The founder of the field describes how to make these cells useful
James Thomson published the first paper on deriving primate embryonic stem cells, human embryonic stem cells, and one of the first two on making human iPS cells. Nature Reports Stem Cells spoke to him on to get his view of the field he helped launch.
How does it feel to have made both human ES cells and human iPS cells?
Human ES cells created this remarkable controversy, and iPS cells, while it's not completely over, are sort of the beginning of the end for that controversy. Having a hand in both is very satisfying. One of the legacies is if those culture conditions hadn't been worked out for human embryonic stem cells, iPS cells wouldn't have worked.
Should people still be trying to clone embryonic stem cells through nuclear transfer?
From a practical point of view, I've never seen that as a viable therapeutic, just because of economics, the source of the oocytes, the inefficiency of the process. That being said, the nuclear transfer process creates insight into nuclear reprogramming that can be gotten by no other method, so it can still answer questions.
When you published your iPS cell paper in 2007, you said scientists would gravitate toward those cells.
Making human ES cells is a pain. Even though there are a few hundred lines out there, it's not increasing that much now. But we've already derived lots and lots of iPS cell lines, and we'll derive very large numbers of them. So the ratio of lines we use is shifting. Despite the fact that we aren't throwing out the old ones, we aren't putting much competition in the ring. We will continue to use those five embryonic stem cell lines [derived in Wisconsin]. It's a nice sort of gold standard to go back to.
What about the newer embryonic stem cell lines?
For our newer cell lines, we published one paper on them, and they've been in the freezer ever since. We could only have a small derivation lab because of the federal funding situation.
When we derived the original [five lines], I was very consciously doing them for experimental purposes only. If you do FDA approval, you have to be tracking every little thing, and I just didn't want to do that.
My assumption was that this would be proof of principle and then there would be a lot of other people deriving new ones. It turns out that ten years later, there's only 21 lines available for federal funding, so each of those lines has huge value because of the Bush ban. Had I known that at the time, I would have been much more careful.
That said, I do think that extensive testing can be done on individual cell lines and that the level of risk has been overstated. Nonetheless if I was a patient undergoing transplantation I'd prefer cells that were derived under modern conditions.
How should iPS cells be incorporated into the scientific community? Should there be standards of what constitutes an iPS cell?
I think there will be a lot of people setting up committees for standards, and I think these are going to be of limited utility. I think the peer-reviewed process works pretty well. So if an investigator publishes a cell line with documented properties and another finds those properties can help answer questions, it doesn't so much matter if some body declares that this is an iPS line.
What about banks that can ship cells to researchers?
I don't know how that will work. We have a bank for stem cells here, and the cost per cell line is very large, but there are economies of scale that can be met because there are many requests for stem cell lines. But what if you have a bank with thousands of lines and there are only one or two requests for cell lines each year? And there will be thousands. Six months after deriving human embryonic stem cells, there were only about a dozen labs working on human embryonic stem cells, whereas we are only about a half a year after the derivation of human iPS cell lines, there are thousands of laboratories working on them, and they'll all be making multiple cell lines.
Just making a cell line is not enough anymore. It needs to have an interesting genetic background or it needs to be genetically modified in a way that would take a lot of time. The technology is changing very rapidly, and what you might want to bank today might not have a lot of utility a couple years from now.
What do you think of the most recent challenge to the patents covering the lines you derived at Wisconsin? How will it affect research?
I don't want to comment on that directly, but I think the value of the patents in terms of blocking the research has been overstated. The pace at which the research has gone forward in academic circles has really not been blocked by those patents. You can argue about whether or not WARF [Wisconsin Alumni Research Foundation] licenses appropriately in the commercial world, but within the academic realm, one major bottleneck for research was the funding restrictions on the cell lines, but the most major one has been the perception of the controversial nature of the field. That's been most damaging because young investigators have been hesitant to enter this field.
Where will pluripotent stem cells have their biggest impact?
The cells will change human medicine, because they will change the way we have access to the human body. It's like PCR, it just amplified the DNA so you had enough to study. This is like PCR for the cells of the body.
