Top 10 Insider Trends on Stem Cells to Look Out for at ISSCR 2015 Stockholm

isscr meetingThe annual ISSCR meeting has started in Stockholm.

This is always a great annual meeting both for the science and for connecting with people including new friends and colleagues as well as old friends.

Another element to the meeting is the insider conversations in the halls, restaurants, and bars that tell a behind the scenes story of the stem cell field.

Below are my top 10 things to look for that might be discussed over a beer or coffee this year. Also be sure to check out the wonderful guide to Stockholm from Heather Main and if you are there at the meeting enter our stem cell contests to win up to $100.

  • Clinics make an appearance? It’s a long shot, but I keep wondering if some of the stem cell clinic folks will show up at ISSCR some day to try to legitimize themselves even if they don’t speak, etc. Maybe they’ll sneak in with some posters or even just attend to make some connections. Unlikely, but if it happened could prove very interesting.
  • I’ll be curious if the Hanna-Silva feud of a sorts continues persist over ground state pluripotency, MBD3 and NuRD.
  • Does anyone still believe in VSELs?  A scandal is still smoldering there.
  • Anybody know what happened to Vacanti and the assumed to exist Brigham & Women’s/Harvard investigation over STAP cells? Last year in Vancouver at ISSCR STAP cells were one of the hottest topics.
  • Will Mitalipov continue to assert that NT-hESC are better than IPSC after the more recent paper (on which he was an author seemed to show otherwise)? More broadly will the SCNT/human therapeutic cloning folks continue to claim a clear path to the bedside?
  • Any news on Masayo Takahashi’s IPSC trial? More preliminary data?. I’m excited to see how that goes.
  • I keep hoping also that more biotechs will present at ISSCR and be given plenary talks.
  • Is ethics/policy given sufficient attention at the meeting?
  • Will CRISPR-Cas9 editing of stem cells be the talk of the meeting? The explosive trend of this amazing gene editing technology in science overall has really gripped everyone’s attention.
  • How many reports of clinical trial data will be given? Sometimes in the past ISSCR meetings have had a sizable tilt towards basic science. Could that be changing?

A Stem Cell Clash: Silva Comments on MBD3/NuRD Debate with Hanna

Researchers probing how to reprogram cells into powerful stem cells (induced pluripotent stem cells or IPSCs) and what the molecular mechanisms are behind this process have become entangled in a conflict.

Of course over the years scientists including stem cell scientists have had their share of disagreements and debates in the past including heated ones, but this reprogramming clash has taken it up a notch beyond past ones and has some unique elements to it.

For example, this scientific clash is unfolding largely in the public domain and involves post-publication review such as on PubPeer.

Looking under the “hood” of cells so to speak, their reprogramming involves a molecule called MBD3 and a corepressor complex called “NuRD” ( for more on NuRD see my review with my postdoc mentor Bob Eisenman on NuRD here in Cell). It seems that most everyone agrees that MBD3 and NuRD play some role in reprogramming.

However, what the exact roles of MBD3 and NuRD might be in this area are very unclear at this time and there are quite distinct views.

Jacob Hanna

On one side we have Jacob Hanna, a well-known stem cell scientist who was previously a postdoc in the lab of Rudy Jaenisch. Hanna (pictured at right) has had a number of very high profile papers including on induced pluripotency.

One major assertion from the Hanna Lab is that a repressive chromatin complex including MBD3 and NuRD proteins is inhibitory for pluripotency (e.g. in their Rais et al. paper that I discussed on this blog when it came out in 2013). I also had a chance hear Hanna talk at the 2013 Till & McCulloch meeting, where I asked him some questions from the audience (see here).

On the other side we have José Silva, another top stem cell investigator. Silva did his post-doctoral work in the lab of Austin Smith. Of course Jaenisch and Smith are two of the top scholars in the stem cell field. The Silva lab has published a Cell Stem Cell paper coming to pretty much the opposite conclusion of Hanna.

Jose SilvaThis stem cell conundrum has been the subject of vigorous discussion on PubPeer. Now this MBD3 disagreement has also spilled over to bioRxiv where further back and forth is ongoing. On Silva’s side of the MBD3/NuRD fence are also well-known researchers Brian Hendrich and Paul Bertone.

In an effort to get to the bottom of this and build a bridge for constructive discussion, I have invited both Silva and Hanna to comment here on this situation.

Hanna has indicated that he would prefer to wait a month or so until additional work is published and then will provide comment. Stay tuned for that as my invitation to him stays open.

Silva has provided comments now, which are included verbatim below:

“Please find below the key elements (in no particular order) being discussed on the ongoing debate on MBD3/NuRD and reprogramming and my view on these:

1- Levels of Mbd3 expression and its relation to reprogramming.

Rais et al. evaluated the potential of Mbd3 depletion primarily in the Mbd3fl/- heterozygous background. Dr Hanna claimed that these cells express hypomorphic levels of Mbd3, corresponding to 20% that observed from wild type cells. Dr Hanna also claimed that these cells could reprogram with near 100% efficiency. However, our analysis of Dr Hanna’s data revealed that Mbd3fl/- cells express instead nearly wild type levels of Mbd3. This is also in line with the quantification of Mbd3 levels in Mbd3fl/- cells assessed in Dr Hendrich’s lab and mine. This evidence led us to question the effective depletion of Mbd3/NuRD function as having been a significant factor in the reported increase in reprogramming efficiency. (Please note that Dr Hanna’s Mbd3fl/- cells used in the Rais et al. study were generated by Dr Hendrich’s lab.)

2- Use of elevated copy number of Oct4-GFP reporter transgenes to assess ongoing reprogramming efficiency

The high copy number of randomly integrated Oct4-GFP reporter transgenes may lead to spurious GFP expression in non-reprogrammed cells.

3- Comparison of reprogramming efficiency to a control cell line harboring a deficient Oct4-GFP reporter transgene.

While Mbd3fl/- cells harbored an intact Oct4-GFP reporter known to be promiscuous for expression in a range of cell types, the control cells were transfected with an alternative Oct4-GFP reporter with much greater specificity for pluripotent cells. This finding indicates that key methodology was absent from the paper, and the comparison of reprogramming efficiency between cell lines representing compatible measurement conditions was potentially invalid.

4- Reproducibility of Dr Hanna’s claims. Rais et al. was regarded as a  landmark paper in stem cell biology and numerous labs around the world have tried to reproduce these results. Their attempts using independent systems have been unsuccessful. We do not dispute that Dr Hanna’s cells reprogram relatively efficiently. However, based on our own experimental work and on the detailed analysis led by Dr Bertone of genomic datasets published by Rais et al., we found no evidence to support the claim that depletion of Mbd3 leads to deterministic reprogramming.

José Silva