NEWS FEATURE
to personally pick up the samples from the sur- Tracking down tissues geons’ offices, eventually building a network of more than 18 surgeons who contribute an aver- FDA inspections of tissue banks remain a work in progress, and no age of 50 liters of fat per month from consenting patients. Using that tissue, Cytori developed an clear path yet exists for procuring human tissues for biomedicine or automated system that separates stem and other drug development. Emily Waltz investigates. regenerative cells from the fat, and the company is now developing cell-based therapies that treat cardiovascular disease and aid healing in recon- Last year’s headlines about an underground structive breast surgery. trade in human body parts in New Jersey1 Cytori researchers are not alone in concocting prompted a public outcry and the formation a patchwork method for gleaning human tissue. of the Human Tissue Task Force (HTTF)—an Companies frequently approach clinical col- internal US Food and Drug Administration leagues, body donation programs, tissue banks, (FDA) body with the specific mission of tight- for-profit brokers and even their own employees ening the oversight of human tissue procure- to get samples for drug studies. Obtaining tissue ment. This summer, the HTTF released its using these methods is usually legal and ethi- first report, which identified several areas in cal, say experts, as long as the proper consent is need of improvement, such as tracking systems obtained and the tissues themselves are not sold and more regular audits2. Two months later, for a profit. FDA inspections of a few hundred (of several Some of the most frequently studied tissues thousand) human tissue banking and procur- are biopsies and tumors from living donors. ing facilities revealed that the number of estab- Like many companies, Bristol-Myers Squibb,
http://www.nature.com/naturebiotechnology lishments with ‘objectionable conditions’ had based in Princeton, New Jersey, collects tissue more than doubled (http://www.fda.gov/cber/ samples from consenting cancer patients in its tissue/inspdata.htm). Although according to the clinical trials to look for molecular corollaries FDA these situations pose little risk to human and potential targets. health, companies requiring human tissue for To help cut down on surprises when a com- R&D still face a mélange of options in a supply pound goes from animal models to the clinic, system that is disorganized and scattered. And as companies sometimes use human tissue as an
the demand for human tissue grows, companies Inc. Researchers, AJPhoto/Photo additional preclinical step. “We do a lot of weed- are having to find their own ways of collecting In the US, the demand for human tissues for drug ing out in that process,” says Mark Cockett, vice material and determining its quality. R&D is growing. president of applied genomics at Bristol-Myers. “There have been a number of programs that Big demand we have stopped working on because we discov- The HTTF was set up last year by the FDA after back to the question: What is the best material to ered that the human biology is different than the Nature Publishing Group Group 200 7 Nature Publishing
© it discovered that a New Jersey tissue recov- use? Time and time again, the answer is human mouse biology.” ery company and several funeral homes were tissue,” he says. “This industry has spent billions “Using human cells allows an early read stealing body parts from the deceased, forging of dollars trying to duplicate what already exists on safety,” adds Neil Warma, CEO of Viron medical records and passing the tissues on to [in nature].” Therapeutics in London, Canada. “It gives hospitals for transplant. The FDA closed down Yet in the United States, there is no central you the advantage of stopping development the company and the principals were indicted. clearinghouse or resource center for these tis- early, and the cost savings associated with that Experts say this kind of egregious abuse is sues. Instead, tissue providers have popped up are enormous.” Viron is developing viral pro- driven largely by the great demand from the all over the country to meet clinical needs, scat- tein–based anti-inflammatory therapeutics medical community for donated human tis- tering the tissue supply. A mishmash of US state and often demonstrates efficacy using human sue—a demand that has increased rapidly over and federal oversight hasn’t helped organize the tissues, such as endothelial cells and hepato- the past two decades. As drug discovery becomes system and, at the same time, has allowed some cytes, that are configured into customized cell- increasingly target driven, scientists are finding nefarious characters peddling dirty body parts interaction assays. more applications for human tissue. Nearly to succeed in the industry. Scientists, especially Hepatocytes, isolated from whole donated liv- any scientist who tests drug candidates, har- those looking for specific or unusual tissue, are ers and liver resections, are a frequent request vests regenerative cells, makes delivery devices often forced to find their own way. from scientists who study toxicology and drug– or creates bioimplants will likely have a use for drug interaction of compounds. The cells, which donated human tissues. Do-it-yourself networks act as a filter through which drugs must pass and But with the unpredictability of death and When the founders of San Diego–based Cytori do a majority of the detoxification and metab- the reluctance of the public to donate, there Therapeutics realized in 2004 that they needed olism in the body, are important indicators of often isn’t enough tissue to go around. “If sup- enormous amounts of human fat to develop whether a drug might change or become inac- ply wasn’t a problem, human tissue would be their technologies, they began collecting it the tive. The FDA requires metabolism and toxicol- used in every procedure out there,” says Jamie best way they knew how: they called the plastic ogy data for every new drug before it is approved Grooms, CEO of AxoGen in Alachua, Florida. surgeons in their address books and asked them and sometimes specifically recommends that a The firm is developing peripheral nerve grafts to save the fat from their patients’ liposuction company test its candidate on human tissue from donated nerve tissue. “It always comes procedures. The company sent its employees before it reaches clinical stages.
