From: L. Stephen Coles, M.D., Ph.D. <scoles@ucla.edu>
Date: Sat, Apr 21, 2012 at 1:12 AM
Subject: [GRG] Poor Lab Technique on Cell Lines Slows Cancer Therapy
To: Gerontology Research Group <grg@lists.ucla.edu>
Cc: Martin Schroeder <martin_schroeder@emmesgroup.com>
To Members and Friends of the Los Angeles Gerontology Research Group:
Poor lab technique slows cancer therapy. We need to fingerprint
each cancer cell line with a full DNA sequence... -- Steve Coles
"Lab Mistakes Hobble Cancer Studies But Scientists Slow to Take Remedies"
by
AMY DOCKSER MARCUS
Eros Hoagland for The Wall Street Journal Pathologist David Tarin at the
University of California, San Diego, where he studies breast cancer,
Thursday. April 20, 2012; 10:25 PM EDT (WSJ) -- Last year, cancer researcher
Robert Mandic got news no scientist wants to hear. After publishing a paper
on a rare head-and-neck cancer, he learned the cells he had been studying
were instead cervical cancer. He notified the journal Oral Oncology, which
retracted the article. To base something on wrong data is bad, so it needs
to be reported and I did," said Dr. Mandic, a researcher at the University
Hospital Giessen and Marburg in GERMANY. "But it wasn't pleasant to call."
Dr. Mandic entered a largely secret fellowship of scientists whose
work has been undermined by the contamination and misidentification of
cancer cell lines used in research labs around the world. Cancer
experts seeking to solve the problem have found that a fifth to a third or
more of cancer cell lines tested were mistakenly identifiedwith researchers
unwittingly studying the wrong cancers, slowing progress toward new
treatments and wasting precious time and money. In hundreds of
documented cases that undermine a broad swath of research, cancer samples
that were supposed to be one type of tumor have turned out to be another,
through either careless laboratory handling, mislabeling or other mistakes.
It is a problem hiding in plain sight. Warnings to properly test
cancer cell lines have sounded since the 1960s, a decade after scientists
started making human cancer cell lines. But researchers who yelled
loudest were mostly ignored by colleagues fearful such a mistake in their
own labs would discredit years of work. Leaders in the field say one
of the biggest obstacles to finding a cancer cure may not be the many
defenses nature affords malignancies, but the reluctance of scientists to
address the problem. "Screaming and shouting, it doesn't do any
good. No one takes any notice for reasons I don't understand," said John
Masters, a Professor of Experimental Pathology at University College London,
UCL. "The whole ethos of science is to strive for the truth and produce a
balanced argument about the evidence. Yet, all this crap is being produced."
Dr. Masters said cell banks report that 20 percent of cell lines
sent for inclusion in their repositories for use by researchers are
improperly identified. He was co-chair of an international committee of
scientists that released voluntary guidelines this year to begin solving the
problem. They call for, among other measures, routine profiling of cell
lines using a DNA technique employed in forensics called "short tandem
repeats," or STR. Much of cancer research seeks answers to questions
of basic biology, so the proper identification of cell lines may be less
important, said Dr. Masters. But when seeking cancer treatment for a
specific tumor, he said, such mistakes "are an utter waste of public money,
charity money and time."
