10 June 2013. A better understanding of neurological and neuropsychiatric disorders, including schizophrenia, requires a detailed examination of the affected organ—the brain. Unlike other organs that can be biopsied in living individuals, the direct study of the brain is only possible using postmortem tissue, a rare and precious resource that is collected and stored at brain banks around the country. With the goal of increasing availability of, and access to, human brain tissue specimens for research, the National Institutes of Health (NIH) has recently announced efforts to take a more integrated approach to brain banking in the United States by establishing a federation of brain banks that will use a centralized data management system.
The new initiative, a joint effort of the National Institute of Mental Health (NIMH), the National Institute of Neurological Disorders and Stroke (NINDS), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), aims to improve the support of brain banks, facilitate access to tissue by researchers, and to better educate the public about the idea of donating brain tissue for research.
The new model will mean dramatic changes to how brain banks are funded and subsequently run. Researchers will no longer submit grant applications to receive money to run their own brain banks. Instead, the initiative will establish several contract collection sites, known as NIH Brain and Tissue Repositories (NBTRs). In order to become an NBTR, prospective applicants will now bid for a contract—a legally binding agreement between a buyer (the government) and a seller (the contractor)—that obligates the contractor to collect tissue and obligates the government to pay for that service. As part of the contract, NBTRs will be required to acquire, process, store, and distribute the tissue according to standardized protocols and to acquire at least 75-100 new cases each year.
Although the new model of brain banking is a big change, many in the community feel it’s for the better. “If [the system] works the way they envision it, it will be really important and good,” said Maree Webster of the Stanley Medical Research Institute in Chevy Chase, Maryland.
Existing “boutique” brain banks, where individual researchers collect for their own purpose, have been very successful, said Webster. However, many researchers don’t have access to brain tissue. “We need to kind of have a culture shift in the way that we think about brain banking efforts,” said the University of Miami’s Deborah Mash, “to ensure that there is widened participation.”
The new initiative will be an improvement in terms of trying to make tissue more widely available, both Webster and Mash told SRF. Existing banks collect the whole brain but tend to study only specific brain areas. The federated system should help to pair unused tissue with researchers who want to use it.
Meeting of the minds
The process of change began with the formation of a Neurobiobank workgroup led by NIMH’s Roger Little and Michelle Freund. In May of 2012, the workgroup brought together brain-banking experts from across the U.S. and Europe for a meeting to discuss issues relevant to the new model. More than 25 brain bank directors, investigators who use human tissue, and experts from a variety of fields were present. “There was a very wide invitation that went out … I thought it was really well done,” said Mash.
Attendees of the Neurobiobank meeting discussed a range of issues surrounding access to tissue, standardization of collection processes, and bioinformatics, and were broadly supportive of the new initiative, Little told SRF. An additional outcome of the meeting was the formation of a subcommittee chaired by Harry Haroutunian of the Mount Sinai School of Medicine, Bronx, New York, and Dennis Dickson of the Mayo Clinic in Jacksonville, Florida, that was tasked with establishing a standard neuropathological and phenotypic characterization of control brains. In a series of weekly teleconference meetings, the group hammered out the minimum standards and data elements deemed necessary for consistent characterization across sites.
Let the bidding begin
A key feature of the new federated model is the use of a centralized information technology (IT) data management system, where prospective researchers can find all kinds of information about the tissue available at each collection site, including subjects' medical history, their exposure to medications and illicit drugs, and an assessment of the tissue quality. As for access to the data generated, Little told SRF that it will not be open access (due to privacy concerns), but will be made available to qualified researchers. In order to ensure that brain banks would consistently use the new IT system, the NIH switched from a grant support mechanism to a contract support mechanism. “Because a contract is a little bit more directive,” Little explained, “we’ll be able to ask that [all sites] participate in the federated IT system.”
As many brain banking sites across the country soon learned, contracts require a very different application process from that of grants. The NIH issued a formal request for proposals on 6 December 2012, with those submitting bids scrambling to decode 134 pages of detailed rules and instructions in time to meet the 30 January 2013 submission deadline.
