NIH funds local teams for daring research

Boston researchers are about to begin a bold experiment that, if it works, could help solve the organ shortage and provide other replacement parts for worn-out humans: They will try to grow heart valves, and parts of a pancreas and a tooth, from scratch in the lab.

A second local group hopes to transform the drug discovery process, taking advantage of a flood of genes being linked to human diseases to rapidly identify potential treatments for those ailments.

The National Institutes of Health plans to announce today that it will fund both of these projects as part of a $483 million initiative to support daring, difficult research that has the potential to solve intractable medical problems and transform patient care. Nine teams nationwide will each get $21 million to $25 million in this round of funding.

"This is knock-your-socks off science," said Dr. Alan Krensky, director of the NIH office of portfolio analysis and strategic initiatives, which is funding the projects.

The agency, the major funder of biomedical research in the United States, wants to bring together scientists from different fields to solve problems that have been resistant to traditional approaches, Krensky said. The organ project, for example, includes a cardiac surgeon and two mathematicians, computer specialists, and tissue engineers.

The NIH traditionally awards most research grants - typically about $250,000 each - to individual doctors and scientists whose work has a high likelihood of success. But hoping to turn a new page on how research is done, the agency has set aside 1.7 percent of its budget in a sort of venture capital fund for large, multidisciplinary projects that are riskier but have a huge potential payoff. Among the other projects, researchers in Chicago will try to develop novel ways to preserve the fertility of women undergoing cancer treatment, and scientists at Yale University will study the connection between stress, self-control, and addiction.

The initiative is occurring, however, at a time when scientists are concerned about funding for research. The NIH budget, about $29 billion this year, doubled between 1998 and 2003 but has not kept pace with inflation since then, said David Moore, senior associate vice president for governmental relations for the American Association of Medical Colleges.

"A lot of people are worried about this. Our institutions are worried about it," said Moore, referring to the overall NIH budget.

Money hasn't been the only barrier to collaboration. Medical schools such as Harvard tend to evaluate young researchers for promotions and tenure based on the quality and quantity of articles for which they are a lead author and how much individual grant money they pull in. To address this obstacle, heads of the schools involved in the organ engineering project pledged to look favorably upon participation in the team project when young researchers come up for tenure, said Dr. Richard Maas, a geneticist at Brigham and Women's Hospital who will head the project.

The team hopes to devise instructions for growing specific body parts by turning on and off certain genes and to use these genetic blueprints to direct embryonic stem cells to grow fully-formed cardiac valves, the insulin-producing "islet cells" of the pancreas, and "tooth germs," which could grow into complete teeth once implanted in the mouth. Researchers will begin by trying to grow these new parts for mice, and then eventually proceed to humans.

"In medicine, a major cause of morbidity is organ damage. Diabetes, heart attacks, stroke, renal failure - they all cause organ damage," said Maas, whose collaborators include 24 scientists from Brigham, Children's Hospital Boston, Massachusetts General Hospital, MIT, and Harvard, Boston and Vanderbilt universities. "The traditional approach has been transplantation and devices. We think nature has figured out a way to do it better."

Tissue engineering already is having a major impact on medicine. Scientists around the world have been working for years to grow functioning tissue in the lab, with some success, so the groundwork for this type of project already has been laid.

Researchers at Children's, for example, have reconstructed the defective bladders of seven young patients using the patients' own cells - the first time that tissue engineering has rebuilt a complex internal organ in humans. At a Texas military base, doctors are treating soldiers who lost parts of their fingers in Iraq with "extracellular matrix" harvested from pig bladders, a sort-of scaffolding that cells latch onto as they form tissue. And, five years ago, scientists at the Forsyth Institute in the Fenway grew tooth crowns from the stem cells in a pig that eventually form enamel.

Dr. Joseph Vacanti, chief of surgery at MassGeneral Hospital for Children who recently coauthored a textbook on tissue engineering, said heart valves, pancreatic islet cells, and teeth have been grown in the lab, either from a person's own cells or from animal cells. "It's been proven in sheep that you can make heart valves from the sheep's own cells and you can implant them and they work as heart valves," he said.

What's new about the experiment Maas and his colleagues will try, Vacanti said, is their plan to develop a blueprint for the use of human embryonic stem cells, which have the ability to develop into any of the multiple types of tissue and body parts. One advantage of using stem cells is that the cell colony can live indefinitely, he said.

Maas said researchers plan to use federally registered embryonic stem cell lines; scientists are allowed to use federal funds when working with these stem cells, created before August 2001, but they are not allowed to use NIH money to work with batches of embryonic stem cells created since then.

The Brigham-led group "has a big bold vision here to take [tissue engineering] to the next step and the expertise to try it," Krensky said. But "this is high-risk, not a slam dunk application."

More than 2 million Americans suffer from Type 1 diabetes, which develops when islet cells stop producing adequate amounts of insulin, and 90,000 Americans a year undergo surgery to repair or replace faulty heart valves. And, by the age of 50, the average American has lost eight teeth.

The Broad Institute of MIT and Harvard, the second Boston group, will work to develop technologies to discover drugs, rather than on finding new drugs for a particular disease.

Dr. Todd Golub, director of the Broad's cancer program and a researcher at the Dana-Farber Cancer Institute, said compounds now generally are screened as potential drugs by testing their ability to interfere with isolated proteins in a test tube. This can be done only after the underlying biology of a disease is largely understood. The Broad team wants to short-circuit this process and make it more efficient, by testing potential drugs directly on living cells and looking for chemicals that modify the activity of genes in a diseased cell so that they act more like the genes in a normal cell.

"We think there are powerful ways to tap into the effects of chemical compounds on cells and measure them in ways previously not possible," he said.

Liz Kowalczyk can be reached at kowalczyk@globe.com.