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clearinghouse for research tissue. It keeps an Table 1 Selected vendors of human whole tissues and cells inventory of frozen samples of everything from Institute/Company Tissues arteries to uteri and also places fresh tissue National Disease Research Frozen tissue inventory and fresh tissue liaison; big selection, directly with researchers. Interchange (NDRI) including rare diseases, HIV, cord blood, stem cells, tissue microar- rays, pancreatic islets, arteries and whole organs Nonorgan tissue destined for implantation International Institute for the Fresh tissue liaison; frozen tissue inventory; whole body donation is sent to processing companies that special- Advancement of Medicine (IIAM) program; normal and diseased tissue; whole organs ize in cleaning and shaping it. Allosource, of (Jessup, Pennsylvania) Centennial, Colorado, specializes in musculo- Lonza Walkersville Isolated cells from fresh, normal tissue; inventory of frozen cells; skeletal tissue and sells everything from patella custom procurement of non-normal tissue wedges to Achilles tendons. They obtain the tis- AllCells (Emeryville, California) Primary cells from normal and diseased tissue, including sue through four large OPOs, screen it for dis- hematopoietic, endothelial, leukemia and dendritic cells eases, eradicate bacteria and then cut and shape Asterand (Detroit, Michigan) Fresh, frozen and formalin-fixed paraffin-embedded samples; it. Tissue distributors, such as Medtronic’s spinal primary cells; tissue microarrays; custom procurement division in Memphis, Tennessee, often connect processing companies with implant surgeons. Other companies specialize in isolating cells In addition, a host of firms incorporate Sharing (UNOS; http://www.unos.org) to find from donated tissues. Lonza Corporation has human tissue into implant products and regen- a recipient and helps coordinate the transfer of a division called Lonza Walkersville, based erative therapies. For example, Organogenesis, the organ. In 2006, nearly 15,000 people donated in Walkersville, Maryland, that specializes in based in Canton, Massachusetts, makes a cir- an organ, but at any given time nearly 100,000 this area and will set up customized donation cular piece of bioengineered skin the size of a people are awaiting an organ transplant, accord- programs to meet specific requests. Columbia, hockey puck that integrates into wounds, such ing to statistics kept by UNOS. Maryland–based Osiris Therapeutics goes to as venous leg ulcers, and helps them heal. The Viable organs, particularly the kidneys, liver, Lonza for bone marrow. Osiris is developing
http://www.nature.com/naturebiotechnology bilayered product is made by incorporating heart, lungs and pancreas, get priority over therapies using mesenchymal cells separated collagen with fibroblasts and keratinocytes research needs when there is a potential recipi- from bone marrow for graft-versus-host disease, from newborns’ circumcised foreskin, which ent waiting for a transplant. For organs that Crohn’s disease, acute myocardial infarction and the company gets from local hospitals where cannot be used for transplantation, some OPOs, arthritis of the knee. parents have consented to donate, according to such as the New York Organ Donor Network, Living donations—such as biopsies, amni- Geoff MacKay, Organogenesis’ CEO. Now that in New York City, have established relationships otic fluid and tumors—that would other- they’ve honed their technique, they can make with researchers and connect them directly with wise be disposed of as hazardous waste, are about 100,000 final products from one piece of the fresh tissue. fairly plentiful and more likely to end up with discarded foreskin. In addition to hospital staff, many others, researchers. For instance, Ervin Wheeler, a Although researchers often need only a few including medical examiners, funeral homes, plastic surgeon in La Mesa, California, who cells to conduct their studies, finding just the hospice caretakers and law enforcement officials, collects fat for Cytori, says none of his liposuc- right kind can be tricky. “If I didn’t know a also have first-line access to bodies, although the tion patients have ever chosen not to donate to dozen plastic surgeons, this would be very dif- usefulness of this tissue is limited by time and the company’s research efforts. Nature Publishing Group Group 200 7 Nature Publishing