My guess is that twenty years from now, when we think about what all the fuss is about and where the value is, if you draw a pie chart of the value, there might be some transplant therapies made from those cells, but it's going to be a small sector of the value. I think the real value is as a tool to get access to the human body to get pieces of it that we didn't have access to until now.
There are several companies, including one of yours [Cellular Dynamics International] that are doing drug screening. How have you seen industry attitudes about using stem cells for screening change?
Drug screening is a no-brainer.
Drug companies have been nervous about it over the last decade, and they've been quietly moving into using [pluripotent stem cells for drug testing]. After the iPS cells, it's really turned into a feeding frenzy. You'll see a dramatic change because the ethical issues, at least for iPS cells, have gone away.
What are you working on now?
In my lab, we're looking at cellular identity: why it's stable and how you can change this. Reprogramming, I think, is just one of many ways to change cell fate. We're interested in doing this in other ways, not just going back to the ES-like cell state.
Lately there's been a spurt of papers on new pluripotency factors. How long do you think the list will get?
The size of the list being large is not surprising. The shocking thing is that such a small number of factors can change a state so dramatically.
Tell me about your position in UC Santa Barbara. Did you take it to be eligible for funding from the California Institute of Regenerative Medicine?
I have an interest in the evolution of pluripotency, how a cell decides to become another cell. It's something that metazoans figured out a long time ago, and sea organisms are one of the models with which to study that, and we don't have access to study them in Wisconsin obviously. I gave a seminar at UC Santa Barbara. From those discussions, that turned into an adjunct position, and they have this interdisciplinary research building in which they gave me a small bit of space next to an engineer [Tom Soh] that I'm going to collaborate with. Clearly part of the interest for me based on this administration is the CIRM funding, but that's not my primary motivation. They have a marine center that's right on the ocean.
In the past you made monkey ES cells, now what about making induced pluripotent cells from other animals?
iPS cells open up a whole realm of possibilities because it's hard to get embryos, but it's easy to get fibroblasts. It would be interesting to see the range of vertebrates for which this technology works.
I heard someone had blue whale fibroblasts, and it would just be cool to make a whale iPS cell line. Teratomas actually recapitulate early embryonic development pretty well, and you might be able to compare early embryonic development using iPS cells.
What advice do you have for graduate students studying stem cells? Where are the interesting questions going to be?
I did get a PhD in molecular biology, but it's not really a discipline now. It's mainly how you want to apply it to the traditional fields. Stem cells are sort of the same thing. You can get a degree in stem cells, but it's really a tool.
The message is there are now tissues that can be studied for the first time in unlimited quantities. Don't think about stem cells per se, think about the new areas you can study.
I guess we're getting closer to that because of the disease-specific stem cell lines labs are making.
Yes. I think we'll see a lot of “gee-whiz we can make the models” papers followed by a lot of hard work. And then the hard work is going to slow everybody down.
What tests are needed to see if cell transplantation is feasible?
Mice are short-lived species. So it's kind of a quick proof of principle, but to really figure out if a therapy has legs, I really think you need to do it in primate species. There will be exceptions for that. You could have something that's going to kill you quickly, and you're going to take a reasonable risk. So I think that primate ES cells that were derived 15 years ago are really going to come back now. That, or their iPS equivalent, and the transplantation research in a primate model will become very important.
Tell me about one of your most exciting days in the lab.
It just doesn't work that way. For the human ES cells, I derived them myself. For the iPS cells, the first author, Junying Yu, did all that work, so my exciting day was when she came and talked to me.
Our experiences were similar though. When the human ES cells started to grow, I sort of knew they were the right thing, but they had to cross all the hurdles, and at any time during that long process, they could have been lost, it could all die. There was never any one point where happiness set in. Then the paper came out, and the press showed up on my doorstep and there wasn't any time to relax.
It's kind of neat in retrospect to have been at the center of the controversy. But in real time, it was more frustrating than anything.
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Baker, M. James Thomson: shifts from embryonic stem cells to induced pluripotency. Nat Rep Stem Cells (2008). https://doi.org/10.1038/stemcells.2008.118
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