Sharing Made Easy

Melina Fan just wanted a few plasmids. In 2004, the young biologist was wrapping up a PhD in the lab of Bruce Spiegelman at the Dana-Farber Cancer Institute in Boston. She was working on a project to identify proteins that interact closely with PGC-1, a protein involved in mammalian metabolism. Fan wrote to 20 laboratories asking for plasmids—pieces of DNA that encode individual genes—for each of the proteins she was targeting. “Maybe only half the labs got back to me,” says Fan. “And even then, I never knew if or when they were actually going to send [the plasmids].” It took 2 to 3 months on average for a plasmid to arrive at Dana-Farber, and some of the ones Fan received turned out to code for the wrong genes. Her project slowed to a crawl. Instead of bearing a grudge, however, she bore an idea. “I figured other labs probably had the same problem,” says Fan. When she queried colleagues to find out exactly why obtaining materials was so difficult, she discovered that the problem wasn’t secrecy or competition—it was logistics. It can be hard to locate materials created by students or postdocs who have come and gone from a lab, researchers said, and packaging and shipping the requested materials sucks time away from research. So in 2004, Fan set out to create a better way to share research materials. With husband Benjie Chen and brother Kenneth Fan, she cofounded a nonprofit repository for plasmids called Addgene. The trio leased space at Harvard University and began collecting plasmids from colleagues at various Boston institutions. Eight years later, Addgene now boasts its own facility in Cambridge, Massachusetts, and stores and distributes more than 18,000 plasmids to scientists around the world. “Labs are very excited to share their materials—now that it’s easy for them to do it,” says Fan. And Fan was not the only one with the idea. While Addgene is one of the most recent of these nonprofit biological resource centers (BRCs), it is far from the first. The American Type Culture Collection (ATCC) in Manassas, Virginia, now the largest BRC in the world, began distributing biological materials in 1925. Another early comer to the sharing game was the Jackson Laboratory in Bar Harbor, Maine, the first national repository for mice, which has been collecting, developing, and distributing strains of research rodents since 1936. Storing and distributing biological materials is not a glamorous or even an easy business—funding, advertising, and logistical challenges abound—but it has become a core service for the biological research community, facilitating the sharing of resources on a scale never before seen in the life sciences. To share or not to share Most researchers agree that the free sharing of ideas, data, and resources is vital to the advancement of science. But a 2002 survey of 1,240 geneticists at 100 universities reflected a view that sharing had decreased during the preceding decade. Forty-seven percent of respondents who had asked other faculty for information or materials from published research said they’d been denied at least once in the preceding 3 years. And nearly 60 percent of those who had been denied access said they were unable to confirm published results. Finally, among the 12 percent who admitted to denying another academician’s request in the previous 3 years, 80 percent reported that it required too much effort to produce the desired materials or information (JAMA, 287:473-80, 2002). WORLDWIDE SHARING: An Addgene scientist prepares the day’s plasmid shipment. Approximately 1,500 plasmids are shipped each week to laboratories around the world. Credit: Kenneth Fan BRCs are working hard to increase the amount of sharing, relieving individual labs of the work required to maintain reagents and process requests. After receiving up to three or four plasmid requests per week, neurogeneticist Mark Cookson of the National Institutes of Health decided to submit his materials to Addgene. Not only did this eliminate the burden of filling individual requests, which required that one of ?his eight lab members take an hour away from research to prepare and mail a sample; it also made the plasmids available to people who couldn’t find them in the literature or hadn’t thought to ask for them. To date, Cookson has deposited approximately 80 plasmids with Addgene (there is no cost to deposit materials), and those plasmids have received more than 500 requests. “That’s 500 things we didn’t have to deal with, and that’s very helpful,” says Cookson. The Jackson Laboratory in Maine (JAX) runs an analogous sharing program for mouse models, with more than 6,000 strains of mice available to researchers worldwide, says spokesperson Joyce Peterson. “If ?you read the fine print in an NIH grant, you’re expected to make any resources you develop available to other researchers,” she notes. “Do you really want to start your own mouse breeding and distribution operation? No? Then you send it to JAX!” When the ATCC was founded almost a century ago by microbiologists at the John McCormick Institute of Infectious Diseases in Chicago, the organization stored only bacterial strains. Today, from its headquarters in Manassas, Virginia, the company boasts the world’s largest and most diverse culture collection: 155,000 items from cell lines to microorganisms to viruses, says company president Brian Pollok. On average, ATCC ships 1,300 to 1,500 orders per week. The price of sharing Contrary to popular belief, neither the ATCC nor Addgene receives government funding for its daily operations. (The ATCC does have several specialized collections funded by the NIH.) Instead, the companies rely on the scientific community to purchase their services, like any other private business. But as nonprofits, they sell materials at cost rather than marking them up. Addgene, for example, sells plasmids for about $65 each, as compared to $300-$500 at a commercial company, says Joanne Kamens, the company’s executive director. Some BRCs do rely on government funding, but a system that charges customers is the most sustainable option, says Yoshihide Hayashizaki, director of the Omics Science Center at RIKEN in Japan. In 1994, when Hayashizaki was a research scientist at the RIKEN Tsukuba Life Science Center, he was part of a team that constructed yeast