Biomedical Sciences Blog

Feb. 7 (Bloomberg) -- The Obama administration is boosting funding for Alzheimer’s research by $50 million this year to further investigate the genetic underpinnings of the disease and test drugs that may arrest its development.

About 5.1 million Americans suffer from the condition and caseloads are expected to double by 2050, according to the U.S. Department of Health and Human Services. The cause of the degenerative condition is unknown and there is no cure.

Patient advocacy groups have intensified lobbying efforts in the last two years, arguing that federal research efforts are underfunded and the disease poses a long-term economic threat, said George Vradenburg, chairman of UsAgainstAlzheimers, a Washington nonprofit.

“If you look at it over the next 10 years, the aggregate cost is about $2 trillion -- which in fact is about the amount we’re supposed to be trying to reduce our operating deficit by,” Vradenburg said. “It is of that kind of scale.”

Medicare and Medicaid, the U.S. health programs for the elderly and the poor, spend about $130 billion combined each year treating Alzheimer’s patients, Vradenburg said.

The National Institutes of Health, the largest source of biomedical research funding in the world, expected to spend about $450 million on Alzheimer’s research this year before today’s announcement. The agency will spend about $3.1 billion on HIV/AIDS research this year and $5.8 billion on cancer.

Critical Challenge

Alzheimer’s “has quickly become one of our nation’s most critical health challenges,” Health and Human Services Secretary Kathleen Sebelius said at an event in Washington today announcing the new funding.

About half of the $50 million will be used to sequence the genomes of people with Alzheimer’s to try to identify genes and gene changes connected to the disease, said Richard Hodes, director of the National Institute of Aging in Bethesda, Maryland, the arm of NIH that directs Alzheimer’s research. The rest will be dedicated to the “most meritorious” Alzheimer’s projects at NIH’s 32 institutes, Hodes said by phone.

Vradenburg, whose wife’s mother died of Alzheimer’s, founded his organization in the fall of 2010 and has since joined with Eric Hall, president and CEO of another advocacy group, Alzheimer’s Foundation of America, to create Leaders Engaged in Alzheimer’s Disease, an umbrella organization.

The groups produced a report last May that criticized funding for the National Institute of Aging as “miniscule and declining” and called for an increase of $300 million per year, to $1.4 billion, for the office.

National Plan

President Barack Obama signed a law in January 2011 that creates a national plan to address Alzheimer’s. Vrandenburg and Hall sit on a board advising Sebelius’ department on the plan, which will be completed in May, Vrandenburg said.

Advocacy efforts for Alzheimer’s patients haven’t previously been as robust as those for cancer and AIDS patients because people with dementia often aren’t able to speak for themselves, Hall said.

Cancer, for example, “has survivors -- the people with the disease are able to raise their voice and engage,” he said. “Alzheimer’s disease is rather unique in that yes, some folks with Alzheimer’s in the early stage are able to speak. But generally they lose that ability; they’re not able to rally, if you will.”

Research breakthroughs are also driving the increased funding, Vradenburg said.

Suspect Protein

Scientists sponsored by NIH reported on Feb. 2 that for the first time they were able to track a protein associated with Alzheimer’s, called tau, as it spread through the brains of mice, destroying neurons. That and other recent developments have inspired confidence that new treatments may be found, said Francis Collins, director of the NIH.

Much of the new research may examine ways to prevent or slow the onset of Alzheimer’s, rather than treatments once it is established, Hodes said.

“The strong sense is that failure to make important in- roads to date is at least in part due to the fact treatment has been directed at established disease,” Hodes said.

Obama plans to ask for an extra $80 million for Alzheimer’s research in his fiscal 2013 budget, to be released next week, Sebelius said. Sebelius’ department also plans to spend $26 million this year for Alzheimer’s efforts unrelated to research, such as support for patient families.

By Alex Wayne

Last week, the National Institutes of Health (NIH) announced that the success rate for research grants, a closely watched indicator of how well investigators are doing in the struggle for funds, fell to an all-time low in 2011: 18%. At first glance, the drop appears to be due to increased competition, reflected in a steep rise on applications last year. But several other factors are also at play, including budget decisions made years ago, says NIH extramural research chief Sally Rockey.

The success rate is the number of funded grants divided by reviewed applications. The 18% success rate, announced by Rockey on her blog, is down 3% from 2010 and is slightly higher than a preliminary estimate last fall. It continues a decline from success rates of around 30% a decade ago when NIH's budget was growing. Part of the explanation is that the denominator is larger: investigators sent a record 49,592 research grant proposals to NIH last year, an 8% rise.

