New Yamanaka interview gives key insights into future of IPS cells

Shinya yamanaka

Wikipedia photo

Where is the field of IPS cells going and how will this impact the overall field of stem cell-based regenerative medicine?

Nobel Laureate Shinya Yamanaka, the discoverer of IPS cells, gave a really interesting recent interview to Nikkei that provides some fascinating insights into the future of this exciting technology that is now more than a decade old.

For simplicity I have indicated top highlights from the Yamanaka interview below as bullet points.

  • More IPS cell trials are on track to start as soon as 2018 in Japan.
  • Yamanaka said that trials for Parkinson’s, Spinal Cord Injury, and Heart Disease are amongst the planned IPS cell trials in Japan.
  • There are also plans for clinical studies on cancer and kidney disease, perhaps further down the road such as 2019-2020?
  • Immune rejection and cancer risks must still be evaluated, he said.
  • There are likely to be important differences in the new studies versus use in the eye.
  • CiRA has started working with Takara on QC of IPS cells and products.
  • Their main focus for all these trials still seems on allogeneic use from IPS cell banks.

It will be interesting to see how trials in Japan develop versus those in other countries such as here in the US where I know of planned autologous IPS cell clinic efforts.

Takahashi team IPS cell vision paper marks major stem cell milestone

Ring the bell for a stem cell milestone.

There’s been a whole lot of commotion about the NEJM article yesterday documenting the experiences of three women with macular degeneration who were blinded by non-FDA approved stem cell eye injections of fat stem cells at a business in Florida, but in the same issue of the journal there also was some encouraging stem cell news that came in the form of essentially a mirror image of the bad news paper. We can call it the “stem cell good news-bad news” issue of NEJM.

Takahashi IPS transplant

Mandai, et al. NEJM 2017 Figure 1C

The good news was the publication of the first paper on clinical use of IPS cell-derivatives in a human patient. A big milestone. This groundbreaking manuscript comes from the pioneering team in Japan led by stem cell scholar Dr. Masayo Takahashi. I’ve written extensively in the past about the work of Takahashi and her team with IPS cells, and she received my Stem Cell Person of the Year Award back in 2014.

In the new paper they detail their data from the clinical study using sheets of retinal pigmented epithelial cells (RPEs) made from IPS cells in this case derived from the patient herself for autologous use. Remarkably in Figure 1C (above) you can see the actual transplanted RPE sheet in the eye of the patient (see dark area indicated by white arrow). The most encouraging part of this study was that the patient’s vision remained stable (rather than declining as expected) following the treatment. Was that due to the transplant? We can’t be sure.

Also, this is just a beginning as it is just one patient, but it is very exciting and represents a big milestone for the IPS cell and broader stem cell field, providing real hope for patients with vision loss along with parallel ESC-based clinical trial work as well.

This paper contrasts so much with the report from the other one in the same issue on the terrible outcomes from the stem cell clinic’s use of fat stem cells in the eye. While the use of fat stem cells themselves is highly questionable in my view for this application, the biggest differences between the two approaches is that the Takahashi team work was extremely rigorous, careful, based on extensive preclinical studies, had governmental approval, and was in essence science-based clinical medicine.

For instance, the Takahashi team was appropriately cautious with Patient 2 since the cells exhibited some genomic changes. At least in part for that reason, moving forward this clinical work will primarily focus on allogeneic use of IPS cells via an IPS cell bank being developed by Shinya Yamanaka.

We can also look to other future IPS cell-based trials coming on-line including for Parkinson’s Disease and other conditions, which are likely to be allogeneic as well in Japan, but probably autologous here in the U.S.

I love a good stem cell milestone!

Multiple filters for stem cell research at Canadian stem cell conference

By Samantha Yammine, PhD Candidate in Derek van der Kooy’s lab at the University of Toronto. See tweets live from #TMM2016 via @SamanthaZY here.

Whistler, BC, Canada.

