The genomic revolution has been heralded as the gateway to personalized medicine, but to make those promises a reality, medical researchers are realizing that they will need access to patient specimens and detailed patient data on a scale never before assembled. The concept of banking patient tissue for research is hardly new; there are some 300 million specimens preserved in biobanks throughout the United States managed by clinical trials cooperative groups, academic institutions, and individual investigators.
The National Cancer Institute has been working since 2002 to unify these biobanks through its planned National Biospecimen Network (NBN), but progress has been slow relative to that in other nations, and future funding for the project has yet to be identified.
The bold mandate issued for the NBN in its "blueprint" calls for a nationwide system of regional biospecimen repositories united under a single management that uses a single bioinformatics and tissue collection system. It calls for building on existing specimen banks, but how these regional biobanks are to be managed and how they would relate to existing tissue resources is unclear.
The trouble, according to NBN project director Anna Barker, Ph.D., is that so many of the biological specimen repositories that have been created over the years were developed by individual investigators, each of whom has a substantial investment in his or her resource and each of whom has unique methods for obtaining and annotating specimens.
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For the NCI, even doing a recent survey of existing repositories of cancer specimens has been fraught with difficulty.
"The NCI [has] never really tracked in any kind of methodical or systematic way their biorepositories," said Barker. "The larger ones we know about and we track, but frankly there are many, many repositories we don't know about."
The NBN plan calls for a 3-year demonstration project, but Barker said its initial survey turned up scientific and organizational issues that must first be addressed. She said that the NCI is planning to bring together representatives from some of the best organized biorepositories to begin to settle on best practices for tissue collection and annotation and allocation of resources. And, as of yet, it is unclear how the endeavor will be funded.
"The concept is it will be a multi-sector funding effort," said Barker. "We are already spending a lot on tissue resources. Our issue is alignment and agreeing on access. It may be there is money in the system that we can deploy in different ways."
Although specific numbers are hard to come by, NCI set aside $40 million in its 2006 budget request for "development of molecularly based interventions," which includes the biospecimen initiative and a cancer genome analysis program. In the meantime, other countries are moving ahead with ambitious biobank projects.
"I am beginning to have some fears here that we are losing ground in terms of the international community," Barker said. "A number of countries have moved beyond where we are and are investing huge sums of money relative to their gross domestic product [in biobanks]."
Iceland, Sweden, Singapore, Australia, and the United Kingdom have already set up national biobanks, many as stand-alone nonprofit entities, with other nations following suit. In July 2004, the Australian government announced that it would spend $14.2 million to establish or extend eight national tissue and cell banks. Singapore is already spending millions on its infrastructure, and in December, IBM and the Karolinska Institute in Stockholm announced that they are teaming to build Sweden's biobank.
But the usefulness of linking existing tissue repositories is questionable, says Christopher Corless, M.D., Ph.D., director of the Cancer Pathology Shared Resource at Oregon Health and Science University in Portland. He said he would not be comfortable ordering tissue from other institutions because of a lack of standardization in tissue acquisition and annotation.
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In addition, he said, many cancer specimens have been preserved as paraffin-embedded tissue, while many genomic and proteomic applications require fresh frozen tissue.
"Whether a specimen is 15 minutes old or 2 hours old is going to have a huge impact on the quality of the RNA and potentially of the proteins," Corless said. "That has to be factored in, and when the sample is stored away and recorded is a critical piece of information about it."
Barker said she ran into the same lack of common terminology problem in trying to survey existing repositories. "To some extent, there was even confusion on what constitutes a biospecimen," she said.
The NCI is trying to play a leadership role in the area of standardization, she said. Beyond surveying existing resources, it has begun several initiatives based on the recommendations of its blueprint. It has adopted a single framework for data management, dubbed the cancer Biomedical Informatics Grid (caBIG), that aims to provide the computing infrastructure for true nationwide connectivity. And it is recruiting a molecular pathologist to lead a research team that will look at key questions such as how anesthesia affects the protein and nucleic acid composition of tissues.
"I think molecular pathology is actually going to be the new order of the day in the post-genomics era," she said. "Pathologists will be playing an entirely new and crucial role in science. We want to know that we are measuring the biology of the disease versus the effects of some external factor."
Daniel H. Farkas, Ph.D., director of molecular diagnostics at the Methodist Hospital at Texas Medical Center in Houston and immediate past president of the Association for Molecular Pathology, said that, although he is not familiar with the details of the NBN plan, he thinks it is crucial for U.S. competitiveness to establish a network of tissue resources that all use the same set of standards.
"It's a daunting challenge," said Farkas. "The National Committee for Clinical Laboratory Standards is working as we speak on a document for [standardizing tissue collection for] microarrays .... There are numerous books, papers and manuals on how to collect tissue for high-quality DNA and RNA extraction, but I don't know that there is a [single] standard out there."
Corless pointed out that organizing a single national network would require a new layer of organization and funding that does not now exist.
"It is very expensive. You are talking about getting academic pathologists to sit down and spend time on stuff that isn't related to their research," he said. "You have to get them [pathologists] to buy into the concept, and then you have to get them all on the same playing field in terms of the use of terminology so that there has to be a standardized nomenclature, and it has to be used in the same way by everybody who is contributing specimens. Otherwise, it's useless."
Some states, including New York, Georgia, and Pennsylvania, aren't waiting for national standards and have moved ahead on their own to develop biobanks. The Pennsylvania Cancer Alliance Bioinformatics Consortium (PCABC) is perhaps the most advanced, with six regional cancer centers banding together to share resources and develop a common bioinformatics platform. Funded by tobacco settlement money, the Pennsylvania program is already moving beyond collecting tissue specimens to including annotation with genomic, proteomic, and biomarker assay data.
"One of the things that's become clear to me is the tissue itself is very valuable, but it becomes extremely valuable by adding the clinical information that describes the specimen and all of the features of the patient from which that specimen is derived," said Michael Becich, M.D., Ph.D., director of the Center for Pathology Informatics at the University of Pittsburgh Medical Center. "The expensive parts of this are the informatics and the infrastructure to manage it."
Becich, who has been involved in tissue banking for more than 20 years and was a founding member of the NCI-funded cooperative prostate cancer tissue resource (CPCTR) network, said that, in his experience, it is possible to put together a biospecimen network that works, but the organization must be done up-front and under terms that all parties agree upon.
"We've put together over 6,000 prostate specimens over a 3-year period of time through CPCTR, which are now networked and available through kind of an eBay of prostate tissues to the research public," he said.
Becich is now spearheading a pilot project to bring a rural health care network into the PCABC network. To address the complex issues that this network will entail, the University of Pittsburgh is using a commercial partner, Ardais Corp. of Lexington, Mass., to bring in scientific and regulatory expertise and provide uniform standards for tissue collection.
"I agree that it's very costly, and that's why my own personal approach is to synergize among multiple NIH-funded efforts, borrowing from each of them and obviously benefiting each of them with the infrastructure that other funded components bring to the table," said Becich.
Barker agrees that the key to making the NBN work will be buy-in from its investigators and the public by establishing what the NCI is calling the "chain of trust."
"They have to know this is going to work and serve them well," she said.
John Newton, chief executive officer of the U.K. Biobank, agreed, cautioning, "If you get half way through designing a project like this and you suddenly find you haven't got support for some element of it, it's too late to go back and get it."
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