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Biological Chemistry

Research Pitfalls

by Rudy M. Baum
May 26, 2014 | APPEARED IN VOLUME 92, ISSUE 21

Three stories in this week’s issue illustrate, in different ways, pitfalls researchers can fall into if they’re not careful. And it’s not just science that suffers when these problems are encountered. People’s lives can hang in the balance.

Associate Editor Andrea Widener addresses the increasingly common “reproducibility problem” in biomedical research (see page 38). She cites a 2003 clinical study of minocycline, a potential drug to treat amyotrophic lateral sclerosis (ALS), that actually made patients worse. The fault was in a poorly designed preclinical study involving only 10 mice.

Widener quotes Story C. Landis, director of the National Institute of Neurological Disorders & Stroke, which funded the minocycline study. “The notion has existed for quite some time that science is self-correcting,” Landis said. “While that principle remains true over the long term, over the short term that is not quite as true as we would like. The checks and balances that would normally allow science to be self-correcting have been perturbed to the extent that we have a significant problem.”

While openness and reproducibility are the central values of science, they may not be the prime motivators for all scientists on a daily basis. The pressure to publish can lead scientists to cut corners in interpreting their results. A variety of factors can lead to bad study design, and these problems can lead researchers to draw conclusions that go beyond their findings.

Treatments for ALS are of paramount importance to Steve Perrin, CEO and chief scientific officer of the ALS Therapy Development Institute, who is profiled in the C&EN Talks With feature by Senior Editor Bethany Halford (see page 51). Halford points out that “80% of compounds that animal studies indicate are safe and effective ultimately fail when tested in humans.”

Lab animals take much of the blame for this lousy track record, but Perrin begs to differ. “Creating a good animal model for a human disease is hard,” he told Halford. Just putting a gene linked to a disease into an animal model doesn’t mean you’ve created an animal model of the disease, Perrin insists. “That’s the foundation. The next step is to take that model and to really start to ask the hard questions, the first one being: Does the animal model really look like the human condition you’re trying to model?”

Unfortunately, the hard work involved in refining useful animal models is “not very sexy science,” Perrin notes. “Who wants to take something that’s already been published in a high-tier journal and now start doing the real work that may not be publishable at all or will certainly not be publishable in a high-tier journal.” And it is not just the considerable economic cost of the clinical trial that’s at stake, there’s also a human cost. “The patient often only has one shot of getting into a trial for an ALS therapy,” Perrin told Halford.

The lead News of the Week story by Deputy Assistant Managing Editor Stu Borman illustrates a completely different sort of research conundrum (see page 7). A Penn State cancer researcher found that a compound, TIC10, in a National Cancer Institute database has anticancer properties. Penn State patented the compound and licensed it to the drug company Oncoceutics.

Researchers at Scripps Research Institute California also became interested in TIC10 as an anticancer agent. However, when they synthesized the patented structure, they found that the compound was inactive. They then obtained the compound from NCI, found it was active, and characterized its structure with X-ray crystallography and total synthesis. What they had was different from the patented compound. They then proceeded to patent the correct structure and license it to another drug company.

It’s not yet clear how the incorrect structure wound up associated with the active TIC10, but the confusion over the structures and the patents is profound and could have human costs, as well. TIC10 has shown promise against a variety of tumor types, but as a venture capitalist pointed out to Borman, it is unlikely that investors will support expensive clinical trials on a drug whose ownership is in question.

Thanks for reading.

Views expressed on this page are those of the author and not necessarily those of ACS.

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