November 8, 2010
Glimpsing the Future as Fields Heat Up
By GINA KOLATA

About 25 years ago, before I came to The Times, I had a job interview at U.S. News & World Report. I really wanted the reporter position, and it seemed to me that things were going well. Then I was asked, “What will be the important medical news next year?”

I replied that the reason science reporting is exciting is that the big discoveries are so unpredictable.

But, the interviewer pressed, surely there must be some stories I was following that were on the verge of a breakthrough. I realized I had to come up with something, so I said: “Gene therapy. It is likely that next year gene therapy will be shown to work and medicine will be transformed.”

Well, I am still waiting for that to happen. And, for whatever reason, I never heard from U.S. News again.

But was I right to say advances are unpredictable? Yes and no, scientists say.

“I’ve learned over the years that the best predictor for what will be new and exciting is, ‘Expect the unexpected,’ ” said Dr. Joseph L. Goldstein, a Nobel laureate who is professor and chairman of the department of medical genetics at the University of Texas Southwestern Medical Center in Dallas.

Dr. David Baltimore of CalTech, another Nobel laureate, said, “If you could predict it, it wouldn’t be a breakthrough.”

But even if it’s impossible to predict a particular major discovery, one can sometimes sense when a particular area of science is taking off, says Dr. Richard Klausner, a former head of the National Cancer Institute who is now a managing partner in the Column Group, a venture capital firm. “It gets on a Moore’s Law curve,” he said, referring to an observation in computer science that the speed of computing keeps increasing exponentially.

When that happens, Dr. Klausner said, “barriers and unknowns seem to be falling,” and it is pretty much predictable that even more exciting discoveries will be made.

That’s happening now in stem cell research, he said, though not in the much-heralded sense of using embryonic stem cells to treat diseases. Rather, the accelerating discoveries relate to what determines a cell’s fate — is it going to be a heart cell, a liver cell, a brain cell? — and how to turn one type of cell into another.

The field came to life in 1998 when scientists found very versatile cells, stem cells in embryos that could turn into any cell in the body. As they worked on finding ways to direct those cells to turn into various types of cells, suddenly, Dr. Klausner said, “this whole field took a turn.”

In 2007, two groups of scientists discovered they did not have to start by plucking stem cells from embryos. Instead, they could turn an already developed cell, like a skin cell, into a stem cell by adding four genes. Then other researchers learned that they did not need to add the genes — they could add instructions from genes instead.

At this point the idea was to take a cell, like a skin cell, make it sort of reverse its development and turn into a stem cell, then direct that stem cell to develop into a different kind of cell, like a nerve cell.

But was it really necessary to go through that process of backward, then forward, development? With what Dr. Klausner sees as a sign of the breathless pace of this field, scientists found over the past two years that they could do what they call “transdifferentiation.” They are now taking cells, like nerve cells, and turning them into other types of cells, like muscle cells.

In theory, of course, it should be possible. All cells in the body have the same genes — what makes a nerve cell different from a muscle cell is that some genes are silenced in a nerve cell and others are silenced in a muscle cell. Only specific subsets of a cell’s genes are used.

But it is one thing to know this in theory. It is quite another to turn one cell type into another.

Yet now, three groups of researchers have done it. One group turned connective tissue into nerve, another turned connective tissue into heart muscles, and a third turned exocrine cells of the pancreas, which secrete digestive enzymes, into the very different endocrine cells of the pancreas, which make hormones like insulin. The value of being able to transform one type of cell into another, Dr. Klausner said, is that now scientists have “a totally novel source” of cells that they can convert.

“I find it so wild,” Dr. Klausner said, “You go from nobody being able to do this to everybody being able to do it.”

So maybe the likelihood of unpredictable discoveries can be predicted, once a field really gets going.

But often, the unpredictable is just that — unpredictable. The result is a well-recognized problem in deciding what research to finance.

The National Institutes of Health, which pays for most research, evaluates grant proposals with committees, called study sections, that give them scores. The highest-scoring grants get financed.

The difficulty, says Dr. Rudolph Leibel, head of the Division of Molecular Genetics and co-director of the Naomi Berrie Diabetes Center at Columbia University Medical Center, is the way grants must be written. Scientists must state the problem and explain how they will approach it experimentally, giving a relatively narrow view of what will be accomplished and predicting success.

“If you don’t do that in a grant application, the study sections — despite all the blandishments to do otherwise — will probably say your aims are too diffuse,” Dr. Leibel said.

The result, he said, is that scientists abide by what he calls the “Kabuki-like presentation.” But all along, he adds, “the unwritten message is, ‘Boy, we hope we stumble upon something that is novel and unique.’ ”

Yet it is not easy to change things, Dr. Leibel acknowledges. The National Institutes of Health does have some grants that encourage high-risk proposals. But most grants are the traditional sort. And, Dr. Leibel said, “You can’t take every harebrained scheme and fund it and see if it works.”

One result is that more and more private foundations are being formed to support high-risk, high-reward research. Often they are founded by advocacy groups frustrated by the slow pace of progress in understanding or treating a particular disease. In Dr. Leibel’s field there is the Helmsley Type 1 Diabetes Research Consortium, which is trying to find a cure for Type 1 diabetes and is led by four investigators from four institutions, including Dr. Leibel.

In Alzheimer’s, there is the Alzheimer’s Cure Foundation. “Our mission and vision is to dramatically accelerate the cure for Alzheimer’s disease,” the group writes on its Web site.

Dr. Baltimore noted that even when breakthroughs occur, they are not always recognized.

For example, he says, micro-RNAs — small molecules used to silence genes — were discovered in 1993. But they were found in roundworms, and scientists did not realize until around 2000 that they were a universal mechanism for gene control.

“It’s a breakthrough in retrospect,” Dr. Baltimore said. “That kind of thing happens all the time. You don’t recognize how important something is until its generality becomes apparent.”

Now, though, the micro-RNA discoverers have gotten just about every major prize except the Nobel. “And I expect the Nobel will come,” Dr. Baltimore said.