But that's not the whole story, Rockey says in a blog post today. Much of the rise is explained by a 17% increase in proposals for a specific category of funding—short-term R21 grants. The mainstay for most labs is the larger R01, NIH's individual investigator-initiated grant, for which the success rate slid from 22% in 2010 to 18% in 2011. Applications rose 3% for R01s. Another reason for success rate slippage is that NIH funded fewer R01 grants copmpeting compared with 2010. That's partly because the size of the average grant grew slightly and because NIH had less to spend overall on R01s (its budget was cut 1% last year).

But the most important factor, accounting for 1.5% of the success rate drop, is that a larger portion of R01 money than usual was tied up in already-awarded grants. Because most NIH grants last 3 to 5 years, each award creates several years of unfunded future commitments. The amount of money needed for these ongoing grants rose by $189 million in 2011, Rockey reports. "This demonstrates how carefully we need to manage our funds since funding decisions in any one year have implications for the out years," she writes. She posted a graph showing how the share of NIH's R01 money committed to ongoing grants fluctuates year to year. In 2011 it jumped to 78%, the highest level in 4 years.

A close NIH observer, Howard Garrison of the Federation of American Societies for Experimental Biology, says managing that out-year commitment is a delicate balancing act for the agency. If NIH gets a generous increase one year and doesn't fund more grants, "People like me go crazy because the money isn't going out on the streets," he says. Yet if Congress cuts NIH's budget a couple of years later and NIH's commitment has grown, "you're toast," and success rates plunge.

Rockey's bottom line: "The success rate is complicated and it's not just a single factor" that drives it, she told ScienceInsider. She adds that success rates don't necessarily reflect "the quantity of science" NIH is funding. The pool of funded investigators has remained fairly steady in recent years, she says.

Although NIH received a modest 0.8% increase in 2012, the agency appears to be girding for a period of austerity. A notice today states that continuing grants will get no inflationary increase in 2012 and new awards will not receive inflationary increases in future years.

by Jocelyn Kaiser on 20 January 2012 at science.com

January 24, 2012

Top biomedical scientists from 12 countries will receive an important boost at a critical time in their careers from HHMI’s inaugural International Early Career Scientist (IECS) awards.

The 28 recipients, chosen from 760 applicants, represent a wide range of disciplines, from neuroscience to virology to plant science. All the awardees trained in the United States as a graduate student or a postdoctoral fellow and have published important research. “These are the people who, 10 years from now, we expect will be the scientific leaders in their countries,” HHMI President Robert Tjian says.

The countries with the most IECS awardees are China (7), Portugal (5), and Spain (5), but recipients are also based in nine other countries: Argentina, Brazil, Chile, Hungary, India, Italy, Poland, South Africa, and South Korea. Nine of the 28 (32 percent) are women.

“We want their association with HHMI to have a significant impact on their careers,” says Jack E. Dixon, HHMI’s vice president and chief scientific officer. “It is important to have highly educated, effective scholars around the world, and we want to help those people build successful labs.”

These researchers—who have all run their own labs for less than seven years—will be integrated into HHMI’s scientific community, attending meetings and giving talks to HHMI’s investigators and early career scientists. HHMI funds 327 HHMI investigators and 48 early career scientists who direct laboratories at universities and research organizations throughout the United States. Among them are 13 Nobel Prize winners and 147 members of the U.S. National Academy of Sciences.

“This program is about building connections internationally,” says Edwin W. McCleskey, a scientific officer at HHMI who helps run the IECS program. “We have chosen talented people who we feel can build connections with our scientists.”

International programs are an important focus of the Institute, and Tjian was especially interested in strengthening ties to international labs given the worldwide connections of HHMI’s scientists. A June 2010 survey by HHMI of its investigators and early career scientists showed that 73 percent of those who responded collaborate internationally, and 62 percent have international postdoctoral students in their laboratories.

“Some young scientists really want to succeed in the scientific arena but see no opportunity to do that in their own countries,” Tjian says. “We hope this program will help change that.”

The 28 IECS awardees will each receive $650,000: $100,000 a year for five years plus $150,000 the first year for major equipment purchases and other investments (an additional supplement will go to their university or research institution). This represents a total commitment by HHMI of more than $20 million. The funding will start in February 2012.

The IECS program is the latest incarnation of HHMI’s international grants to individual researchers. Since 1991, HHMI has spent more than $145 million to fund international scientists working in specific geographic areas—including Canada, Latin America, and Eastern Europe—or in a specific field of research, such as parasitology and infectious disease.

When it came time to rethink those grants, Tjian and Dixon decided to design a program that provided support for early career scientists who would benefit most from a financial boost and the connection with HHMI’s scientific community. The research arena for early career scientists can be challenging internationally. For example, funding to help new scientists start up their labs can be quite variable, and often much less is available than in the United States.

