Stem cell controversy highlights difficulty of judging contrarian research

The strangest and most gripping story in science over the past few weeks has been the Japanese and Boston stem-cell papers, in which researchers appeared to show that mature mouse blood cells could be transformed into powerful stem cells with a startlingly simple method.

As soon as they were published in Nature, the discovery was greeted with amazement, excitement, and also a heavy dose of skepticism. This week researchers seem to be backing away, with one calling for the papers to be retracted, and as I type this post, we’re awaiting an announcement from a Japanese research institution on Friday that will reveal the progress of an ongoing investigation into alleged problems with the research. But as of now, the papers stand, and nobody wants to dismiss a technique that really could be a breakthrough.

The difficulty of sorting out visionary ideas from crackpot ones—or even outright fraud—has long been part of science, especially at the cutting edge.

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“Many weird ideas (weird, that is, after the acid test of time) have been advanced in the canonical form of true science. Yet there are many examples in history of people we now regard as outstanding scientists whose early writings look like those of a raving lunatic,” Fred Gruenberger of the Rand Corporation wrote in “A Measure for Crackpots,” published in the journal Science in 1964.

It’s a discussion that happens in the scientific community any time a profoundly unexpected, game-changing discovery is published: Is this real, or is it too good to be true?

Chris Miller, a professor of biochemistry at Brandeis Univeristy, has been mulling over this question for years, when he isn’t doing his research on ion channels in cell membranes. He recently gave a talk at the Oxford University Museum of Natural History about the topic. Although he wasn’t thinking of the unfolding story of the Japanese stem cell research, his review of the pantheon of scientific characters who push unpopular ideas helps illuminate how science works and also how difficult it can be to tell which character you’re dealing with in real-time.

Miller said he began thinking about the question when he was a graduate student working for a scientist he would only slowly realize was a crackpot who was persistently and blindly pursuing a dogma-challenging idea.

Miller was working for Gilbert Ling, a professor at the University of Pennsylvania, whose exciting ideas about cells—that they didn’t actually have membranes—had entranced him.

“I came into his lab as a convinced acolyte; I had read his book and didn’t know any biology and I was a physicist and I said, ‘Oh, he’s got to be right,’ ” Miller recalled. “He advised us, ‘Don’t read the literature, it will only confuse you.’ We had night-time subversive meetings where we’d actually read the literature and we’d come to realize this is just not tenable.”

Miller spent five years in the laboratory and ultimately did experiments that showed his adviser’s predictions were not correct. Ling did not show up for Miller’s thesis defense, and his thesis committee had to draft a passerby at the last-minute so that they would have a quorum.

“You have to realize, at the end [the finding of] my thesis was not exactly controversial to the rest of the world,” Miller said. “It was like, ‘OK, membranes exist.’ It was hardly a radical notion.”

When Miller began to think hard about it, he decided there were distinct flavors of scientific crackpottery.

First, and most obviously, are the con men. Those are frauds who fabricate data. Those are people who break the rules of science and Miller said it’s hard to predict them in advance because they look just like other hard-working scientists until they are found out. As they inevitably are. Frauds are easily outed because the scientific method of repeating experiments means that their deceit will be revealed.

Second are the mountebanks, people who masquerade as experts.

Miller finds those the least interesting types in science. What really interests him are the heretics—both the ones who turn out to be right and the ones who get stuck on a crazy idea and just can’t let it go.

His favorite scientific hero is Peter Mitchell, a British biochemist who had an unconventional idea about how mitochondria generate energy in cells in the 1960s.

“All of the big shots in that field really hammered on him and he couldn’t get a grip, couldn’t get his stuff published,” Miller said. Mitchell happened to be independently wealthy, so he quit his academic job and built a laboratory at an estate in Cornwall where he pursued his ideas, Miller said. Eventually, he was awarded the Nobel Prize.

Similarly, scientifc crackpots persist in a dogma-challenging idea even when it’s been proven untrue. What makes them different, then? It can be subtle—they have to be dogged, ignore people’s doubts, and persist. But in his search for signs that could distinguish crackpots from heroes, Miller said that there is often a tone in the writing—a lack of openness to new ideas or other ideas.

Miller points to Lynn Margulis, a University of Massachusetts at Amherst biologist who did extremely important work early in her career, but in her later years began to push a crackpot idea, that AIDS was a form of syphilis.

“At the same time she was saying these crazy things, she was writing in a crazy way,” Miller said. “You could identify very Napoleonic statements you never saw in her early writing.”

It’s hard to talk to Miller without wondering where the stem cell story will take its next turn. If the work is repeated by other scientists, the Boston researcher who came up with the idea would have the hallmarks of a heretic hero—Dr. Charles Vacanti, an anesthesiologist at Brigham and Women’s Hospital, is a non-expert whose dogged pursuit of an idea would have been validated by rigorous work of collaborators who were experts. But recent revelations about possible problems with images and alleged plagiarism in other work by the Japanese scientist, Haruko Obokata, who led the work, give hints of the possible con-man storyline.

“Every one of the examples I cited in my talk on the heretic heroes were ... people who came from out of left field. ... They were considered nobodies by the experts in their fields, most of them, and they were considered, ‘God this is crazy and the guy is a nutbag,’ ” Miller said. “But they turned out to be right and I think that is an unusual situation, but not exceedingly rare for big changes in a field. ... It’s always satisfying to have mud thrown in the face of experts who are complacent in their expertise.”

It’s an attractive narrative, but expertise is also valid for a reason; it is often the source of progress in a field. What is great about science, Miller said, is that ultimately truth will prevail. Everyone turns out to have bad ideas that turn out to be wrong, and that’s part of the point of the endeavor.

“The real beauty of science is the ambiguities that we all have to figure out how to navigate through,” Miller said. “When you’re starting to work on a new problem, it’s as though you’ve been dropped into a dark room, a dark auditorum, and you don’t know what is there and you’re stumbling around and you’re trying to find out in the dark what are the objects in there. Of course you’re going to stumble and trip and bang into things, but if you’re good at it, you’re going to eventually resolve some of these ambiguities and make a discovery.”