Mary Jo Mulligan-Kehoe is also helping to analyze the samples. "We have looked at those samples and asked the question, 'Can we see cleaved or truncated PAI-1 in those samples?' And the answer is 'yes' to varying degrees."

Doing science can be exciting yet tedious, satisfying yet frustrating, creative yet boring. But all of these researchers seem to love it.

"I love the science," enthuses Mulligan-Kehoe. "Everybody down in my lab is the same way. We have this high level of excitement over what the results are going to be. We discuss the mechanisms and where we're going with it, and they're as excited about it as I am."

"I feel it's exciting because it's fairly new research. . . . I sort of stumbled upon this, but it's cut ting edge," says Jannine Walsh, one of Mulligan- Kehoe's research assistants.

"Every day you come in you're finding out something new that nobody's looked at before," says Mary Drinane, a research assistant in the same lab. "I find it very exciting. And I especially like this area of research because of all the clinical applications to it. I feel that I'm contributing back, and that this will someday be helpful."

Dartmouth is one of the few medical centers anywhere that does angiogenesis imaging. "There are other places doing perfusion-sensitive imaging," a technique that is also done at DHMC, says Pearlman.

While not every day is exciting, most researchers don't seem to mind the routine tasks, the repetitive and tedious procedures. M.D.-Ph.D. student Arye Elfenbein, who works in Mike Simons's lab, listens to classical music while he gathers materials for his experiments. He gently removes culture dishes from an incubator that looks like a mini-fridge, mixes cells and reagents, places tiny vials into a centrifuge, scrutinizes cells under a microscope, and performs countless other tasks. The pace can vary. Sometimes his work has a slow, almost meditative, rhythm and other times it's like a quick, timer-driven race. Still, it's usually a creative process.

"For me, the science is almost an art form," says Mulligan-Kehoe. "You're able to express your creativity in the lab on a regular basis," whether by genetically engineering proteins, understanding

Top: Justin Pearlman, who brings imaging expertise to the angiogenesis group. Above Right: Jannine Walsh. Above Left: Zhenwu Zhuang, right; Karen Moodie, in purple; and colleagues.

molecular mechanisms, or writing the papers.

But some of the researchers do admit to feeling frustrated at times. "It's 95 percent frustrating. Absolutely," confesses Radu Stan. "An experiment that worked for years—last week somehow something happened." He laughs. "So we are trying to figure that out."

Yet he finds doing research to be very satisfying, too. "At the end of the day you know, if someone asks me 'What have you done for your field?' I say, 'Well, I found this marker and I found the function of this protein.' It's something that not many people can brag about. That's pure research." But no matter how dedicated these scientists are, they still face a lot of challenges before they can translate successes in the lab and in preclinical trials into therapies for real patients.

"I think we have underestimated the complexity of the angiogenesis system," says Simons. "It turns out that when you have disease and when you have advanced age, all these agents don't work the same way as in young, healthy animals. So it's a challenge, even though there are a lot of ongoing clinical trials at the moment. But I don't really think they will be successful. It's just another step on the way."

Yet there's a sense of hope. And still more interesting research going on. One question being explored is whether it's possible to change the size of organs or even of entire organisms by changing the vascular system.

"We have a fascinating set of experiments where we have increased the

vascularity of a normal heart in an adult mouse—the size of the heart has markedly increased," says Simons. "That implies that you can manipulate organ size by changing the vasculature size. So that's a very interesting fundamental biological question. Why is a mouse smaller than an elephant? It could be because it doesn't have as many vessels. And if you made a mouse with lots and lots of vessels, that will be a big mouse. So you can increase the organism size by increasing the size of the vasculature."

Simons worries, too, that a deeper understanding of angiogenesis might be misused to grow bigger muscles in athletes. "If this ever gets through professional sports, we will never see the end of doping," he says. He contends that there would be no test that could see whether increased muscle size was the result of stimulating angiogenesis. "Nobody would ever know, because there will be absolutely no way to check. There's no test for it. It's a natural thing."

Ebo de Muinck chuckles. "Right now that's not been a worry because we haven't been terribly successful. What we're worried about now is creating normal blood vessels that are capable of transporting oxygen and that are not leaky," he points out. "Many of these new blood vessels that we've seen so far . . . are some kind of leaky tube-like structure. Some of them are also forming abnormal outgrowths—hemangioma-like structures—if you give too much growth factor."

Simons—who agrees that it will be a while before anyone has to worry about such a misuse of angiogenesis therapies—is active in an NIH initiative called the Trans-Institute Angiogenesis Research Program (TARP). Under TARP's auspices, several NIH agencies have partnered with each other and with other organizations to take a multidisciplinary approach to doing angiogenesis research.

So with funding organizations, agencies, and academic researchers banding together to try to understand the complexities of angiogenesis—how it underlies so many different diseases, how the proteins and genes that regulate it may also drive other processes, such as nerve growth—advances in one area may soon fuel advances in others.

"I guess the only bad thing is I wouldn't expect a cure of all the diseases tomorrow," Simons says. "Next week, maybe," he adds.

Then he laughs.