Anatomy of the Minnesota Stem Cell Controversy
The New Scientist is generally credited with calling attention to problems with publications from Minnesota in the area of stem cell research.
A summary article has appeared in the New Scientist:
Briefing: Anatomy of a stem cell controversy
* 14:56 13 October 2008
* NewScientist.com news service
* Peter Aldhous
A former member of one of the most prominent stem-cell research teams has been found guilty of falsifying data. New Scientist explains why the group's work is important, looks at where the findings stand now, and asks: what are the implications for the rest of stem cell biology?
Why is this research team so well known?
The team, led by Catherine Verfaillie of the University of Minnesota in Minneapolis, claimed to have isolated a rare type of cell from bone marrow that could develop into most, if not all, of the body's tissues. Previously, only embryonic stem cells (ESCs) had been shown to be this versatile.
Did this mean that ESCs were redundant?
Politicians and activists who oppose embryo research argued that the discovery of multipotent adult progenitor cells (MAPCs) made continued work on ESCs unnecessary.
"It shows, once again, that we can find cures for the many diseases that plague humanity without destroying human embryos," said Republican US senator Sam Brownback of Kansas, after New Scientist first reported on the work in January 2002.
Verfaillie and other stem cell biologists, however, have always argued that continued research on ESCs is needed.
How did scientists react to the results?
Initially, with great interest. In July 2002, the Minnesota team published a paper in the journal Nature (vol 418, p 41), after other experts in the field had reviewed the findings. It described a series of experiments suggesting that MAPCs could develop into a wide range of other cell types.
However, crucial experiments showing that mice born from an embryo injected with a single MAPC were "chimeric" – that is, cells derived from the MAPC appeared throughout their bodies – have never been repeated. This is a key test previously passed only by ESCs.
Still, several teams around the world have continued to study MAPCs from bone marrow and they do seem to have some interesting properties.
For instance, Irving Weissman, a stem cell biologist at Stanford University has collaborated with Verfaillie, now the Catholic University of Leuven in Belgium, to show that MAPCs can give rise to all the cells found in blood.
Why did the group's work come under official scrutiny?
Given the problems repeating the work, New Scientist started looking closely at the Minnesota team's results in December 2005.
We found that six plots in the Nature paper, describing characteristic "marker" molecules carried by the cells, also appeared in a second paper in Experimental Hematology (vol 30, 896), where they were supposed to refer to cells isolated from different mice.
Were these results found to be falsified?
No. An inquiry held by the University of Minnesota, after New Scientist queried the results, ruled in October 2006 that the duplications were merely errors.
However, the inquiry also decided that the marker molecule results were in any case unreliable because of flaws in the way the experiments had been run. In February 2007, Verfaillie informed Nature of the problem, and the paper has since been corrected.
So where was the falsification?
In an earlier paper, published in Blood (vol 98, p 2615) in 2001. In March 2007, New Scientist noticed that images from this paper, documenting the presence of proteins as the stem cells developed into other types of cell, including those found in bone and cartilage, appeared in a patent granted in 2006, where they were supposed to represent different proteins.
One image, flipped through 180° and slightly altered, was also used twice in the Blood paper to describe the results of different experiments.
The University of Minnesota launched a second probe, which has now ruled that this and other images in the Blood paper were "altered in such a way that the manipulation misrepresented experimental data". The investigating panel pinned the blame on Morayma Reyes, then a PhD student at Minnesota, who was the first to isolate MAPCs. She is now at the University of Washington in Seattle.
Was Reyes also responsible for the errors in the Nature paper?
No, those plots were compiled by another junior member of the team. Reyes was also not involved with the most exciting results in the Nature paper, including the chimera experiments.
Where does stem cell research stand now?
It seems clear that MAPCs are not as versatile as ESCs. In any case, biologists can now make a variety of adult cells behave like ESCs, using a genetic "reprogramming" technique pioneered by Shinya Yamanaka of Kyoto University in Japan (read our interview with Yamanaka).
If MAPCs aren't equivalent to ESCs, what are they?
Most probably, they are a type of mesenchymal stem cell, which normally develop into tissues including bone, cartilage and fat.
Indeed, researchers with the biotech company Genzyme of Framingham, Massachusetts, have argued that MAPCs isolated using the Minnesota team's methods are indistinguishable from other mesenchymal stem cells, based on studies of marker molecules and their ability to form other types of cell.
Are mesenchymal stem cells useful?
Yes, but their main value in medicine probably will not come from the other cells that they can grow into. Instead, they could help treat a variety of diseases because they release biochemicals that help damaged tissues heal, prevent scar tissue from forming, and damp down immune responses.
What lessons are to be learned from the affair?
Biologists who spent months – in some cases years – trying to repeat the Minnesota team's results feel frustrated and let down.
This is not the only time that exciting results in stem cell biology have proved hard to repeat. Stem cell experiments are technically demanding and can give ambiguous results, creating plenty of room for scientists to over-interpret their findings – or worse.
The most notorious example, of course, is the fraudulent claim to have created cloned human ESCs by South Korea's Woo Suk Hwang.
Stem cell biology is also an intensely competitive field that has generated huge public and political interest. Under these circumstances, as the Minnesota team has found, rushing into print with exciting findings can get scientists into serious trouble.