During World War II, before the advent of laser-guided missiles, battle ships were equipped with cannons that weighed 2,000 tons and required dozens of sailors to muscle them toward their target. The National Human Genome Research Institute, as it transitions from sequencing genes to understanding how they work, moves in much the same lumbering way — though without the sailors.
These days, the US National Institutes of Health, and especially the NHGRI, is starting to turn its focus toward functional genomics, and has formally begun to “closely examine” how its resources can be applied to pharmacogenomics, according to an NHGRI official.
And while the initiative is still in its early stages — the agency has only just begun talking with industry and academia about ways to help it define its expanded role — when the NIH starts to point the working end of its $27 billion annual budget at a new research area, people take notice.
“The guns here have been focused very squarely on the sequence, and now they’re moving to apply that same kind of energy … to the translational problems,” said Christopher Austin, who advises Francis Collins, director of the NHGRI, on translational research issues. “The question now facing NIH, and especially NHGRI, is, ‘When we have [those data], what will we do with them?’”
Austin offered this hint: “Pharmas want to use [pharmacogenomics technologies and data], the FDA wants them to use them, but there’s a certain amount of inertia at this point because nobody’s quite sure who’s going to take the first step. I think the NIH is certainly interested in helping that dialogue. It’s such an obvious issue.”
These initial steps are part of the NIH’s broader attempt to become more involved in genomics, particularly functional genomics. In fact, these initiatives — which chiefly include the ENCODE program, additional resources to develop new sequencing and genotyping technologies, greater comparative sequencing programs, moving NIH funding farther down the drug-development continuum, and the International HapMap project — are the first young buds of a program, the NIH Roadmap, that Elias Zerhouni, the NIH director, launched in September.
Some of these projects have been ongoing for more than two years, others are still in the early planning stages, and most are likely due for additional cash, the vast majority of which is slated for extramural research projects. Though accurate and timely financial details are difficult to obtain — the NIH, like most government agencies, is bound by federal budgetary machinations — the thought that even a sliver of the $3 billion that supported the Human Genome Project might now be shifted to pharmacogenomics is enough to have many in that space rubbing their palms.
“It’s nice to know that NIH is on board,” Ronald Salerno, director of experimental medicine and worldwide regulatory affairs at Wyeth Research, and co-author with Lawrence Lesko of a seminal Pharmacogenomics article one year ago, said after hearing at a recent conference that the agency wishes to play a greater role in pharmacogenomics.
Indeed, in fiscal year 2003, which ended Sept. 30, the NIH funded 380 pharmacogenomics-related projects across its 18 institutes and centers. Austin said these figures will most certainly increase, though he could not elaborate. Mark Guyer, director of the NHGRI’s Division of Extramural Research, which tracks funding for external projects, was unavailable for comment. However, it is known that the NIH is set to receive a 3.2-percent increase in funding in 2004, which would increase its budget to $27.1 billion, and that basic and applied research projects, which account for nearly all of the agency’s budget, would enjoy a 7-percent funding increase, to $26.9 billion, according to the agency.
Research that received the most funding in 2003 — and which is likely to receive the lion’s share in fiscal 2004, which began Oct. 1 — include initiatives such as “pharmacogenomics in the treatment of breast cancer,” a National Cancer Institute program; “pharmacogenetics and antithrombotic therapy,” a program spearheaded by the National Heart, Lung and Blood Institute; “ethnic variations in antidepressant response,” led by the National Institute of Mental Health; and “selection of drug resistance in malaria parasites,” organized by the Fogarty International Center. Austin mentioned these programs during a speech at a pharmacogenomics conference sponsored by the Drug Information Association and held in Washington, DC, last month.