© ficult,” says Eric Daniels, senior director of busi- competing interests. A medical examiner’s top Clinical trials are a good place to collect living ness development at Cytori. priority is to determine the cause and manner of donor samples accompanied by follow-up health Even the National Institutes of Health death, says Kristin Roman, medical examiner for data. The National Surgical Adjuvant Breast (NIH), in Bethesda, Maryland, is struggling to Staten Island, New York. Certain tissues may not and Bowel Project (NSABP), in Pittsburgh, is a track down samples for its $100 million cancer be removed if they interfere with the autopsy. clinical trials cooperative group that requires its genome atlas project. The project aims to iden- For instance, a drug called papaverine, which is member institutes to send tissue samples from tify all the genetic mutations associated with sometimes used to cut street drugs, is also used trials. Over the past 40 years, the group has col- cancer and requires thousands of tumor sam- to preserve blood vessels for donation and could lected samples and clinical follow-up from more ples. So far, despite access to major tissue banks, be misleading on a toxicology report, according than 100,000 people, according to Soon Paik, the agency has only a fraction of the particular to Roman. director of the division of pathology at NSABP. tumors it needs3. Some ethical rules for collecting tissue The method for preserving the tissue long-term limit donations as well, often for good reason. requires fixing it in formalin and then encas- Scattered supply Aborted fetuses offer a wealth of important tools ing it in paraffin, or wax, which limits what can The supply of tissue starts with formal dona- for scientists, but a federal law prohibits medi- be done with the tissue. But companies such as tions, mostly through hospitals where staff are cal staff from requesting consent from parents Genomic Health, of Redwood City, California, required by federal regulation to report deaths who are considering abortions, as it may sway which makes a breast cancer assay and other to their local organ procurement organization, their decision4. molecular diagnostic services, have been able to or OPO. The OPO acts as a liaison to find recipi- There are a host of tissue banks in the United harness information from the NSABP samples ents for transplantable organs and homes for the States that store the tissue once it is procured. to create their products, according to Steve Shak, rest of the tissues. Some of these banks specialize in tissues such chief medical officer at Genomic Health. Organ donation for transplant is one of the as eyes or bones. A few organizations special- But with such a decentralized system, many few areas in which there are highly organized ize in getting tissue from primary sources to industrial researchers are choosing to forfeit the networks for tissue distribution. The OPO researchers (Table 1). One of the largest, the hunt and start their own collections. Pfizer, of checks the computerized national waiting list Philadelphia-based National Disease Research New York City, has a biobank where it stores operated by the United Network of Organ Interchange (NDRI), is the closest thing to a both animal and human tissue. When Bristol
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Myers needs blood samples to study plate- let targets for thrombotic disease, the com- Box 1 The regulations pany often turns to its own employees for The FDA, through its Center for Biologics Evaluation and Research (CBER), regulates tissue volunteers. Like many universities, Indiana intended for transplant under 21 CFR Parts 1270 and 1271. The regulations focus on University (IU), in Bloomington, Indiana, preventing the use of tissue contaminated with infectious disease and preventing tissue has several tissue banks set up by various handlers from contaminating the tissue, says Paul Richards, a spokesperson for CBER. If schools or collected by individual investi- the results of processing cannot be verified by inspection and tests, the processors must gators. Indianapolis-based Eli Lilly recently use established procedures (good tissue practices or GTPs) during all steps in recovery, set up a deal with IU that gives its scientists donor screening, donor testing, processing, storage, labeling, packaging and distribution. access to many of those tissues. The regulations also focus on screening donors before tissues are released, says Richards. Manufacturers must screen and test donors for risk factors for, and clinical evidence of, Messy laws a number of communicable disease agents including HIV, hepatitis B and hepatitis C. In The multiple layers of rules that govern the addition, reproductive tissues and donors of leukocyte-rich cells must be screened for tissue trade certainly haven’t helped solidify additional pathogens. the industry. On the federal level, the FDA Tissue intended for research use only is not regulated by the