The location of this year’s annual TMM in Whistler, BC, Canada.

Last week, 430 Canadian scientists, trainees, industry professionals, science communicators and international guests gathered in the picturesque ski town of Whistler, British Columbia for the annual Till & McCulloch meeting (TMM). This is Canada’s premier conference for stem cell research, which is co-hosted by the Centre for Commercialization of Regenerative Medicine, the Stem Cell Network, and the Ontario Institute for Regenerative Medicine.

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Yamanaka’s baby turns 10 so here’s a top 10 list of IPS cell hot button bullet points

Shinya yamanaka

Wikipedia photo

Has it really been 10 years since induced pluripotent stem cells (aka IPS cells or IPSC) came onto the scene in the stem cell field?

Yes, it was a decade ago that now Nobel Laureate Shinya Yamanaka (山中伸弥) published that seminal Cell paper on reprogramming to make mouse IPS cells and then human IPS cells came the next year.

From the moment I read that first mouse IPS cell paper, I was very excited about the science and the ideas in it. The domain name of this blog The Niche is named after those remarkable cells,

In honor of the 10-year anniversary, below I outline the top 10 IPS cell related questions and key points as of today looking to the future.

  1. IPSC and ESC as partners rather than competitors. Are IPS cells equivalent to hESC derived from leftover IVF embryos? Even if they are a bit different, does that matter? With both in the translational pipeline and available as the basis for research, we can achieve more as a field. Let’s see what develops. Will nuclear transfer ES cells (NT-ESC) ever fulfill the aspirational name of their production,” therapeutic cloning”? Or will they mainly be a cool, but somewhat esoteric tool for advancing knowledge and one used by only a few groups in the world? I hope there can be clinical impact from NT-ESC, but I’m very doubtful that it will become a reality any time soon.
  2. IPS cell trials. How will clinical translation of IPS cell-based products proceed in the next 10 years and sooner? How soon will the Takahashi study get back up to speed in its new form? Will other trials get going relatively soon (i.e. in the coming 3-5 years)?
  3. Diseases in a dish. Disease modeling using IPS cells continues to grow in importance. Will it continue to give the cell therapy side of IPS cells a challenge in terms of total positive translational impact from IPS cells? So far I would say disease modeling has had more impact, but that could change.
  4. Auto and allo. Autologous versus allogeneic IPS cell approaches are both generating buzz. As to the latter, what about those IPS cell banks in various places?
  5. Mutations matter but here’s the key context. Do IPS cell mutations matter? Of course they could, but most likely in the same way that ES cell mutations do. It’s more a question of genomic stability in general. What about mitochondrial mutations in IPS cells? The key thing here overall with genome issues is careful preparation and handling of cells and validating them rigorously. That doesn’t always happen.
  6. IPS cell sex. What about female IPS cells? Can we somehow “put an X” through the problems that sometimes appear associated with loss of X inactivation in female IPS cells? What about issues with imprinted genes? We don’t hear much about these things lately. As with the previous point, the bigger issue is validation of anything stem cell-wise that you’re studying, particularly if you have clinical intent down the road. Epigenomic validation more generally is very important for IPS cells.
  7. Patent big tent? Putting the IP in IPS cells or taking it out? Will there be any patent disputes of major significance moving forward or clinical research that is impeded by expensive licensing fees…or not so much?
  8. Directed direction. Is direct reprogramming going to heat up more so that it becomes a major alternative to IPS cells in certain cases? I hope so. The more cell types and methods we have, the better as long as they are supported by rigorous data.
  9. A vision for vision and beyond. Will the eyes continue to have it? Will IPS cell therapy development go beyond vision-related conditions soon? I’m sure it will, but eye conditions are dominant now as a focus for products made from IPS cells and ES cells. I can’t wait to see more trials for other conditions.
  10. Differentiation destination. In nearly all cases IPS cells will themselves not be used for therapies. Instead, differentiated cells made from IPS cells will be the actual therapeutic product. As with ES cells, a challenge with IPS cells is consistently making pure differentiated cells of the desired type. For instance, if you make 98% of say a neuronal cell type that you want and 2% of some undefined mesoderm or endoderm cells, that’s going to be a hurdle to overcome. The goal of cellular purity and specificity achievable with human pluripotent stem cell differentiation, but it can also be a real challenge.

