I was working on the section of my book that deals with iPSC stem cell trials in Japan– a little bit about the history, Yamanaka’s discovery of iPSC cells in 2006, and how it all got to where we are now. There’s a lot of material about where we actually are at this point, too. Reading over what’s there so far, it’s kind of hard to avoid the conclusion that I’m sounding pretty negative about the Japanese research. It’s not that I want to take a negative attitude about it– I’d much rather see that research succeed– but they’re moving so fast, and I just can’t get on the rah-rah bandwagon. Here’s a good example of what I mean.
Over the past couple of years, Paul Knoepfler has posted a lot of concerns and critical thoughts about the process of getting iPS cells to clinical trials, and he’s used some pretty strong language. For example, here’s part of what he posted in October 2012:
Are iPS cells being rushed to the clinic or has their time come?
Just the title alone kind of tells us what his thoughts might be, but there’s much more. Here’s a very relevant quote:
The iPS cell field has run fast and furious over the past 6 years reaching a big milestone surprisingly quickly on Monday with Shinya Yamanaka winning the Nobel Prize.
But is the field going too fast?
In August I argued that iPS cells are not quite ready for primetime (i.e. clinical trial studies).
Now in October I mostly feel the same way.
But reportedly, some iPS cell researchers are working to start clinical studies wherein iPS cells would be transplanted into human patients as early as next year in Japan.
This is both exciting, but also potentially very risky if not flirting with disaster.
It would be tragic if the excitement and creativity exploding from iPS cells became diminished in the future by a rush to the clinic that harmed patients.
Pretty strong words. In fact, let’s look back at the August 2012 blog post that Paul referenced:
iPS cells not quite ready for primetime?
I like and support the idea of iPS cell banks (as discussed by Yamanaka). However, I do not believe the field has advanced far to support clinical use of iPS cells in the near future.
I realize that clinical use may nonetheless be on the horizon just a few years out in certain countries such as Japan, but in my opinion iPS cells are “not ready for primetime”, meaning not ready for clinical use. Not yet.
I also realize that some people in the stem cell field are going to be mad at me for saying this, but I believe it is true. People don’t read this blog to get sugar-coated, politically correct statements, right?
Are we ready to start using iPS cells in patients in the near future? Say in just a couple years?
Are they ready for primetime?
I think the answer is clearly “no”.
Guess what? This blog post was written in August 2012; Takahashi and company performed the first human transplant in September 2014. This means that the EXACT situation that Paul warned about, the EXACT one that he said absolutely should not happen, is EXACTLY the one that happened. (!!!) (feel free to add more exclamation points.)
But that’s far from all he had to say. Now, let’s fast forward to April 2013, only a year and a half ago:
As iPS cell studies in humans approach, accessible relevant pre-clinical data remains minimal
This dealt with Japanese scientist Takahashi and her attempts to get the first-ever human trials with iPSC’s off the ground (again, this actually did happen in September 2014.) Here’s what he had to say then, only a little over a year before that happened:
In her ISSCR seminar given 10 months ago, Takahashi presented some safety data from mice on the RPEs, but not from larger animals such as monkeys. To be clear, larger animal studies are not also not required, but this is an important distinction since larger animals are sometimes better models for humans and also because there were some anecdotal reports that said she had in fact presented larger animal pre-clinical safety data at the ISSCR meeting.
My understanding from Geron’s and ACT’s experience at the FDA here in the US is that the short-term nature of this iPS cell safety data along with very low animal numbers and lack of a clinically-relevant transplantation paradigm would be far from satisfying regulators here in the US that human studies should begin.
Unless there are a lot more, longer-term studies (e.g. 1 year or even longer) done on many more animals (e.g. 100s) yielding equally encouraging safety results specifically on transplants in the retina (not just sub-Q teratoma assays), I am deeply concerned as to whether the field is really ready to make the jump to transplanting iPS cell-based therapies into people any time soon.
Those long-term studies simply did not happen. There was never another large animal used in a study besides that one monkey (I have a copy of the study; I might post it later.) No additional long-term studies, certainly no hundreds of animals. I’m not sure about the transplant safety results, but I don’t really see how those could have been done when the long-term, additional studies themselves weren’t done. One thing we do know is that preclinical research wasn’t published until after this article (I want to say July 2013, but I would have to look this up.) Dr. Takahashi was given the go-ahead to start recruiting for the clinical trials in August 2013.
So what happened to the concern? Well, we don’t really know. It hasn’t been brought up in relation to the incredible rush to the clinic that the Takahashi study has turned out to be.
Here’s what I posted on Paul Knoepfler’s blog on November 18:
Paul, do you really, SERIOUSLY feel that only a year and a half later, anyone is really ready to transplant iPS cells into human beings? Isn’t a year and a half later “anytime soon?” Between your articles in 2012/2013 and today, we saw the STAP disaster take place at Riken, the SAME place that is responsible for the Takahashi trials. Some of the people involved are the same (such as Wakayama) Do you feel comfortable with the kind of self-policing that Riken has done since then? Do you think that all of the questions and concerns you had only a year and a half ago have been well addressed? Don’t you think there’s at least a real chance that these scientists are rushing terrifyingly and dangerously fast into human trials?
I just feel like the problem with the situation surrounding these human trials in Japan isn’t exactly rocket science. When pared down to its essentials, it’s pretty simple.
Ultimately, it comes down to this:
1.) Paul K. criticized the imminent rush to the clinic of iPSC’s in 2012 and 2013 in no uncertain terms
2.) He specifically said exactly two years ago that he didn’t think these cells would be ready for that IN TWO YEARS, which would be, well, today
3.) He listed some steps that he thought needed to be taken in order to be even a bit more confident that iPSC’s were ready for clinical human trials, and those steps weren’t taken,
4.) He brought up a ton of serious concerns, and now… can he SERIOUSLY be jumping on the rah-rah train? I don’t know if it’s exactly that bad, but he suddenly seems to have dropped all genuine criticism.
I really, really love Paul K’s blog, I think he’s an amazing scientist, he’s done so much good work, and I have so much respect for him… but when it comes to this issue, I think that he should return to his earlier and much more critical stance. Stem cell research is literally a matter of life and death. It’s worth being critical about.