artificial chromosomes (YACs) for gene mapping. The Japanese government funded the group to distribute the YACs freely to the community, but when a budget cut put an end to the free distribution, public relations became difficult. “Once the government funding stopped, the community started to complain a lot, so we had a tough experience,” says Hayashizaki. The ordeal led him to a belief that is now a cornerstone philosophy for many BRCs: “Once we establish a distributing system, we have to continue, and everybody in the world has to be able to access that resource,” he says. “The best way to do so is by charging the customer.” Today, RIKEN is home to the popular RIKEN BioResource Center, established in 2001, which collects materials developed mainly by Japanese scientists, including cell lines, mice, plant seeds, and more, and charges customers per order. In addition to large BRCs like RIKEN and the ATCC, smaller, scientist-run centers provide a variety of specialized resources. In 1993, Pieter de Jong, then at Roswell Park Cancer Institute in Buffalo, New York, received government grants to build a collection of bacterial artificial chromosomes (BAC), bacterial vectors that hold large segments of DNA for cloning. The collection became a major source of clone material for the Human Genome Project, and today forms the BACPAC Resource Center at Children’s Hospital Oakland Research Institute, a nonprofit distribution arm of de Jong’s laboratory. De Jong made the conscious decision not to hand over his libraries to the ATCC or another large BRC, but to instead maintain them himself. “I wanted to have a feel for how people used [the resource], so I could better tailor it to their needs,” he says. Still, he admits, “some days, it’s a headache.” After 30 years of de Jong’s work building more than 150 libraries, BACPAC consists of 120 freezers filled with 40 million recombinant DNA clones—from bacteria, humans, mice, and numerous other organisms—used by some 13,000 scientists internationally. “When I look back, sometimes I think I’m a hoarder,” de Jong says with a laugh. “We don’t get rid of anything.” That includes the platypus and elephant clone libraries, which aren’t requested too often, he notes. Benefits of sharing Many researchers say they deposit materials into BRCs to advance research and the free spread of information. But such donations are not always entirely altruistic. At Addgene, for example, depositors accrue points with each sale of their plasmids and can spend those points to purchase plasmids for their own lab. In addition, a 2011 analysis by business professors at Boston University and the Massachusetts Institute of Technology found that scientists get a citation bump simply by depositing in a BRC.In a comparison of journal articles that did and did not link to ATCC specimens, the researchers found that depositing specimens with the ATCC boosted a paper’s citations by 57 to 135 percent. In the future, BRCs will continue to improve their offerings, says Pollok. Currently, the ATCC is developing specialized material sets, such as tumor cell panels and groups of microbes associated with antibiotic resistance. Addgene has the same idea. In the spring of 2012, the company announced a collaboration with the Michael J. Fox Foundation to provide a collection of plasmids relevant to Parkinson’s disease. The collection currently contains 100 plasmids donated by four researchers, including Cookson, and continues to grow. “If there’s ease of access, it diminishes barriers, engages researchers, and ultimately accelerates research,” says Sonal Das, associate director of research programs at the Michael J. Fox Foundation, who contacted Addgene about starting the Parkinson’s collection. “We’re trying to foster a way for [researchers] to continue to work on what they’re doing, but also put their research out there for others.” Behind the scenes In addition to sharing biological resources, BRCs play several underappreciated roles in the life science community. For instance, they function as massive physical backups for biological materials. Addgene maintains three physical copies of each plasmid—two on site in Boston and one in Washington, DC—and numerous digital backups of their sequence data. The ATCC also maintains a physical backup of every material and offers a unique service for researchers or companies that work with especially valuable resources: biological safe deposit boxes. For a fee, customers can lock materials in highly secure freezers kept behind a cage and accessible only by the depositor. Several hundred companies, including international organizations depositing microorganisms awaiting patent approval, utilize this service, says ATCC spokesperson Jaleel Shujath, though the exact number is confidential. BRCs also play a unique role in maintaining the integrity of the community’s biological materials by performing extensive authentication testing. By verifying the identity of the materials as they are deposited, BRCs have likely already prevented numerous contamination incidents that weren’t caught in the past, such as the 1970s contamination of numerous cell lines with hardy, proliferative HeLa cancer cells. Even today, some estimates suggest that 15 to 20 percent of all cell lines are contaminated or mischaracterized. BRCs, however, are trusted sources of materials because they guard against these problems. Addgene, for example, tests each plasmid to verify the gene identity, a service that Fan and other scientists used to perform on their own. Finally, certain BRCs provide methodological continuity for the research community. In January 2012, for example, the ATCC, which is accredited by the American National Standards Institute as a standards developing organization, announced a new standard for authenticating human cell lines, a valuable tool given the significant proportion of misidentified human cell lines used in research. “What ATCC can do, as a nonprofit but also nongovernmental organization, is to drive consensus around methodologies for measuring aspects of biomaterials,” says company president Brian Pollok.

Sharing Made Easy

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Megan Scudellari

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September 2012

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