The contract proposal, far more detailed than a grant proposal, required institutions to submit lengthy technical and business plans detailing all aspects of the brain banking process and the associated costs. The short time window for proposal submission made for a very intense few weeks, said Haroutunian and Mash, though they added that for those involved in the initial meetings, the conceptual and intellectual part of putting the application together had a much longer lead time.
SRF Advisor Karoly Mirnics of Vanderbilt University in Nashville, Tennessee, noted that the short time window for applications favored the existing brain banks that already had protocols in place that could be easily inserted into the application and potentially discouraged new institutions from submitting bids. Smaller institutions looking to develop new collections may have been at a disadvantage, agreed Mash.
Standardization across sites
One big change to existing psychiatric brain banks that currently operate independently will be the standardization of all protocols across contract sites. Currently, there is a lot of variation among existing brain banks in terms of collection protocols and donor characterization. This standardization will bring the mental health community up to the level of the Alzheimer’s and Parkinson’s brain banks, said Haroutunian, which already have minimum standards and consistent protocols in place. “The mental health community is now, through this initiative, coming closer to the other neuroscience-related brain banking approaches,” he added.
However, many of these details have yet to be decided, leading Mirnics to characterize the recent call for contract bids as “premature.” For example, how the brains are cut, whether the tissue will be fixed or frozen, and who will have access to the data are all issues that have yet to be worked out, he noted. "We were in the process of discussing all these important issues, and we were making progress. We should have concluded that process first," Mirnics said. He worries that this lack of consensus will hinder the ability of the contract awardees to integrate into one federated system. “The carriage and the horse are in the wrong order,” Mirnics told SRF. “The horse is pushing the carriage. That’s how it looks to me right now.”
Mash disagrees. “You’ve got to start somewhere,” she said. With the initiative being directed by multiple neuroscience institutes and involving key leaders in the field—from brain bankers to tissue users— “we will quickly move towards a consensus plan to ensure that the needs of the recipients are met,” Mash told SRF.
Broadening the scope of collection
Another major change to existing brain banks, which currently are largely specialized to collect tissue from a few related brain disorders, is that individual collection sites could be asked to collect tissue from any one of the myriad of diseases within the interests of the NIMH, NINDS, and NICHD. Control brains will also be collected at a variety of developmental ages in an effort to provide a clearer picture of normal human brain development.
The NIH recognizes how much effort and expertise goes into establishing a brain bank, said Little. Having a bank “only collecting one or two diseases … is kind of a lost opportunity,” he said. Broadening the scope of disease tissue collected will increase the efficiency of the system as a whole.
However, priorities will still have to be established, so it is unlikely that each site will be asked to collect tissue for every brain disorder, Little told SRF. “We’re always in a situation, especially in the current budget climate, of having to determine what the best use is of very limited funds, so we’ll have to make strategic investments and do the best science that we can,” he said.
In addition to improving access to collected brain tissue, another important advantage of the new federated system is that it will allow for the pooling of samples across NBTRs, dramatically increasing the number of subjects available for studies. Sharing samples will give users more variety and enable them to test a larger range of hypotheses. This will be especially valuable for the collection of normal control subjects, which are the limiting factor in any brain bank and crucial to making comparisons to disease, said Webster. “It’s very difficult to get good normal control tissue,” she added, but having a nationwide pool will make matching control and diseased brains much easier.
Another benefit of the initiative is its potential to improve brain donation through public outreach. Included in the IT system will be a central website where potential donors and families who have recently lost loved ones can get information about all of the banks, as well as learn about the process of donating. The new initiative also plans to enlist the help of disease advocacy organizations to raise awareness among the public about the importance and critical need for brain donations. Mash praised the federated system for “bringing this dialogue front and center.”
The hope is that the new brain banking model will increase the amount of tissue available for research, which will in turn translate to a better understanding of brain disorders in the future. As for the current status of the initiative, the NBTR contract bids are now under review at the NIH, with early August award dates anticipated, Little told SRF. Although he couldn’t disclose the number of applications, he said, “We had an even better response than we hoped for.”—Allison A. Curley.