Losing your lab

For Alan Schneyer, everything changed in June, 2006. The scientist was running a lab in the reproductive endocrinology department at Massachusetts General Hospital (MGH) in Boston, and had recently logged some interesting results from his knockout mice. The results suggested a protein with a suspected reproductive function could also have a significant effect on glucose metabolism - and, perhaps, diabetes.

However, one morning when he arrived at work and went online, he found that, to his surprise, the grant application he had submitted to explore this hypothesis had been returned, without review. For many scientists, this news would be discouraging. But for Schneyer, who was funded largely on soft money, it was much worse. It meant he had to close his lab.

The process was already slowly underway. One of Schneyer's technicians had decided to go back to school, and he didn't have the funds to replace her. His postdoc soon transferred to another institution. Another technician began to spend more of her time with other groups; she eventually moved to industry.

Alan Schneyer at his new home, PVLSI.

Courtesy of Shawn Henry

In the summer of 2006, Schneyer's lab was surviving off of "not much money" (he doesn't recall the exact number). He had hoped that this metabolism grant, which would replace a 2000 R01 that had run out, would enable him to continue the work. But without this grant, he had only a few months of funding left. His wife was vacationing in Hawaii, five hours behind him. He waited as long as he could to call, then finally woke her to break the news. "'Life's about to change here,'" he told her.

Every NIH-funded biologist can rattle off the story of the agency's budgetary rise and fall over the last 15 years. In the 1990s, President Bill Clinton pledged to double the NIH budget within five years. He did, and the agency's R&D budget jumped from $13 billion in 1998 to $26 billion in 2003 - triggering a flood of scientists into the field, a burst of building activity at institutions, and the expectation that any well-respected scientist with a reasonable idea could receive federal funding.

That all ended in 2003, when the country was consumed by terrorism, a budget deficit, and a war. So in 2003, NIH's R&D budget began to, as many now say, flatline: tracking inflation and inching from $26.4 billion in 2003, to $27.2 billion in 2004, and $27.9 billion in 2005. The situation has not changed much since then: For fiscal year 2009, President George W. Bush requested $29.5 billion.

The trouble is, science doesn't shift as quickly as political focus does, and NIH grant applications continued to pour in, even when the amount of available money slowed to a trickle. In 1999, scientists submitted 8,957 applications for R01 grants classified as type 1, or new submissions (these figures include only original applications, not resubmissions). The agency awarded 1,761 applications, for a success rate of 19.7%. By 2005, the number of applications rose to 10,605, and only 970 were approved. That means only 9.1% were successful, and 9,635 were rejected - more than the total number of submissions only six years earlier.

For type 2 grant applications, which request to continue an already-awarded R01 grant, the numbers tell the same story. In 1999, 3,214 funded scientists requested renewals; 1,772 received them, for a success rate of more than 55%. By 2005, 3,896 needed renewals of their grants, but only 1,262 requests were awarded; the success rate had fallen below 33%. So among nearly 4,000 scientists who were working off NIH funds in 2005, more than 2,600 lost that support. In 2007, more than 4,100 scientists were denied renewals of their R01s.

Scientists always have the option to revise and resubmit their original applications, but that process puts funding on hold for approximately one year. For Schneyer and others who are supported by soft money, they might need that NIH grant funding for all their expenses: other researchers in their lab, supplies, their own salaries. Without it, how do they make it through the year?

A few years ago, things were looking good for Schneyer. He received an R01 in 1999, and another in 2000. He'd been at MGH for almost 20 years, paying people in his lab using grant money, since his institution contributed very little. It was a generally productive time: According to ISI, Schneyer's nearly 100 papers have accumulated more than 2,000 citations.

Schneyer with his new lab group at PVLSI, (L to R): Jessica Zina, Lara Bonomi, and Fuminori Kimura.

Courtesy of Shawn Henry

Lately, he'd been getting some interesting results: When he created mice that lacked follistatin-like-3 protein, which he thought played a role in reproduction, he was surprised to see that the mice appeared to reproduce just fine. Instead, he noticed metabolic changes, including larger islet cells, altered fat distribution, and fatty liver, a sign of insulin resistance -only, these mice weren't insulin resistant (Proc Natl Acad Sci, 104:1348-53, 2007).

