WSJ on biomedical research

Monday April 10, 2017

I do not have a subscription to WSJ. Usually a first-click to any WSJ article there would be no paywall as long as the article is recent enough. Refresh the page, you are dead. Sooner or later I might need to subscribe it.

I am referring and summarizing this story on the WSJ, The Breakdown in Biomedical Research by Richard Harris from NPR (he also wrote a somewhat similar article on Slate Future Tense). At the article’s footer it says that this piece is adapted from his new book on sloppy science.

It begins with the story of HeLa cells (Henrietta Lacks). HeLa cells, as anyone in biomedical science would know, is the first cancer cell line established by Dr. George Gey from John Hopkins. This cancer cell line was derived from cervical cancer taken on February 8, 1951. The HeLa cell line has contributed a lot to biomedical research and was used to create the first polio vaccine by Dr. Jonas Salk (University of Minnesota) in 1954.

How Harris relates HeLa cell line with sloppy science? HeLa cell line has a tremendous growth potential. If you have a single HeLa cell contaminating your culture flask, there is a pretty good chance that the HeLa cell will outgrow anything that is growing inside that flask. This reminds me of Dr. Leonard Hayflick (that Hayflick limit) and his famous quote: “she assured me that my worst fears were unfounded”. This was after Dr. Stanley Gartler dropped the infamous “HeLa bomb” in 1966.

It happened when Gartler discovered cell lines were contaminated with HeLa cells, including the WISH cell line whose it is related personally to Hayflick. This is because the WISH cell line was derived from the amniotic sac of Dr. Hayflick’s unborn daughter. Dr. Gartler tested for a rare genetic marker, the G6PD, which is present on HeLa but not on most caucasian (Henrietta Lacks was an African-American woman). This exchange between Dr. Gartler and Dr. Hayflick is recorded in Rebecca Skloot’s book: The Immortal Life of Henrietta Lacks.

What’s the issue when Harris points out about HeLa contamination? Is it because biomedical research inherently sloppy? Yes and no. Sloppy not because researchers are incompetent. I am biased here. Most researchers I met are really good at asking questions and pointing out how things can go wrong, indicating that they are aware of their science. Perhaps it is more of a systemic problem: funding is scarce and researchers have to make ends meet with a skimpy budget. Not to mention that any biological form of life tends to not fully cooperate when needed. Do you tell your doctor you smoke pot when you caught fever the morning after?

Harris points out that biomedical research is self-correcting in the long run. I agree with this. Studies done several decades ago could be invalidated/corrected by recent findings. This does not necessarily indicate that the previous studies were sloppy, but it provides the narrative that either we found a better detection method with high-resolution data or we have a new technique to elucidate the elusive behavior of certain biological elements. For example, Dr. Jason Sheltzer’s work on CRISPR/Cas9. Sheltzer utilizes CRISPR/Cas9 to downregulate the expression of MELK gene. Previous studies with RNA interference (RNAi) and small-molecule inhibitors targeting the MELK gene had blocked the proliferation of various cancer cell lines. Here, the Cas9 protein is used to mutate the MELK gene. The catch? They found no evidence that MELK is implicated in cell proliferation.

Going back to the sloppy part, how sloppy a science could be? Dr. John Ioannidis (Stanford University) published an article in 2005 with the argument that small sample sizes and bias in studies were the major problems in the field and could inflate positive results. Small sample sizes? Yes, especially in animal studies. I have seen a study that only used 2-3 mice. The funny part? Look at the error bars.

Harris also mentions several meta-studies:

  1. Dumas-Mallet et al., 2017, PLOS One, 10.1371/journal.pone.0172650
  2. Prinz et al., 2011, Nature Rev. Drug Discovery, 10.1038/nrd3439-c1
  3. Begley and Ellis, 2012, Nature, 10.1038/483531a

Do we have more problems? Yes we do. Contaminated research could be the prime culprit. The International Cell Line Authentication Committee (this is a thing?) has counted about 450 misidentified cell lines with HeLa as the contaminant in 113 of those cases. Aside from HeLa, MDA-MB-425 was misidentified as breast cancer when it is, in fact, a melanoma (skin cancer).

So we have the issue with budget and cell contamination and/or misidentification to blame. What else? Oh yeah, researchers are incentivized to publish splashy results, a result of a hypercompetitive environment in biomedical research. Splashy results do happen but often at the expense of dark magic. To quote my professor, “seeing all the calisthenics done on data, I was crestfallen”.

Are we trying to circumvent these problems? Yes we are.

As of January 2016, NIH requires federally-funded researchers to authenticate cell lines to make sure HeLa isn’t haunting them. Just a few days ago on April 4, PLOS announced that they are partnering with ProtocolsIO to provide authors better ways to share their methods. ProtocolsIO is the work of a genius art with regard to fixing the reproducibility crisis (seriously, go check it).

In short, science is just hard. More the reason why we should communicate about science to the public so they could appreciate our work here. And we should tell the public not to read tabloids too.

“At best cultured cells are mediocre models of their organismal counterparts. At their worst, they are not what we think they are.”

My instructor for Biology of Cancer (RIT, Spring 2017) posted this link on Facebook recently (October 18): The ghosts of HeLa: How cell line misidentification contaminates the scientific literature.