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NIH Says Flaws in Cell Authenticity Must Be Fixed, But Calls Gov’t Mandate ‘Impractical’

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WASHINGTON, DC — The National Institutes of Health last week told investigators that although it agrees with the contents of an open letter recommending that academic centers and the federal government help abolish misidentified and cross-contaminated cell lines used in biomedical research, it would be “impractical” for the agency to require all grant applications to use uniform methodologies.
 
Instead, the NIH recommends that journals which publish or granting agencies that fund research using cell lines “consider these issues carefully in order to protect and promote the validity of the science” the agency supports.
 
The notice, which can be seen here, was issued in response to an open letter dated July 11 from Roland Nardone, professor emeritus of biology at the Catholic University of America and 18 members of the cell biology community and other experts to Secretary of Health and Human Services Mike Leavitt.
 
In the letter, seen here, the researchers expressed concern about the ongoing use of misidentified and cross-contaminated cell lines in biomedical research. They said that major cell line repositories, including the American Type Culture Collection, have received submissions that were found to have been misidentified when they underwent authentication testing.
 
According to the letter, such misidentification and cross-contamination wastes taxpayer and private dollars and has serious public health consequences, which include the possibility that vaccines and therapies may have been developed using misleading or false data.
 
The authors suggested that relevant professional societies should work together to launch educational initiatives, and that fund-granting agencies and scientific journals adopt a policy of no authentication/no grant or publication.
 
In response, Norka Ruiz Bravo, NIH deputy director of extramural research, and Michael Gottesman, NIH deputy director of intramural research, said that while they agree with the contents of the letter, “because authentication methods can be quite specific and are continuously evolving, it would be impractical for the NIH to require application of particular methods in all grant applications.”
 
Setting Standards
 
According to Thoru Pederson, a professor of biochemistry and molecular pharmacology at the University of Massachusetts Medical School, many authentication protocols exist, but no widely accepted standard has been adopted by the scientific community.
 
In principle, the US Food and Drug Administration is responsible for overseeing mammalian cell lines, including stem cells, which are used to create therapeutics, he said.
 

“Whenever you are wasting money, you are also wasting time and you can mislead others in the field.”

“The optimistic thing I can say is that most experts in the use of cultured mammalian cell lines, including both embryonic and adult stem cells, would have a fairly good consensus of what a standard operating manual should be, if you got them around a table,” Pederson told CBA News.
 
Nardone’s letter does not go into what a standard operating procedure should contain, but it does set down a framework by which a number of experts could develop guidelines that the FDA could find acceptable if the agency decides to legally move to take jurisdiction, said Pederson.
 
It is a question of whether and when the FDA wants to get involved, Pederson said. The agency is endowed with the authority, but not required to fulfill it. 
 
“The best thing that could happen is that there would be broader emphasis on a wide consensus [regarding] the standards,” Pederson said. He added that he thinks leadership could come from the National Academy of Sciences through the National Research Council rather than through the NIH, although the NIH would certainly support the NAS and NRC position “in spirit.”
 
However, Pederson said that he does not think the NIH would take responsibility for setting and enforcing standards because many labs that use human embryonic and adult stem cells use private funds and therefore operate outside of the NIH’s jurisdiction.
 
The problems of cell line authentication are exacerbated because cell culture is so “sexy” to the biomedical community that investigators from other areas of biology, who have little or no cell culture experience, now want to do cell culture, Nardone told CBA News. Unfortunately, such researchers often do not understand what is required for good cell culture quality control.
 
Nardone said that although the NIH notice was “diplomatically worded,” he feels the message got across because “I have already had five people call me and ask about how to authenticate!”
 
Ron Smith, a graduate student in pediatric nephrology at Northwestern University, agreed with the points in the open letter. “I think the bigger issue is that whenever you are wasting money, you are also wasting time and you can mislead others in the field,” he said.
 
If investigators publish results and they are not what they claim them to be due to cross-contamination or misidentification of the cell lines used, this could result in significant controversy, he said.
 
Sujata Lahke-Reddy, a research associate at Case Western Reserve University, suggested creating a database that includes information such as cell morphology and characteristic doubling time, so that researchers can compare the cells they have in their lab to the information in the database.