In 2003, he began applying for a renewal of a 1999 R01 grant, which explored the role of three different types of follistatin made from the same gene. It was returned without review; so was his revised application. The same thing happened to his 2000 grant renewal request, which focused on the follistatin-like-3 knockouts. Schneyer had weathered funding dips before, avoiding severe belt tightening by postponing new hires until another grant came in. But this time, there was no money on the horizon for months, if not a year or more, given the amount of time resubmission would require.

His staff slowly began dripping out of the lab. One of his technicians moved to Genzyme, a Boston biotech. He helped his postdoc find a post at Brigham and Women's Hospital. When his grant was returned without review in June, 2006, Schneyer warned his research associate, Yisrael Sidis, who was still partly dependent on Schneyer for his salary, that he would also need to start looking for other work. "I said, 'we have enough money until October. After October, there's no money.'" It was a "depressing but also anxious moment, because I didn't know what was going to happen," Schneyer says. "But I think that was the point when I realized I was definitely going to have to leave."

After the summer in 2006, Schneyer kept up his salary with bridge support from MGH, small grants from Pfizer, and collaborations with other scientists. He also received money from NIH to maintain special resources, such as his knockout mice. However, at only $14,000 per year, it was significantly less than the $20,000-$25,000 the mice typically cost.

In the fall of 2006, he began looking for new positions, and had some prospects in Pittsburgh, Philadelphia, and Chicago. But with a home in Concord, Mass., and two teenagers in high school, Schneyer didn't want to uproot his family or shuttle between states. The only viable opportunity within commuting distance was Pioneer Valley Life Sciences Institute (PVLSI), where he would receive a stable salary not dependent on grants. But it was a long commute - a 90-minute drive from Boston, to Springfield, Mass. - and thus a major drawback that required much thought. "I guess it's one of those things that takes a while for you to accept." Eventually, he decided it was better than taking a job even farther away. Recalling that decision, he rocks back on his heels and folds his arms. "Everybody I know who's done that, the marriages didn't survive it. And that seemed like an awfully high price to pay."

In May, he left the facility where he had worked for 20 years. His boss threw a get-together for him a week or two before his last day. "It was really sad to leave MGH. It was a great place to work." He spent his last days sorting through old files, papers, and notes about experiments he now realized he would never finish - "mostly just clearing out the evidence of my existence there."

In the MGH's reproductive endocrinology unit on the fifth floor of a red brick building called Bartlett Hall, researcher Yisrael Sidis points to a narrow closed door with a glass panel. "Dr. Schneyer used to have this office," he says. Inside the office, piles of papers obscure the floor, and a scientist stirs. The sign on the door now reads "Nelly Pitteloud." (She declined to be interviewed for the article.)

Sidis, Schneyer's soft-spoken former research associate, points out two small lab benches, still unmanned at 8:30 A.M., where Schneyer's group previously worked. He quickly checks one of his gels before heading into a small office, which he shares with an officemate who sits less than 1 meter away. Currently, Sidis is working on the genetics of gonadotropin-releasing hormone (GnRH) deficiency. He is hoping that clues from patients with disorders that cause the problem (which come with symptoms such as late sexual development or no puberty) will reveal basic information about reproduction. The genetics component of the lab has slowly expanded, and now occupies Schneyer's old benches.

Sidis says he doesn't recall the exact moment when Schneyer told him he was closing his lab, but he remembers how it felt. "Alan is a very strong person, he's very optimistic," Sidis says. "I'm not as strong a person, so it was harder for me," he jokes. Sidis had come to MGH 10 years before to work with Schneyer, and had never had his own grant. Fortunately, Pitteloud was applying for a new grant and needed a new person like Sidis. When Schneyer left, she moved into his office.

