When the Whitehead Institute announced last October that it had appointed a new director, few people in the biomedical research community had to look up the name Susan Lindquist. Known for her research in prions-clumps of misshapen proteins responsible for, among other conditions, mad cow disease-the former University of Chicago professor helped flip conventional biology on its head by demonstrating how prions spread disease without a scrap of genetic material. This, added to her pioneering research in protein folding and its role in evolution, earned her the prestigious Novartis/Drew Award in Biomedical Research last year, an honor she shares with human-genome luminaries Eric Lander and Craig Venter.Having settled into the Whitehead helm, Linquist squeezed some time out of her hectic schedule for technologyreview.com staff editor David Cameron, with whom she discussed protein computers, why biologists need engineers, and if we should expect an outbreak of mad cow any time soon.
TR: What was it about the Whitehead that pulled you away from the University of Chicago?
Lindquist: Mainly, it was the scope of the institute. Its scientific mission is very innovative. It’s not concerned with channeling science to a particular end. Rather, its philosophy is that if you take the best people and give them the right resources, they will do important work. There was also a real spirit of collaboration here which, for a group of this size on the forefront of biological sciences, is quite remarkable. That makes for a great environment to work in.
TR: You’ll also be teaching at MIT. I’m sure that was a draw.
Lindquist: Absolutely. Biological problems have really reached a level of sophistication that’s going to require input from physics, chemistry, engineering, computer science, imaging, robotics, material science-and MIT is really good at all of those things. Ask anyone where the best people are in any of these fields, and out of two or three names, one is always from MIT.
The reason why this inspires me so much goes back to my time at the University of Chicago, where I began interacting with physicists and chemists in what I think is an example of a new kind of paradigm for biological sciences. Biology has now reached a level that will require new platforms and new technologies and developments that engineering and computer science will help us with. But even beyond that, I think that biology now presents problems that those groups themselves find enticing and intellectually engaging. Biology is no longer a descriptive science. Rather, it’s a science where you really try to understand on a molecular level how life’s processes work-and that’s truly an extraordinary problem.
TR: Could you give me an example of this new “level of sophistication”?
Lindquist: Well, for starters, genomic data. It’s hard to even conceive of how much genomic data we now have. And more is accumulating. In order to use it to produce new paradigms and solve major problems, we need to find ways to see things in that data that we normally wouldn’t be able to see. That’s a problem that we will not solve without the highest level of computer science.
Another example would be a problem that got me interested in collaborating with physicists and chemists. It’s a problem in protein folding. In fact, it’s an unusual self-assembly process by which a protein that normally has one particular type of shape can take on a new shape. When it acquires that new shape other proteins of the same type will assemble with it. Keep in mind that the mechanism by which this happens is still unknown. But this process, it turns out, is a major force in many different devastating diseases-such as Alzheimer’s, Huntington’s disease, Parkinson’s, and mad cow-where protein misfolding, and self-perpetuation of that misfolding state, is a driving factor in these diseases.
Now, we’ve found that in some cases this misfolding process can serve a normal biological role. For example, in yeast cells a similar process actually seems to contribute to genetic inheritance. A protein changes shape, and because it’s self-perpetuating, it then changes the function of the protein, which in turn produces a new trait, a new appearance or a new way of metabolizing something. And it’s inheritable; it gets passed on from generation to generation in these cells because the protein gets passed from cell to cell and the protein informs a new protein that it should also enter into that altered state. As I said, we’ve seen this in yeast, but I think we’re going to find that this happens in other organisms as well.
TR: Basically, you’re talking about inheritance without the genetic component.
Lindquist: That’s right. Obviously there’s the gene encoding the protein, but when you inherit a new trait by this particular method, you don’t inherit the trait by having a change in your DNA. You inherit the trait by having a change in your protein conformation, which once it gets started is self-perpetuating.
So now, going back to this “new level of sophistication” I was speaking about, the difficulty that we have reached in this field-and that requires an interface with engineering, physics and chemistry-is that we don’t understand the nature of the way that this change in protein conformation occurs. And the traditional tools that have been developed for understanding protein structure-such as x-ray crystallography-don’t work.
We need to develop new kinds of ways of looking at them, new methods, new probes, new ideas. And some of the conversations I’ve had with physicists led me to believe that they’ll help us provide new ways of being able to interrogate molecules, to understand the forces that govern how those molecules assemble.
TR: What would the gain be for a physicist or chemist?
Lindquist: Well, in this example, this protein self-assembly has real potential for materials sciences. These proteins can self assemble on a nanometer scale. And not only that, you can also engineer interesting functions into them. This is something that chemists have been trying to create de novo in polymer chemistry. But here, biology’s done it for you. Evolution’s been honing the properties of certain molecules for a couple of billion years to create something that really has quite remarkable traits. So, let’s use these traits; let’s take advantage of them to create some new kinds of materials.
TR: What sorts of applications could potentially come from this?
Lindquist: Micro circuitry for proteins, to begin with. You could potentially have these proteins conducting light-harvesting and transmitting light. You can have them conducting electricity and can thus build circuits on a much smaller scale.
TR: Like DNA computing?
Lindquist: Yes, like DNA computing. DNA has wonderful properties that could be harvested for this, and I think that proteins do as well. So from the standpoint of the biologist, we need a much wider palette in order to understand the processes that we’re looking at, at the next level up.
Quite honestly-and this may sound corny-but I can’t imagine any question more fundamentally exciting than what is life, and how does it work. I think it’s an extraordinary question. And it turns out that as you start to probe biological processes at a very detailed level, it’s really quite beautiful and extraordinary how well it works.
TR: Has anyone done any preliminary research into the self-assembling, potentially conductive properties of protein?
Lindquist: Well, a lot of people are creating, for example, protein nanotubes and self-assembling protein structures. We’re beginning to do that here at the Whitehead, and several other labs are beginning to do it. But people have only really recognized this potential in the last year or two.
Now, understand that this is just one example from my own work. There’s really a whole world of other places where we can use biology to create new kinds of materials that will really influence people’s lives. Spider silk is one of the most amazing materials on earth. And there’s also biological adhesives that are beyond anything human ingenuity has been able to devise.
Biology is just exploding out there. We’re actually reaching a level where you find yourself imagining questions that a year ago you couldn’t even formulate. There’s a whole realm out there of biological materials that have been developing because nature has needed to produce them. If you work on something for about a billion years, you can be sure it’s going to work pretty well.
TR: You received a lot of press a few years ago when your work elucidated how mad-cow disease works. In spite of what some public health experts predicted, so far there’s been no major mad-cow epidemic. Are we out of the woods yet?
Lindquist: Well, we don’t really know. This disease can have a slow onset, as long as twenty-five years. This past year, while it’s still small, there’s been a rise of cases in England. It may just peak at a few hundred. But the jury’s still out. It’s just that there have been other things in the headlines lately that have captured people’s imagination. Like anthrax.
TR: And exploding sneakers.
Lindquist: Yes, exploding sneakers.