Worse, he added, "It may be causing drugs to be used which are
inappropriate for that particular type of cancer." Cancer research relies
on cell lines that originate in patient tumors. The cells are usually grown
in plastic containers and, with the proper nutrients, can live indefinitely
in a laboratory. Scientists store them in freezers for years. The cells
mimic particular kinds of tumors, giving researchers a way to understand
what drives a disease or to test promising drug treatments. It may
take a year or more to find the right combination of nutrients to keep
cancer cells growing. Once a line is established, scientists often share
them with colleagues, who then grow them in their own labs. The problem is
that many scientists don't test the cells when shipping or receiving a
batch. The most famous and ubiquitous human cancer cell line was the
firstan aggressive, fast-growing cervical cancer taken from Henrietta Lacks
of Maryland before her death in 1951. It has been shared with scientists
world-wide in the decades since, playing a broad role in medical research
spanning polio to hemophilia. The so-called HeLa cells, named for
Ms. Lacks, also have taken over other cancer cell lines, many times unknown
to researchers. These mix-ups are maddeningly difficult to pinpoint:
an improperly sterilized pipette, a lab worker momentarily distracted, a
misread label or a typo on a record sheet. Cell repositories in the
U.S., U.K., Germany, and Japan have estimated that [18 - 36] percent of
cancer cell lines are incorrectly identified. Researchers at Glasgow
University and CellBank Australia found more than 360 such mistaken cell
lines, including 100 that turned out to be the late Ms. Lack's cervical
cancer cells. "All of this sharing of cell lines, it's a bit like
having unprotected sex," said David Tarin, a Pathologist at the University
of California, San Diego. Dr. Tarin himself is at the center of a
lingering debate over the true identity of a famous breast cancer cell line
known as MDA-MB-435. Dr. Tarin has spent 25 years working with that cell
line - or so he thinks. A body of research suggests that MDA-MB-435 isn't
breast cancer; many scientists now believe the cells growing in labs and
used in decades of research are Melanoma. The line originated at the
M.D. Anderson Cancer Center in Houston, using cells from a 31-year-old woman
who died in 1976, less than a year after she was diagnosed. The cell line
was among the most widely used in metastatic breast cancer research.
In 2000, scientists at Stanford University, working in collaboration
with the National Cancer Institute, started testing the 60 cell lines in the
institute's permanent collection. Michael Eisen, then part of the
Stanford team, said they found something surprising about the breast cancer
cell line: genes that mimicked melanoma. "It stuck out as problematic," said
Dr. Eisen. At the time, the scientists didn't suspect contamination.
They thought the breast cancer patient also might have had undiagnosed
melanoma. Other scientists, following up on the observations at
Stanford, demonstrated that MDA-MB-435 behaved like melanoma because it
likely was melanomain particular, a skin-cancer cell line called M14.
As word spread, Michael D. Johnson of Georgetown University Medical
Center and a team of colleagues tested stocks of MDA-MB-435 from their lab
and others around world. He said the group assumed their laboratory cell
lines were the "real ones," and that other scientists' lines had been
corrupted. Instead, the group found every one of the cell lines tested was
melanoma, not breast cancer. Decades of research had been built on
insights from research using that cell line. Now, said Dr. Johnson, "I'm not
going to use them to study breast cancer. I don't believe they are breast
cancer." Dr. Tarin disagrees, citing his own study that
showed breast cancer tumors can have melanoma-like genes.
Increasingly, medical journals won't accept research on breast cancer
involving the MDA-MB-435 cell line, throwing into question decades of
experiments and innumerable published papers based on the line.
Seeking to solve the problem, a committee led by ATCC, a nonprofit
group based in Manassas, Va., released guidelines this year to establish
standards to authenticate cancer cell lines. ATCC is working with
the National Center for Biotechnology Information, a branch of the National
Institutes of Health, to establish a central repository and database of cell
lines that have undergone genetic testing and whose origins can be verified.