Schneyer was a very well-respected member of the unit, Sidis says. "When he left here, people felt like he was the basic scientist for the [reproductive endocrinology] unit. He was an important contributor to discussions in meetings." When Schneyer left, he took his mice, reagents, and equipment. "It was a bad time. For me, it was very hard," says Sidis. "It was ridiculous that such a large research institute didn't have support for such an established researcher. He was here for 20 years."

Actually, MGH did provide Schneyer with support: two grants of $30,000 each in the late 1990s when he ran low on funds, and two $50,000 grants in 2005 and 2006, says Rick Bringhurst, vice president for research administration. "That's an unusually generous amount," he notes. Last year, the institution spent $3 million in interim funds for faculty who'd lost federal support, but with approximately 500 NIH-funded principal investigators, MGH can't keep everybody in business. "I don't doubt that we have" lost faculty who, like Schneyer, couldn't keep their labs open, he says. "This is a fact of life in an academic medical center like this."

Bringhurst says he, too, was sad to see Schneyer go, since they'd known each other for years. But PVLSI could offer Schneyer something MGH couldn't: A stable income. "I thought [Schneyer's departure] was a tremendous loss for the institution. But there wasn't much we could do. He had a good opportunity, and I think he chose wisely."

By 2006, Dana Farber Cancer Institute (DFCI) president, Edward Benz, and his colleagues saw what was happening to the NIH budget, and they realized that the "contingency fund" they were setting aside wasn't going to be enough. The institute typically provided less than $1 million to keep researchers who lost funding afloat until they could resubmit their renewal applications. However, for fiscal year 2007, the institution increased that amount to $4 million (from discretionary accounts generated by fundraising). "We would, in a sense, substitute for the National Cancer Institute," says Benz.

DFCI researchers were eligible for so-called bridge funding if their NIH grant application score fell within the top 15% of applications, but was still not good enough to merit funding. The DFCI "arbitrarily" capped these awards at $200,000 per scientist, Benz says. Over the course of the year, the NCI became able to award a higher percentage of grants, so only four faculty members applied for the awards - all received them, Benz says. "There was virtually none we thought were under-performing. They were just in a bad environment." For FY2008, the institution has set aside "just under" $2 million for bridge funds, and Benz says he's hoping that amount will be enough. "We're holding our breath on this." Bridge funding ends up costing more than it seems, he adds: For every scientist who loses a grant, the DFCI loses the approximately 70% in indirect costs it would receive (more than $500,000 on an $800,000 grant).

At the University of Pittsburgh, the institution offers bridge funds to researchers who lost a grant but are likely to resecure NIH funding within a year, says the dean of the School of Medicine, Arthur Levine. The school also gives preference to researchers who will suffer most if they lose funds. For instance, if a clinical trial goes unfunded, is there a cohort of patients who would drop off, ending the study? Levine estimates that the university has received between 10 and 20 applications for bridge funds within the last six months, and all but one of the Pitt researchers who have received supplementary money eventually were funded by NIH. (He declined to say how much money he put aside for bridge funds.)

Both Levine and Benz say they believe in bridge funding because scientists, their labs, and their research are investments: Over the lifespan of a typical lab, its institution provides some funds to keep it running. "I'm not going to close any lab where the likelihood of resubmission [of an NIH grant] is high," says Levine. "I've made a big investment in that lab ... closing [it] is absolutely a last resort."

The NIH, too, makes efforts to save strong scientists from closing shop. In 2007, the agency announced the NIH Director's Bridge Award, in which NIH institutes can nominate applicants who score well but aren't funded, and have little additional support (less than $400,000), for a one-year grant of up to $500,000. In FY2007, NIH received $91 million to support these "vulnerable research programs," according to the agency. The program "basically buys the investigator time," says Norka Ruiz Bravo, deputy director of NIH's Extramural Research.

Like institutions, the agency sees top scientists as investments it doesn't want to lose, Ruiz Bravo adds. If a lab has to scale down operations, it will let go of highly trained people, which can severely set back a project, even if funding eventually returns. "It's hard to regain that momentum and regain those persons back in the laboratory."

