Some scientists get from their retiring mentors a small and symbolic gift: a book, a tool, a picture. In the late 1970s, Edward L. Kaplan got from his about 40,000 tubes of blood serum encased in a mass of ice that he said “looked like a wooly mammoth.”
The tubes contained blood samples from 9,000 airmen collected from 1948 to 1954 to study rheumatic fever, a disease that sidelined thousands of soldiers during World War II. A pediatrician at the University of Minnesota Medical School, Kaplan had an interest in rheumatic fever. But that wasn’t why he accepted the present.
Although this was long before the genomics revolution and the discovery of “biomarkers” for disease, Kaplan had a hunch that there were secrets waiting to be discovered inside the ice-encrusted tubes. He was right.
In 2000, the serum was used to help elucidate hepatitis C, a viral infection that was unknown when the blood was drawn. In 2009, it was used to shed light on celiac disease, an intestinal ailment that, unbeknown to them, 14 of the airmen had. Today, three decades after Kaplan’s rescue of it, the tubes are in the custody of the U.S. government, waiting for more researchers to ask them questions.
“This collection is priceless. It’s absolutely priceless,” the 76-year-old Kaplan said recently.
The Warren Serum Collection (named after an air base in Wyoming) is one of many biological repositories — the exact number is unknown — whose potential usefulness grows each year.
In being well known, digitally annotated and relatively accessible, it’s an exception. Many collections — which include serum or preserved tissue, sometimes both — are obscure, catalogued only on paper and hard to get at. Some also date from an era before modern informed consent, which complicates their use and occasionally makes their custodians leery about inquiries. But there’s little doubt about their value as science finds better ways to retrieve enzymes, hormones, antibodies, fragments of infectious agents and pieces of genes from preserved tissue.
“You’ll never be able to collect samples like this again,” Jonathan Chernoff, scientific director of Fox Chase Cancer Center in Philadelphia, said of 450,000 tubes of serum that the center houses in a 40-year-old freezer room.
The samples were collected from people on five continents and in hundreds of isolated villages by Baruch S. Blumberg, who won a Nobel Prize in 1976 for discovering hepatitis B. It is highly that unlikely a single collection containing such genetic diversity could ever be amassed again. If for no other reason, getting informed consent from so many people in so many places would be nearly impossible.
“Nobody’s using them at the moment,” said Chernoff, who’s seeking a new, permanent home for the collection. “But that doesn’t mean that when the next epidemic appears you won’t want to go back and see if these samples have antibodies, or even the organism itself.”
The federal government is the most organized in preserving and publicizing collections.
Its most important one is held by the Joint Pathology Center in Silver Spring, an entity created after the closing last year of Walter Reed Army Medical Center, where the collection was part of the Armed Forces Institute of Pathology. It contains material from 7.2 million people — nearly all of them service members and their dependents — cared for by military doctors. The holdings include 55 million microscope slides, 28 million paraffin-embedded blocks of tissue and 700,000 preserved organs (“gross specimens”), dating back to 1917.
“We know of no collection anywhere that is comparable in size,” said center spokeswoman Louise T. Cooper. “It is the largest collection of tissue samples in the world.”
The government has smaller collections created specifically for research. They include serum from 16,000 white male twin pairs who served in World War II; from 7,000 twin pairs from the Vietnam War era; and from 3,000 Vietnam veterans who were either exposed or not exposed to the defoliant Agent Orange. The collections are managed by a combination of the Department of Defense, the Department of Veterans Affairs and the Medical Follow-up Agency, which was created by the National Academy of Sciences at the end of World War II.
The Institute of Medicine keeps a “cohort catalog” of the military collections. But there’s no similar list of collections held by universities, private research institutes and individual scientists.
“There isn’t a central source of information. As a researcher myself, I wish there was,” said David Butler, director of the Medical Follow-Up Agency.
The National Museum of Health and Medicine in Silver Spring has dozens of well-catalogued collections donated by institutions as diverse as the New York City medical examiner’s office and St. Elizabeths Hospital in the District. For the moment they are more useful for historical research than for scientific studies.
“Most hospitals don’t keep materials going back forever,” said David Louis, chief of pathology at Massachusetts General Hospital in Boston. “The large reason is purely financial. It’s the cost of storing things.”
That Harvard-affiliated hospital has autopsy records dating back to 1896, with the oldest tissue samples dating from about 1920. What’s saved long term, however, are special cases, or rare-disease material in which a researcher has taken special interest.
“We’ve discarded huge numbers of tissue blocks. We go through fairly routine purges,” Louis said. Before a mass of samples is discarded, researchers at the hospital are invited to speak up and ask that something be kept, “or forever hold your peace,” he said.
Some institutions have gone to great lengths to save old tissue.
When two bombs hit Royal London Hospital in World War II, almost the first thing the staff did was move the autopsy collection, which dated to 1880, into limestone caves in Cheddar Gorge, about 150 miles away.
When the material was moved back in the early 1950s, it was clear that some of the tissue blocks had been attacked by fungus and that the records from 1880 to 1908 had been lost, making the samples from those years useless. They were destroyed. What remains may be the oldest well-documented collection of human tissue in the world: thousands of matchbox-size containers holding wax-embedded pieces of organs (usually brain, lung, spleen and liver or kidney). They were obtained from the 300 to 400 patients who died in the hospital each year. The practice of routine autopsy ended in the 1940s.