Tjian and Dixon also decided to home in on countries where HHMI’s funding or connections could make the most difference. They thought HHMI support wouldn’t make much difference in countries where research funds are already plentiful, but they realized that not all countries make science a priority. “We chose countries that had the economic and educational infrastructure to support the level of science that we’re talking about, which is very expensive,” Tjian says.

Scientists from 18 countries were eligible to apply, and HHMI received 760 applications. A rigorous peer-review process narrowed the field to 55 semifinalists from 14 countries. For the first time, HHMI invited the semifinalists to give a 15-minute scientific presentation as part of the selection process. They delivered their talks to an international panel of scientific reviewers at a symposium in early November 2011 at HHMI’s Janelia Farm Research Campus in Ashburn, Virginia.

“The major criterion was really scientific excellence: what have they accomplished in their young careers; what kind of potential did they have; could they explain their science in a clear way,” Dixon says. See a bio of each awardee here.

The IECS program is just one part of HHMI’s current international efforts. In 2009, HHMI committed $60 million to build a new research institute in Durban, South Africa, the KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), dedicated to studying the deadly co-epidemics of HIV and tuberculosis. The Institute also funds International Student Research Fellowships to support international graduate students doing research at U.S. universities.

Meet the International Early Career Scientists

Newswise — When you experience a new event, your brain encodes a memory of it by altering the connections between neurons. This requires turning on many genes in those neurons. Now, MIT neuroscientists have identified what may be a master gene that controls this complex process.

The findings, described in the Dec. 23 issue of Science, not only reveal some of the molecular underpinnings of memory formation — they may also help neuroscientists pinpoint the exact locations of memories in the brain.

The research team, led by Yingxi Lin, a member of the McGovern Institute for Brain Research at MIT, focused on the Npas4 gene, which previous studies have shown is turned on immediately following new experiences. The gene is particularly active in the hippocampus, a brain structure known to be critical in forming long-term memories.

Lin and her colleagues found that Npas4 turns on a series of other genes that modify the brain’s internal wiring by adjusting the strength of synapses, or connections between neurons. “This is a gene that can connect from experience to the eventual changing of the circuit,” says Lin, the Frederick and Carole Middleton Career Development Assistant Professor of Brain and Cognitive Sciences.

To investigate the genetic mechanisms of memory formation, the researchers studied a type of learning known as contextual fear conditioning: Mice receive a mild electric shock when they enter a specific chamber. Within minutes, the mice learn to fear the chamber, and the next time they enter it, they freeze.

The researchers showed that Npas4 is turned on very early during this conditioning. “This sets Npas4 apart from many other activity-regulated genes,” Lin says. “A lot of them are ubiquitously induced by all these different kinds of stimulations; they are not really learning-specific.”

Furthermore, Npas4 activation occurs primarily in the CA3 region of the hippocampus, which is already known to be required for fast learning.

“We think of Npas4 as the initial trigger that comes on, and then in turn, in the right spot in the brain, it activates all these other downstream targets. Eventually they’re going to modify synapses in a way that’s likely changing synaptic inhibition or some other process that we’re trying to figure out,” says Kartik Ramamoorthi, a graduate student in Lin’s lab and lead author of the paper.

Genetic regulation

So far, the researchers have identified only a few of the genes regulated by Npas4, but they suspect there could be hundreds more. Npas4 is a transcription factor, meaning it controls the copying of other genes into messenger RNA — the genetic material that carries protein-building instructions from the nucleus to the rest of the cell. The MIT experiments showed that Npas4 binds to the activation sites of specific genes and directs an enzyme called RNA polymerase II to start copying them.

“Npas4 is providing this instructive signal,” Ramamoorthi says. “It’s telling the polymerase to land at certain genes, and without it, the polymerase doesn’t know where to go. It’s just floating around in the nucleus.”

When the researchers knocked out the gene for Npas4, they found that mice could not remember their fearful conditioning. They also found that this effect could be produced by knocking out the gene just in the CA3 region of the hippocampus. Knocking it out in other parts of the hippocampus, however, had no effect. Though they focused on contextual fear conditioning, the researchers believe that Npas4 will also prove critical for other types of learning.

Gleb Shumyatsky, an assistant professor of genetics at Rutgers University, says that an important next step is to identify more of the genes controlled by Npas4, which should reveal more of its role in memory formation. “It’s definitely one of the major players,” says Shumyatsky, who was not involved in this research. “Future experiments will show how major a player it is.”

The MIT team also plans to investigate whether the same neurons that turn on Npas4 when memories are formed also turn it on when memories are retrieved. This could help them pinpoint the exact neurons that are storing particular memories.

“We’re hunting for the memory, and we think we can use Npas4 to mark where it is,” Ramamoorthi says. “That’s because it’s turned on specifically and now we can label the cells and maybe fish out where in the brain the memory is sitting.”