The National Institute of General Medical Sciences (NIGMS) has its own bridge-funding program, which began in the late 1990s. First-time renewal applications receiving a score that is within 10 percentage points of the payline (the score below which all applications are funded) can typically receive around one-third of the funding they would have received if renewed for one year, says director Jeremy Berg. Now, the agency is looking at how many scientists who receive bridge awards end up with successful applications, and it is figuring out how to coordinate the NIGMS awards with the NIH Director's Bridge Award (which is higher), he says. In FY2007, NIGMS issued 62 interim awards totaling nearly $7 million, and the NIH Director's Bridge Award gave 51 awards, or a total of $14 million, to NIGMS grantees. "The intent is really to keep labs in business," says Berg.

Alan Schneyer's new lab is surrounded by warehouses and parking lots. The region used to be rife with bustling manufacturing facilities, and local politicians, including Massachusetts Senator Edward Kennedy, are trying to establish a biotech corridor that runs from Boston to Springfield. The five-year-old facility where Schneyer works is affiliated with the University of Massachusetts at Amherst and Baystate Medical Center, which sits across the street. The hope is that PVLSI will eventually attract other biotechs to fill the empty lots that now surround the facility.

On a foggy President's Day in February, the labs at PVLSI are also largely empty; most of the chairs are draped with the lab coats of people who have taken off for the holiday. However, tucked away in a corner, three people sit close together, plugging away at Schneyer's latest project. One scientist taps her pencil rhythmically against an image of wild-type mouse islet cells as she counts the insulin cells, to determine how that number changes in knockout mice. Another scientist flips through published papers. A gynecologist from Japan, Fuminori Kimura, turns from his computer to explain that he decided to come to PVLSI to work with Schneyer. Here, Kimura plans to spend a few years looking more deeply at the reproductive phenotype of knockout mice, to determine how follistatin affects ovarian function. (His wife and three children, 11, 9, and 3, moved to Amherst in September, and the oldest are in public school. When asked if they have learned to speak English yet, he shrugs, and says: "They cannot.") In the microscope room, Rong Shao smiles as Schneyer explains that he received his first R01 a few days ago, after two years and three tries.

Schneyer brought his knockout mice to his new post, along with some equipment he had bought with his grants. The rest remained at MGH. Only a couple of weeks after he started at PVLSI, he found out that his 1999 grant renewal application (which, after two tries, he submitted as a new application, then revised twice more, for a total of five submissions) had been accepted by the NIH. With that, he became the first full-time PVLSI scientist to receive an R01. (Shao was the second.)

In the end, Schneyer could have remained at MGH, since one of his grants eventually was funded (although at only two-thirds the requested level). He says he would have preferred to have stayed at MGH, but felt that the risk of holding out this long was too great. And there are many advantages of being at PVLSI, Schneyer says. He pulls out a small, waxy block that contains a yellow shadow within, roughly 1-cm long: "That's the pancreas." Here at PVLSI, there are two full-time histology experts in the pathology department who can help Schneyer section pancreatic tissue, a notoriously difficult process, producing 20 slices in around three hours. "When I was at MGH, I had to do this myself," sometimes taking all day, he says. Even if his grants were funded while at MGH, his research was moving in a metabolic direction, which would have been an issue in a reproductive unit. "I was already moving beyond MGH, in a way," he says. "I was trying to learn metabolism, and the people I was learning from weren't in my unit."

And there's the security of knowing his salary doesn't depend on a study section in Bethesda, Md. Only a few days earlier, he learned that his 2000 grant was not funded - his third attempt. "I was surprised at my reaction," says Schneyer in his PVLSI office over coffee. "It didn't bother me, because I knew that I had resources here already."

The application was returned, again unscored. "When I was at MGH, every time I looked at my computer to see what the score was, it was a very stressful day. And here, I just forgot all about it." He needs the extra funds, and will reapply, but it's no longer a matter of life or death. "We're already doing the work. Eventually, I have to get it funded by the NIH, but I don't have this, you know, guillotine coming down [as if to say] 'Okay, after this third submission, this grant's dead. You're dead. Goodbye'."