The National Institutes of Health have, so far, not required cell
line authentication as a condition of receiving federal grants. The NIH in
2007 called for more stringent peer-review when cell lines are used in
papers submitted for publication. Journals of the American Association For
Cancer Research now require authors to disclose how and when their cell
lines were tested. One challenge is getting scientists to
acknowledge their cell line is contaminated. The prevailing attitude,
according to researchers, is that the other lab's cell line may be
contaminated but not mine. Osamu Tetsu, a head-and-neck cancer
researcher at the University of California, San Francisco, did a study in
2009 that concluded all six known cell lines used by researchers studying
adenoid cystic carcinoma were contaminated. All of the work done on
the rare cancerpublished papers, research, drug studieshad been conducted
with mislabeled cell lines, Dr. Tetsu concluded. He called the findings
"catastrophic." Jeffrey Kaufman, Executive Director of the Adenoid
Cystic Carcinoma Research Foundation, said the group lost about $150,000 on
a project that had to be scrapped. He alerted Dr. Mandic, who had a lab
perform STR profiling on his cell line, which came from a colleague, who got
it from another scientist a decade earlier. Tests revealed it was Ms. Lack's
cervical-cancer cell line. The scientist cited in Dr. Tetsu's paper
as the source of one of the corrupted cell lines said his lab wasn't
responsible. Ruy Jaeger of the University of São Paulo in BRAZIL wrote in an
E-mail to The Wall Street Journal that his cell line was, in fact, Adenoid
Cystic Carcinoma. He also pointed out he had not directly provided the line
used in the published paper. Dr. Tetsu said he tested a cell line
created from Dr. Jaegar's line by a scientist in the U.S. The only way to
resolve the dispute, said Dr. Tetsu, would be to perform STR profiling of
Dr. Jaegar's cells and compare them to the DNA of the original cancer
patient. The problem is particularly damaging for research into such
rare cancers as adenoid cystic carcinoma, which strikes 1,200 people in the
U.S. each year. The lack of a good cell line slows research and few in the
field have the time or resources to create new lines. More broadly,
the sharing of cell lines is such an intrinsic part of scientific culture,
Dr. Tetsu said, that "it is almost impossible to stop." University
of Washington scientist Stanley Gartler warned about the practice in 1966.
He had developed a pioneering technique using genetic markers that would
distinguish one person's cell from another. Using the process, he tested 20
of the most widely used cancer cells lines of the era. He found 18 of the
lines weren't unique: They were Ms. Lacks' cervical cancer. "People
were upset," said Dr. Gartler, who published his findings a year later in
the journal Nature. "No one wants to admit they made a mistake." Dr.
Gartler, an 88-year-old professor emeritus, said a decade after publication
of his findings he attended a conference and introduced himself to a
scientist. Dr. Gartler recalled the man told him, "'I heard your talk on
contamination. I didn't believe what you said then and I don't believe what
you said now.' " That became a long-held view. Nearly 40 years
later, Dr. Masters, in a study of scientific papers published between 2000
and 2004, found nearly a 1,000 citations of the same contaminated cancer
lines revealed in Dr. Gartler's 1966 findings, which have since been
replicated many times using more advanced techniques. "They are either
crooks or stupid," said Dr. Masters. Financial donors to cancer
research are unaware of the problem, Dr. Masters said, and "it would be a
pity if money stopped going to cancer research" because scientists fail to
test their cell lines, a procedure that costs about $200. From San
Diego, Dr. Tarin wrote to the ATCC to say his studies show that MDA-MB-435
is a breast cancer line, not melanoma. He has not heard back. Yvonne
Reid, who works for the ATCC and was a member of the committee that wrote
the new guidelines, said, "It is hard to come down for one or the other"
without testing tissue from the breast-cancer and melanoma patients who
originated the cell lines. Donald Morton, who was part of the team
at UCLA that in the 1980's grew the original melanoma line now believed to
have contaminated MDA-MB-435, said his cell line has genetic markers that
match the original patient with melanoma. Dr. Morton, currently the
Melanoma Program Director at the John Wayne Cancer Institute in Santa
Monica, CA, said he would share frozen tissue samples from the melanoma
patient with scientists seeking to test against contaminated cell lines.
His melanoma cells, Dr. Morton said, are indeed melanoma. "What happened
after that cell line left my Lab," he added, "I cannot say."
Write to Amy Dockser Marcus at amy.marcus@wsj.com A version of this article
appeared April 21, 2012, on page A1 in some U.S. Editions of The Wall Street
Journal, with the headline: Lab Mistakes Hobble Cancer Studies But
Scientists Slow to Take Remedies.
L. Stephen Coles, M.D., Ph.D., Co-Founder
Los Angeles Gerontology Research Group
URL: http://www.grg.org
E-mail: scoles@grg.org
E-mail: scoles@ucla.edu
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http://heybryan.org/
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