven are going to begin to be used routinely in clinical research. And that's an exciting period.

What will that mean for ordinary people?
In the 20th century, we didn't know the biological basis of most diseases. If there's a biocentury ahead, its foundation is in knowing the biological basis for disease. That's what these tools for the genome have brought us. It doesn't mean we can cure them. But it does mean for the first time that we will have met the enemy.

NEWSWEEK: When you first developed DNA sequencing technology in the 1980s, did you foresee where it would lead?
Hood: The most eye-opening experience I had was in 1985, [at] the first meeting on the Human Genome Project. I became convinced then that the project was going to be transformational. But 90 percent of biologists were bitterly opposed to it on really doctrinaire grounds—it was Big Science, so it must be bad, or there wasn't going to be any interesting information. And it was very hard to change people's minds over the first few years. One of the bitterest opponents was the National Institutes of Health, which ended up being a major funder of the project here in the United States.

That's a nice irony.
Scientists are conservative, and they feel uncomfortable with big changes. I've had five experiences in my career where I proposed some change, and every time the reactions were the same. In the end, of course, you had to prove these changes were going to work. But you also had to go out and build completely new organizational structures to let the ideas achieve their full potential. To make [the Genome Project] work in the context of NIH, we had to establish a completely new institute whose only mission was sequencing the genome.

What's the most surprising research being done with the techniques you've developed, such as DNA sequencers? What has shocked you most?
The realization that biology is an informational science, and that there are really two pieces of biological information. One is the digital code of the genome, and that's what the sequencer lets us translate. But the other is the way the environment impinges on the genome and changes it. We can now analyze biological complexity in ways we could never have conceived before.

The other point is that living organisms have had 4 billion years of evolution to figure out really clever solutions to integrative computing, to material science, to spectacular new kinds of chemistries. [Biology is] going to make major contributions to other kinds of scientific disciplines. Biology is really going to be dominant science in the 21st century because we have the tools now for solving biological complexity.

What are you working on now?
One of the big technological changes that will be transformational in biology is single-cell analysis. [We'd like to be] able to read the biological information of the DNA, the RNA and proteins inside a cell—to actually interrogate individual cells. I have a great deal of confidence—and this is all experimental and hypothetical at this point—that we'll be able to ascertain the past infectious history of an individual and the current status.

What will that do for patients?
In 10 years there will be devices in every home on which you can prick your finger. [The device] will take protein measurements to diagnose what disease you have and where it is and how far along it is.

NEWSWEEK: Where is genetics research headed?
Preventative medicine. The No. 1 theme I have is, there are no yes-or-no answers, or very few that will ever come out of the human genome. [But] you don't have to have 100 percent certainty to avoid risk and take preventative medicines. People talk about personalized medicine, with drugs made for each person. I don't think it will ever happen in that way. Statistical information can be very useful in prevention. As we get more of these genomes [sequenced], statistics will start to have an impact on people's lives.

NEWSWEEK: What's going on in your lab these days?
Since the genomes have been sequenced for humans and hundreds of other organisms, there is a new level of interest in how the genes interact and work together [at] the system level. That's what we work on. I've worked most of my career with yeast—the same organism that makes beer and bread—and it turned out to be a very good organism to work with, for genetics, biochemistry and evolution. We're trying to figure out how the genetic circuits are wired, and how they interact with each other because, for the first time, we have the ability to look at what all the genes are doing at once.

We also have both undergraduate and graduate programs that support this kind of research, because it requires that you not only be a biologist but also be good at quantitative things and computation.

In what way do you think this will ultimately be beneficial?
Under some circumstances when yeast stop growing they will stop their cell cycle in an orderly way and conserve the remaining nutrients, glucose especially. And in other cases, they will [come to] a disorderly stop and waste the glucose. This is also a characteristic of cancer cells. They can't stop their cell cycle in an orderly way and they waste glucose.

So could this help in cancer research?
Well, in understanding, yeah. Basically the thought is that if we really understood the integration of metabolism and the cell cycle in yeast, [we may understand the same processes] in higher organisms, like our own cells. What we understand in simple systems can sometimes be enlightening for the more complex ones.

Starting from the fungi and going all the way up to humans and birds, the basic organization of the most essential functions of life are conserved. So, we're all built on the same basic plan. Understanding comes when you are really able to dissect something. That's much easier to do with a simple microorganism like yeast or a little worm than it is on trying to work on humans.

How do you think this will be important in the future?
There's a modest possibility that we'll discover something that's directly of use—a protein, for example, that has to be inhibited in order to make something go away. But yeast is something very far from humans, so I think that such a direct find is relatively unlikely. But you can understand how the system works and then find the analogous system in a higher organism and have a go.

NEWSWEEK: You are trying to sequence the genome of a Neanderthal. Why?
The genetic differences we find between humans and our closest relative—who happens to be extinct—will tell us how fully modern humans were able to spread over the world, develop technology, start producing art, and so on. By sequencing the genome we will be able to make a catalogue of all the genetic changes that happened in our ancestors after we separated from Neanderthals, and this will help scientists identify which genetic differences are unique to modern humans.

