The Grant Chase

Researchers across the nation devoted to basic science—the people who mine the unknown and map out the pathways to new cancer drugs—have had their quest curtailed.

Federal funding for their work plunged and then flatlined over the past decade.

The cutbacks came after Congress had doubled the budget of the National Institutes of Health (NIH) between 1998 and 2003. Appropriations for the National Cancer Institute (NCI), which totaled $5.86 billion in 2004, diminished to $4.95 billion by 2015, according to a real dollar comparison adjusted for inflation.

The decline for investigator grants—the most commonly used NIH funding program— has been more precipitous. The number of Research Project Grants (R01) awarded nationally went from 29,626 to 24,026 over that time frame, a 19 percent decrease.

Vanderbilt scientists received 66 of these investigator-initiated grants for basic science discovery in 2004 totaling $21.6 million—a figure that is actually $26.7 million in today’s dollars. That investment in basic discovery research shrank to $18.9 million in 2015 when 52 grants were awarded.

Pharmaceutical companies won’t fill this void, said Christina D. West, assistant vice chancellor for Federal Relations for Vanderbilt University.

“Companies focus on the bottom line and the next investors report,” West said. “They don’t have the luxury to pour resources into basic science when they don’t necessarily know where it is going to end up.”

Donors are helping ease some of the pressure through discovery grants, which provide scientists with funding for preliminary research that often positions them to compete for scarce federal dollars. Discovery grants funded by private donors have enabled Vanderbilt scientists to leverage millions of dollars in external funding. For example, the VICC Ambassadors awarded discovery grants totaling $585,000 in their first five years of operation. As a result, Vanderbilt scientists have attracted $11.8 million from NIH and other outside sources.

Although other NIH grants exist—and Vanderbilt University Medical Center (VUMC) has moved up to be one of the top 10 recipients of NIH funding over the past decade—the R01 program funds scientists at the thresholds of new inquiries.

The NCI is asking for annual increases of 7 percent over the next decade. Congress increased funding for NCI by 5.25 percent for 2016.

On the following pages four Vanderbilt-Ingram Cancer Center (VICC) researchers explain what that funding means for their work.

 

Freedom to explore key for basic science discovery

A few years ago, Bill Tansey, Ph.D., was at a crossroads. He had worked on MYC—a family of three related oncogenes that drive cancer—since starting his independent research career as an assistant professor in 1997. He had been successful and well funded by the NIH, but now only about one in 10 grants were being funded, and his wasn’t the one.

MYC proteins are over-expressed in cancer and drive the expression of genes linked to cell growth, proliferation, metabolism and genome instability. About 100,000 Americans die every year from cancers that have too much MYC, says Tansey, Ingram Professor of Cancer Research and professor of Cell and Developmental Biology.

MYC is highly validated as an anti-cancer target, but because it doesn’t have a “pocket” that’s key to its activity—like an enzyme or receptor—it has been considered “undruggable,” Tansey explains. It hasn’t been clear how to design a small chemical compound that can block MYC activity. Until now.

Tansey and his team had focused on understanding how a cell regulates its expression of MYC. But with only a year of secure funding left, Tansey decided to go in a different direction and explore a large uncharacterized central region of the MYC protein.

Tansey and Lance Thomas, Ph.D., research assistant professor of Cell and Developmental Biology, discovered that the central MYC region binds to a protein called WDR5, and that this interaction is critical to MYC’s function—and its ability to drive cancer.

Steve Fesik, Ph.D., Orrin H. Ingram II Professor of Cancer Research, used crystallography to take “molecular photographs” of MYC bound to WDR5 and discovered a small groove on WDR5 where MYC binds. The investigators showed that perturbing the interaction of MYC with WDR5 eliminated MYC’s ability to cause tumors in mice.

The exciting thing, Tansey says, is that the WDR5 groove is a druggable pocket, and Fesik’s team is now searching for molecules that bind there and block MYC function.

“It’s a viable way of targeting MYC directly,” Tansey says. “If we can find a compound that works, and if our theory is correct, it should have quite an effect on a range of tumor types.”

Tansey was curious about an unknown region of MYC, and with support from foundations and VICC, he went “fishing” for its function.

NIH grants, he says, don’t usually allow this type of approach.