“Storage is huge problem,” said Graham Tate, manager of the human tissue resource center at the hospital. The samples are in several buildings, separate from the paper documentation, which makes use more complicated. The oldest samples are in a basement in floor-to-ceiling stacks of wooden boxes with dates stenciled on their ends.
“You know the last scene of ‘Indiana Jones and the Lost Ark’? It’s a little like that,” Tate said.
But for a single-handed act of preservation, it’s hard to beat Edward Kaplan’s rescue of the airmen’s blood samples.
Although the collection always belonged to the federal government, its creator, Charles Rammelkamp Jr., took custody of it when the research laboratory at the Wyoming air base closed in 1954. He moved it to Cleveland, where he was a professor at what became Case Western Reserve University. When he retired in the late 1970s, he asked Kaplan to become the collection’s next protector.
The tubes were in 83 homemade wire trays, under a leaking condenser that had covered them with ice. The big question was how to get them from Cleveland to Minneapolis, where Kaplan worked, without letting them thaw. Flying was prohibitively expensive.
Kaplan explained his problem to a neighbor two doors away who owned a trucking company. The man said his firm didn’t have refrigerated trucks, but he knew of someone in St. Paul who did. Those trucks were used to ship frozen pizzas made in Duluth to East Coast customers.
Kaplan contacted the shipper, who agreed to pick up the frozen tubes at no cost on a return trip, provided that Kaplan write a testimonial about how the trucking industry was helping medical research. Kaplan agreed. He sent someone from his lab to Cleveland to supervise loading. Twelve hours later, the Warren Serum Collection was in University of Minnesota freezers.
“Everyone won,” Kaplan recalled, adding: “It would be impossible to pull off these days. Not hard, impossible.” (Among the many obstacles would almost certainly be a trucking company’s unwillingness to transport blood specimens in a truck normally used for food.)
At the Fox cancer center in Philadelphia, Jonathan Chernoff is hoping such heroics won’t be required to save Baruch Blumberg’s half-million blood samples.
He is trying to get a grant to computerize the collection’s paper annotation, a task he believes must be done before he can find a permanent home for it. He’s in early negotiations with Binghamton University in New York, which has a graduate program in medical anthropology and a biospecimen archive.
That archive holds about 200,000 serum samples collected by D. Carleton Gajdusek, a longtime researcher at the National Institute of Neurological Disorders and Stroke. Gajdusek worked on kuru, a brain disease found in a remote New Guinean tribe that practiced ritual cannibalism; it turned out to be caused by prions, a protein-based infectious agent. He received the Nobel Prize in Physiology or Medicine the same year Blumberg did, 1976.
Both collections include thousands of samples drawn from people in extremely remote villages in the Arctic, Oceania, Africa and Asia. Their ethnic and genetic diversity is unrivaled in the world.
In most cases, the samples are labeled by the age and sex of the donor, the village and date of collection. Occasionally there is health information and a name. Almost everything was collected without modern standards of informed consent. Often a tribal leader would give permission for everyone in the village to have blood drawn.
The archaic standards for consent and the fact that most donors weren’t told their samples might be kept and used for decades make some of the custodians defensive. When the director of the Binghamton archive, Ralph M. Garruto, was asked recently whether any of the Gajdusek samples had names on them, he said: “There are no names that will ever be released to the world. The names are not available. These people are dead!” and terminated the interview.
In fact, there are few ethical impediments to using old materials, assuming researchers are willing to jump through the required hoops.
Federally supported research (and, in practice, nearly all research) is governed by a “human subjects protection” policy that requires informed consent for all studies involving living, identifiable people and biological samples linked to them.
“I would be surprised if any consent from that time would still be valid today,” Carol Weil, an expert in regulatory and ethical affairs in the Office of Biorepositories and Biospecimen Research at the National Cancer Institute, said of the old serum collections.
However, informed consent can be waived by institutional review boards, the ethics committees at hospitals and universities to which researchers must submit their plans. Permission to anonymously test old samples for a virus or a disease would almost certainly be granted. Research that is even more aggressive — such as tracking down people who tested positive for a previously unknown condition — would not be out of the question.
But exactly how useful is old material for new tests for a virus or disease? For blood serum, the answer appears to be: very useful.
The samples from the Wyoming airmen were tested for hepatitis C antibodies in the late 1990s, and 17 of 8,568 came up positive. A few years later, different researchers looked for an enzyme and antibodies used to diagnose celiac disease, which is caused by sensitivity to gluten in grains. Fourteen of the airmen had that condition.
(In both cases, the researchers examined what happened to the people in the roughly 50 years after their blood was drawn. They found that hepatitis C increased the risk of death slightly and celiac disease increased it substantially, and that in many cases the people never knew they had the disease.)
The ability to get such information from preserved tissue — especially from whole organs that have been sitting in formaldehyde for decades — is less certain.
“A heart from 1955 can be used to make glass slides, but it may be of limited utility in today’s world,” said Col. Thomas P. Baker, the interim director of the Joint Pathology Center, who is hoping to make its huge collection more available to civilian researchers. “The real benefit of many of these tissues depends on whether you can use them for molecular studies. We don’t have an answer to that. It is one of the many things on our list to find out.”
The search for biomarkers is a major priority in medical science. There are dozens in clinical use and hundreds under investigation. Their presence or absence may provide information on a person’s nutritional state and fertility; the presence of a disease or increased risk for one; previous encounters with microbial invaders and environmental hazards — and lots of other things.
If it turns out old blood and tissue carry legible biomarkers, the time may come when these biological equivalents of letters mailed long ago can finally have their messages read in full.
This is the second of a two-part series.