Overall, I predict the IPS cell field will continue to mature and have even more impact in the next decade. A growing fraction of that impact will hopefully be coming from cell therapy-based clinical trials. There are likely going to be bumps in the road and even setbacks in the coming decade, but overall I’m very optimistic about IPS cells.

Shinya Yamanaka at #ISSCR2016 on reprogramming of cells & scientists

The second day of ISSCR 2016 started off with a great session on pluripotency and plasticity, and the first talk was by Shinya Yamanaka. He changed the title of his talk to “Reprogramming of Cells and Scientist”. As with my other posts on this meeting, this one is a stream of quotes and impressions from the talk. The beginning was more autobiographical on his part and then the second half was on basic science. I really enjoyed this talk overall.

It’s now been a decade since Shinya Yamanaka’s seminal paper on mouse IPS cells. Shinya started his talk going back in time to the early 1990s of his postdoc at the Gladstone. He cloned NAT1 as a postdoc (Yamanaka et al. Genes & Dev, 1997).

Shinya Yamanaka

He found that NAT1 is required for early mouse development. He made NAT1 null mESCs and found that the NAT1 KO mESCs could not differentiate.

He got his own lab in 2000 and he and his group tried to induce pluripotency in somatic cells. It was 6 years later that they published the first IPS cell paper.

IPS cell technology has “reprogrammed me too” he said. One of the things I enjoy most about Shinya’s talks over the years (besides the wonderful science) is that he is very free with discussing what it means to be a scientist and how science effects scientists including on a personal level.

He noted that after human IPS cells, “I have been spending a lot of time in talking with people in government and industry and banks, and also spending a lot of time in fund raising.” I think this is what he meant by reprogramming of him by IPS cells.

“Some portion of myself is refractory to reprogramming. That part tells me I should enjoy basic research” and then he said that’s what my talk will be on: basic science.

He focused on NAT1 and its knockout in mESCs. Could NAT1 KO mESCs be in the ground state even without 2i treatment? NAT1-nulls even without 2i have the same morphology as WT cells in 2i. They did single cell RNA analysis. 2i makes WT mESCs more uniform in gene expression with higher Oct4 levels, etc. NAT1 nulls even without 2i are very similar to 2i WT cells. It seems NAT1 is an inhibitor of the ground state.

What about NAT1 in human ES cells?

Conventional gene targeting in human cells didn’t work. They could only get hets but no homozygous KOs (unpublished work of Kazu Takahashi). So it seems NAT1 is essential to human ES cells. Importantly, Kazu could get homozygous in the context of Dox NAT1 transgene. When you then remove Dox you get basically a complete NAT1 knockout. 2i LIF supports self-renewal of NAT1 null IPS cells. The NAT1 null IPS cell show higher than WT levels of OCT4 and NANOG as well as other pluripotency factors.

What does NAT1 do as a protein?

NAT1 is similar to eiF4G and it is known itself also as eiF4G2. They function in translational control. eiF4G is an essential linker in translational initiation. They searched for NAT1 binding proteins by doing flag tag IP. It binds to many translational proteins and many similar factors as eiF4G. There are a few things that eiF4G binds that NAT1 doesn’t.

Does NAT1 have general or specific translational regulatory functions? There might be some specific ones.

When NAT1 is turned off some specific proteins are elevated including KLF4 and PRDM14, two key TFs that are required for transition from primed to naive state. RNAs of these two are not changed so the change is at the translational level.

I can’t wait to hear more in the future about NAT1’s role in pluripotency.