“My dream grant would have a lot of freedom and would be based on the talents of the investigator or the general approach, rather than the specific questions that were being addressed,” Tansey says.

“There was an article several years ago that said if Charles Darwin wrote an NIH grant to hop on a ship and go to the Galapagos Islands to look at the finches, he wouldn’t get funded.”

It’s a “sad reality” that the government doesn’t have enough funding available for biomedical research, he says.

“Cancer research is vibrant; it’s a heyday in terms of what we can do now, and yet we’re at a point where two-thirds of what I think is likely to be fruitful science is not funded by the NIH.”

– by Leigh MacMillan

 

Macara worries about drop in R01 funding

Ian Macara, Ph.D., considers himself to be very lucky. The chairman of the Department of Cell and Developmental Biology at Vanderbilt University Medical Center has been continuously funded by the National Institutes of Health (NIH) for more than 30 years.

Each successive grant has built upon the preceding one and led last summer to what he considers to be his “dream” grant—an Outstanding Investigator Award from the National Cancer Institute (NCI).

The grant, nearly $6.6 million over seven years, was awarded to support the “unusual potential” of his research, which seeks to understand and predict cancer cell behavior.

Macara, the Louise B. McGavock Professor of Cell and Developmental Biology, was one of about 60 researchers recognized in the first year of this award, which is designed to provide longer-term support for innovative research.

“With seven years of uninterrupted funding, NCI is providing investigators the opportunity to fully develop exceptional and ambitious cancer research programs,” said Dinah Singer, Ph.D., director of NCI’s Division of Cancer Biology, announcing the awards.

For Macara, who was recruited to Vanderbilt from the University of Virginia in 2012, cancer is not only the result of mutations in tumor promoter and suppressor genes, it is a disease of cell behavior and cell “context.”

If normal epithelial cells lining the internal and external surfaces of the body “suppress the proliferation of their neighbors,” he wrote in the award application, “transformed cells might be unable to express their oncogenic potential unless they escape from (that) environment.

“How cells escape the epithelium and proliferate (elsewhere) is central to understanding cancer initiation and metastasis,” he wrote.

Macara said the grant will enable his team “to push our research in new directions, to develop new tools and new models that will identify the types of cells from which breast cancers arise, and provide insights into how these cancer cells evade the suppressive influence of the normal tissue in which they are originally embedded.

“The seven-year period of the grant is particularly valuable, as it will enable us to try riskier approaches that can take a long time to develop,” he added.

“Cancer biology in particular can be very slow. It might take nine months or more for tumors to appear in a mouse model of breast cancer, for example, and we cannot move on to the next step in the study until we know the outcome of the first, so the years add up very quickly.”

Since 2005, VUMC’s federal bridge funding program has helped faculty members sustain their research programs when competitive NIH grant renewals are unfunded.

“The bridge program has been a lifesaver for several members of my department. And ultimately it pays for itself. Maybe the Medical Center gives an investigator $100,000 to keep his or her lab running and then that investigator gets a $2 million grant,” he said. “That’s a pretty good return on the investment.”

Still, Macara worries about what he called a “catastrophic drop” in the percentage of individual research investigator-initiated grants, called R01 grants, which are funded by the NIH.

“Basic research is the absolute driving force behind the entire economy of the Western world, and the driving force behind all advances in medicine,” he said.

– By Bill Snyder

 

Funding crucial for next generation of scientists

Good science is not only about discovery. According to Jeffrey Rathmell, Ph.D., good science is also about building community and about investing in the next generation.

On Sept. 1, Rathmell was recruited to Vanderbilt from Duke University to lead a new Center for Immunobiology. A professor of Pathology, Microbiology and Immunology, he also serves as co-leader of the Host Tumor Interactions Research Program at Vanderbilt-Ingram Cancer Center.

In his laboratory research, Rathmell has examined the metabolism of blood cells.

“I study metabolism in the immune system and how cells get their nutrients and grow, which also allows them to proliferate and change their functions. This system is altered in leukemias where the cells are growing out of control and the same processes are altered in autoimmune diseases and inflammatory settings like asthma or in anti-tumor immune responses,” Rathmell said.

His work at Vanderbilt will focus on the field of immunometabolism and how nutrient and metabolic pathways can influence immune responses in normal and diseased settings.