This a good time to be a biologist.
It's certainly an extremely exciting time to be a biologist. We've seen the determination of the first genomes of single individuals by Craig Venter and James Watson, and this is just the beginning of the determination of many hundreds of thousands of individual genomes. This will vastly increase our abilities to look for genetic contributions to diseases and other human traits.

Would you call this a revolution?
It is of course always very hard to realize if you are experiencing a revolution when you are in the middle of it. Let's not forget that when we discovered the structure of DNA in the 1950s, which in hindsight we would say was truly revolutionary, it actually took around four years before anybody realized it was important. It may certainly be that we overlook things when we're in the middle of them.

Right now there seems to be a number of simultaneous advances in biomedicine. [But] I would not necessarily say that there is a reason why. At the moment there appears to be some sort of synergy between a number of fields, but this is possibly an illusion.

How could your findings benefit people down the road?
In the long run, aspects of what we do might become important medically. It may be that we can understand, for example, human speech and how language evolved. This could enable us to understand and eventually treat language problems more efficiently. That may also be true for things such as autism, and other diseases that seem to be specific to humans.

NEWSWEEK: Your focus now is on RNA Interference, which opens the door to a new type of disease therapy.
Drugs basically treat the protein product of the gene, but with RNAi you can treat the gene [itself]. This is possibly another class of therapeutics that would be usable in a very direct manner to treat almost any type of disease. The big challenge in making that real is to deliver these small molecules [called microRNAs] to cells in the human body. If I can get them there efficiently enough and without toxic side effects, they'll silence genes and give me therapeutic effects.

NEWSWEEK: What's the focus of your current research?
Dr. Jaenisch:
Human embryonic stem cells are made from leftover fertilized embryos, [which makes them] ethically controversial and [potentially] immunologically different from the patient because they're not the patient's cells and would be rejected. A solution, we think, is customized patient-specific stem cells [made from skin cells] through nuclear transfer, which could do the same thing as cells derived from an embryo.

NEWSWEEK: Why is the year 2007 significant?
There is new technology and a new understanding of how you should apply [it]. It is not just the new technology for genotype sequencing, it is also the understanding that to make discoveries you need information about people, their diseases and their health. In Iceland, we have so much data on the health care of people, and that has put us in the driver's seat.

What are you working on now?
The genetics of a lot of common diseases—heart attack, stroke and rheumatoid arthritis—and on the development of diagnostic tests. [Soon] we are going to be able to offer a service whereby we can genotype individuals who want to learn about their ancestry and predict the likelihood of their getting certain diseases.

What inspires you?
Iceland is a nation of storytellers. It is extraordinarily exciting to be allowed to participate not only in the discovery of disease genes but also the variants in the genomes that tell the story of man. I love being able to tell this story.

NEWSWEEK: What are you working on now?
We develop technology for reading DNA from natural systems and writing DNA that has been designed. You could think of it like harvesting the information from the world: how does one person differ from another? That's reading. And then, how do we make pharmaceuticals and chemicals—by engineering DNA. The practical applications are biopetroleum, vaccines, biosensors.

How do you develop the technology to do this?
We look for any progress in the physics world, and by physics I mean computers and cameras and microscopes and all that. Then we think economically which of those, put together with interesting combinations of what we know about the chemistry and the biology, will result in a huge savings. We're not talking about 10 percent—more like tenfold.

You're credited with helping scale down the costs of biology research.
That's probably been my longest, [most] passionate mission. I've been doing that for 30 years. It's to make it affordable for each of us to get the information from our genome on to a computer so that we can understand it and act on it as consumers.

You said last year that you want to get the cost of sequencing a genome down to $1,000 by 2008. Is that still possible?
It's essentially there. It's like with computers—there was a point where a computer came down to an affordable range, say $1,000 or $2,000. [In genetics], the $1,000 will get you 1 percent of your genome this year, but that 1 percent contains 90 percent of the information. As time goes by, it'll get exponentially better, the same way your computer gets exponentially better, at the same price.

What benefits will that bring?
If you have cancer predisposition, you can get early diagnosis. You can get a mastectomy so you remove the tissue that's likely to cause trouble. For stomach cancer, for colon cancer, there are various things that people do in advance. Or, you could [find out you] have a bad drug reaction, [and] you could just never take that class of drugs or food.

NEWSWEEK: You work on engineering living organisms, like microbes, to make drugs. Can you give some examples?
We've engineered yeast and E. coli to produce a precursor to artemisinin, the antimalarial drug. We're also engineering microbes to produce a biogasoline and a biodiesel, and the drug prostratin. Originally discovered by healers in Somoa who made tea from the bark of the namala tree, it's been found to have activity against HIV. If it survives clinical trials, a lot of the drug will be needed. Do you want to cut down the rainforests for the namala trees, or get the genes out of a piece of bark and produce it as a microbe? I'd choose the latter.

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