FDA at present. However, the requires every establishment that handles tis- American Association of Tissue Banks is currently developing standards for research tissue sue for transplant to register with the agency, and will require infectious disease testing of donors whose tissues may only be recovered for and it audits several of these establishments research use. This would be applicable only for those research banks that seek accreditation each year (Box 1). Anyone donating tissue for research tissue banking (in development), according to Scott Brubaker, chief policy for transplant must be tested for infectious officer for the AATB. diseases, and donors must be screened for risk factors such as drug abuse, according to FDA guidelines. Most nonorgan transplant Public attitudes identifiable material,” says Eric Meslin, a bio-
http://www.nature.com/naturebiotechnology tissue, such as meniscus or bone, must be Since the 1800s, when the bodies of those who ethicist at IU. “If the public [says] ‘no bloody processed to rid it of bacteria, but the stan- couldn’t afford a burial were often donated to way’, then it would be good to know that dards vary from processor to processor. medical schools for dissection, the research in advance.” Tissue used solely for research or education community’s access to cadaverous human tis- Emily Waltz, New York, New York
is almost completely unregulated. sue has been somewhat taboo. And although the 1. Waltz, E. Nat. Med. 12, 487–488 (2006). In addition to FDA regulations, four states benefits of life-saving transplants from tissue 2. Human Tissue Task Force. 2007 Report (Department of license and inspect tissue establishments on donations are becoming better known, high- Health & Human Services, Public Health Service, Food and Drug Administration, Bethesda, Maryland, USA, their own. Accreditation of tissue banks is left profile scandals involving ethical malpractice 2007). © to approve the specifics, such as consent ing to give permission to use more and more comment/0,431159,00.html>. forms. The Uniform Anatomical Gift Act of 1987 provides guidelines for states on how to govern donated tissue for transplant, and Box 2 A global problem? every state has adopted the act, but in vari- ous forms. It was revised in late 2006 with The US isn’t alone in needing to hone its oversight of tissue procurement procedures. In language that makes the donation process the UK, it was discovered that doctors were collecting organs from deceased infants and easier for donors and families, and as of children without discussing it with the parents. Although no one was prosecuted in the most 5 October, 19 states had adopted it. On top highly publicized case , this incident raised awareness of the issue, which provided an of the federal regulations, suppliers tend to impetus for tightened regulations surrounding human tissue donation. Last year, for the first get audited by their customers, which means time, the UK began requiring formal consent from all donors and set up the Human Tissue inspections can happen on a weekly basis, Authority in London to inspect tissue establishments and regulate the use of human tissue says Kevin Cmunt, executive vice president for both research and transplant. at Allosource. This year, Germany is also centralizing its tissue banks. In the past, donated tissues were With a variety of US laws, and whole bod- kept in various hospital and nonprofit tissue banks throughout the country. Under the new ies fetching more than $200,000 on the mar- law, donated tissues must be at least reported to a central repository, if not kept there. In June, the bill was passed by the German parliament, or Deutche Bundestag, and was signed ket, some people with access to body parts into law effective August 1. have taken advantage of their unique situ- In 2000, Singapore created a bioethics committee to build a basis for regulation of ations. Several people involved in last year’s the country’s relatively new biomedical sector, and nearly all of the regulatory documents scandal with Biomedical Tissue Services, the since then have focused on donated tissue. “You can’t get away from touching human Fort Lee, New Jersey, tissue recovery com- tissue,” says Edison Liu, who heads the committee. The reports are adopted by Singapore’s pany, face up to 25 years in prison for falsify- regulatory agencies, such as the Ministry of Health, which oversee internal review boards ing records. There have also been instances at hospitals where tissues are collected. A national tissue repository stores a majority of the of ethical malpractice in tissue collection in remaining tissues. the UK (Box 2). 1206 VOLUME 25 NUMBER 11 NOVEMBER 2007 NATURE BIOTECHNOLOGY