Another linchpin in the NIH’s goal of contributing to pharmcogenomics is the ENCODE (Encyclopedia of DNA Elements) project, which the industry welcomed with open arms when it was announced in October. This program, led by Elise Feingold, will cost around $36 million over the next three years and is “aimed at discovering all parts of the human genome that are crucial to biological function,” according to the NHGRI. One pilot component of ENCODE is to test existing high-throughput technologies and methodologies for “identifying, locating, and fully analyzing” the “functional elements,” including genes and the proteins they encode, in a certain set of DNA target regions that cover roughly 30 megabases of the human genome. Currently, the NHGRI has issued grants to 11 academic centers worldwide and two companies, Affymetrix and Nimblegen, for this and similar projects. The NHGRI said if the pilot effort is successful, it will be expanded to cover the entire genome, which will mean additional funding for pharmacogenomics tool vendors.
Results of these trials will not only help the NIH better understand these genomic components, but will also introduce the agency to innovations that may otherwise remain underfunded or ignored.
NIH also wants to develop new technology platforms, according to Austin. Specifically, the institute has set aside an undisclosed amount of money to develop new approaches for gene sequencing, genotyping, expression analysis, and proteomics. The goal, said Austin, is to drive down the cost to genotype a single SNP to $.00003 or less — or around 30,000 SNPs per dollar — and to lower to $.01 the cost of synthesizing a DNA molecule.
Additionally, the NIH plans soon to establish a central office to receive private-sector queries, Austin said at the conference. Details of this office are still evolving, he added.
NIH: Drug Developer?
One of the boldest new steps the NIH plans to take — which may also carry the greatest promise for pharmacogenomics — is the decision to extend its reach down the drug-development pipeline. The NIH “is taking a very serious look at how it can contribute to drug development,” said Austin, who is a former Merck official. Broadly, he said, the agency wants to ensure that there’s a reason why the word “health” exists in its moniker. Indeed, the agency has never been invested in therapeutic development. Traditionally, the NIH has focused on basic research, and has left the translational and therapeutic-development aspects — those areas of drug discovery and development closely linked to pharmacogenomics — to the private sector. “I think that has served everybody well,” Austin told SNPtech Reporter. “However, I think a number of things have changed, which has led the private and public sectors to rethink how this relationship has worked.”
These days, the NIH funds drug-discovery research in the earliest stages of target identification. Now, with gobs of pharmacogenomics and chemical genomics data and technologies at its disposal, the agency wants to expand its role to fund assay development and high-throughput screening. Collectively, this stretch of the drug-development pipeline covers at least three years, and ushers compounds into lead optimization and toxicology studies.
For the first time, said Austin, the NIH is “beginning to think, in a broad, trans-NIH way, of a way to get itself interested in those applications that will get it closer to patients.” Drug makers “may have more of a partner in NIH than [they’ve] had before.”
“There is no way that the private sector can do all of the target validation studies,” he continued, adding that the agency will collaborate with individuals in the private sector, both from biopharma and from the tool space. “The NIH must help here. The question is, ‘What should NIH do that will be enabling to the private sector … while at the same time focusing on areas that the private sector is not interested in, such as orphan diseases,” he said. This, too, is evolving, and will require new hires as well as a new mindset, he stressed.
“There are fundamental issues that are being dealt with on the level of, ‘What should NIH do, and what aspects of therapeutic development should it catalyze?’” he said. The NIH believes this goal is at least three years out, he added.
Private-sector labs met the new NIH goals with optimism. “I think it is a natural extension from the Human Genome Project to move forward, in their attempt to bolster emphasis in this area [of pharmacogenomics],” said Mark McCamish, chief medical officer of Perlegen Sciences. “It pushes the science and the potential applications” of pharmacogenomics technologies.
McCamish, who was one of the 500 industry, academic, and government participants attending the DIA meeting in November at which Austin spoke, echoed the opinion of many of his peers when he suggested that the serendipitous timing of NIH’s goals and the FDA’s newly released draft guidance on pharmacogenomics bodes well for the discipline [see 11/6/03 SNPtech Reporter]. “To get those two working together would be exciting,” he said. “The FDA really is intrigued about the science of pharmacogenomics, and wants to understand it better and actually help apply this technology in their evaluation” of drug candidates. “The NIH, on the other hand, is looking to create some technologies, and to foster the use of these technologies. The NIH may in fact help us to be able to scientifically develop and refine these technologies,” he said.
“This is an open window, and we need to make things happen,” he added.