“Vanderbilt has great immunologists across the medical school, and the main goals of the new Center for Immunobiology will be to foster basic immunology science, which touches on many different fields and diseases, and to help build the immunology community,” Rathmell said.

“Independent of the research projects themselves I think the education component is important as well,” he added.

That’s where the NIH comes in.

“All the things that I want to accomplish are going to be exceptionally difficult to accomplish without an NIH component,” Rathmell said. “People need to think … about the NIH as a huge investment.

“The payout from the NIH is tremendous … That money also funds graduate students and postdocs (postdoctoral fellows) who then are trained and go forward … It’s not just a dollar in and a dollar out. It’s much, much more than that.”

A research grant not only supports the research but it helps pay for the education of graduate students and postdocs. “That’s the only way they can get to where they need to be,” Rathmell said.

“Vanderbilt is actually really, really well positioned for all of this,” he said. “The interactions between basic science and translational units are already quite strong here.”

And yet because the NIH funding is so tight, across the country more and more students are looking at alternatives to careers in science. “Not as many want my job as they used to,” he said. “That means you’re starting to lose the next generation.

“I think it’s a direct reflection of them seeing their professors struggling and having to spend a huge amount of time writing grants,” Rathmell said.

Because of this situation, the United States is starting to lose some of its competitive edge in science to other countries around the world.

“We’re giving it away now,” he said. “And it’s not just dollars.”

– By Bill Snyder

 

Yeast studies yield insights to human cancer

Yeast. We’ve used the tiny fungi for thousands of years to help bake our breads and brew our beers. And in more recent decades, yeast cells have also become powerful engines of scientific discovery.

Studies in yeast have revealed the “whole molecular machinery that is at the core of the cell cycle,” says Kathy Gould, Ph.D., who started working with the fission yeast Schizosaccharomyces pombe as a postdoctoral fellow at Oxford University.

The cell cycle includes all of the processes involved in producing new cells through cell division—processes that generate cells during development and that replace cells lost through injury or normal wear-and-tear. Cancer is a consequence of uncontrolled cell division, because of genetic mutations or other defects that dysregulate the cell cycle machinery.

The discovery that the yeast machinery has been conserved through evolution made it possible to “understand the regulation in a simpler organism and carry that forward to mammalian cells,” says Gould, Louise B. McGavock Professor of Cell and Developmental Biology. Her postdoctoral mentor, Sir Paul Nurse, was awarded the 2001 Nobel Prize for discovering key regulators of the cell cycle and showing that they are evolutionarily conserved.

After discovering the “parts list” for cell cycle machinery, “it was natural to start asking in cancer: how is that machinery different?” Gould says. “And there have been thousands and thousands of papers describing discoveries related to cancer.”

Basic science research on the cell cycle continues, she says. “There are still things we do not know.”

For example, Gould’s group, which has played a major role in understanding the molecular machinery that controls key processes during the cell cycle, has recently discovered another signaling cascade in yeast that puts the brakes on cell division when chromosome segregation is stalled. The team is now moving into mammalian cells to explore whether the pathway has been conserved.

“You could imagine that defects in that pathway could cause cell division to occur when chromosomes are not properly segregated,” she says. Such defects might lead to the development of cancerous cells, and understanding the pathway could offer another target for possible therapeutic intervention.

Support from the NIH for basic science discovery is critical, Gould says. Since joining the Vanderbilt faculty in 1991, she has been successful in obtaining NIH funding and was fortunate to be an investigator of the Howard Hughes Medical Institute for 19 years.

Gould is concerned about the length of the funding cycle for investigator-initiated R01 grants. The short four-year cycle means researchers are writing grant applications too frequently, before they’ve had time to “bring big complicated projects to fruition,” she says.

“It takes so much time to do science properly, and it takes so much money,” Gould says. “There are many, many examples where knowledge from basic science discovery has been translated to benefit human health, and we can’t predict a priori which experiments we should do to make those discoveries. It truly is research; we don’t know the answers.”

In addition to a longer grant cycle, Gould would like to see more money set aside for young investigators who are having an increasingly difficult time getting a first R01 grant funded.

“We’re at risk of losing an entire generation of scientists who just can’t get traction early on,” says Gould.

– by Leigh MacMillan