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, www.ipscells.com.

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.

Poll: Will NgAgo strongly challenge CRISPR in coming years?

NgAgo CRISPR

 

 

 

 

Stem cell good news: CIRM funds new cutting edge studies

CIRM announced recently the funding of a number of exciting new studies.

ViaCyte received additional funding to support its development of its hESC-based pancreatic progenitor cell product PEC-Direct clinic trials. This work is very promising. CIRM also funded additional diabetes-related research by Humacyte on engineering blood vessels for use in dialysis, which is very creative.

VC-01 post-implant final

VC-01 post-implant

I was happy to see that my colleague here at UC Davis School of Medicine, Professor David Segal, received funding for a cutting edge grant on using gene editing for Angolan Syndrome. The grant is entitled, “MSC delivery of an artificial transcription factor to the brain as a treatment for Angelman Syndrome”.

This funding along with a new grant for Jeanne Loring on stem cells for Parkinson’s came via CIRM’s new basic biology type of funding mechanism. A number of other cool projects got funded via this RFA including one by David Schaeffer at Berkeley on stem cell-produced oligodendrocyte precursor cells to treat neurological injury.

This all is very good news for the stem cell field.

Controversy over CRISPR challenger NgAgo irreproducibility reported

Does the new gene editing method NgAgo work or not? If not, what happened? The answers to both questions seem to depend on who you ask and what you read.

Fang Shimin (方是民) NgAgo

Wikipedia image

As much as CRISPR has been the revolutionary in the genetic modification technology arena over past methods, could CRISPR itself in the next few years become obsolete having been replaced by other new technologies such as the upstart NgAgo? I doubt it.

The odds for NgAgo making a run in this field may have gone down lately, at least based on a comment left by Sheng Qiang on my original post on NgAgo:

“A war of word broke out on the reproducibility of Han’s work these days, especially on the Mitbbs website. The doubters, represented by Zhouzi Fang, said that no labs have repeated Han’s work, especially the Figure 4 results. The supporters claimed that 20 labs in China already repeated Han’s work, yet no data have been shown to support the claim. The doubters suspect that this is another STAP cell incident for China. To be fair, we should probably give more time for labs around the world to repeat Han’s work, which was trumpeted in the Chinese media to be a Nobel prize worthy scientific breakthrough. Let’s just hope that this will not go down the same path as the STAP cells.”

The Zhouzi Fang mentioned seems to most likely be Fang Shimin (方是民), pictured above, who has a Wikipedia page here that mentions his role as a popular science writer who campaigns against pseudoscience and fraud. It also discusses a number of controversies in which he has been involved. I wonder if he might be like Japan’s juuichijigen who played a key role in uncovering STAP. I don’t know.

I’m hoping to learn more about this NgAgo situation so that we all can better judge what the status of NgAgo research might be. The notion that this could be another STAP-like situation would be very unfortunate, but it seems there’s not enough information now to judge and that’s a serious thing to assert. I agree with the commenter that more time is needed before we can be sure what’s what here.

So what is out there on discussions over NgAgo as to whether it works or not?

I did find this page on an “NgAgo” search onMitbbs (which when Google crudely translates it) seems to fit with what the commenter says about a war of words, but I have no idea if that page is reliable.

I also found this Chinese-language science news site reporting on the NgAgo controversy.

This Google group page on NgAgo also has some researchers reporting it doesn’t work for them, but others said it did work.

Overall, I’d say the jury is out, but it’s clear there are strong opinions both ways on NgAgo.

Nervana stem cell clinic: big ads in SacBee & big questions continue

The local stem cell clinic here in Sacramento, Nervana Stem Cell Centers, continues to advertise treatments in The Sacramento Bee and there continue to be big questions about this situation. I’ve blogged about Nervana before and you can see the archived posts here.

Nervana stem cell ad

Nervana must be spending big money on advertising because they have run many full-page ads in the Sac Bee in 2016. Those aren’t cheap. You can see the latest ad above in this morning’s paper.

The focus lately seems to be on marketing stem cells to treat neuropathy. One of the questions I have is whether there is evidence that using stem cells to treat neuropathy and other conditions such as arthritis is safe.

Is there any data showing it is effective?

Are consumers getting their money’s worth? These are expensive experimental treatments and stem cell treatment cost is a big issue in this arena today.

Is this OK with the FDA?

The fine print. As to that last question at least one past ad for this group seemed to suggest FDA compliance. However, in the fine print on today’s ad it says amongst other things, “the use of stem cells is not FDA approved for the treatment of the conditions that we treat and their use is investigational.” Some caution there from the clinic.

The word “investigational” there is also an interesting one as it raises the question again about whether the use of stem cells in this way would constitute the use of an “investigational drug” as the FDA would put it. If the answer is “yes”, then clinics should be getting FDA approval in advance.

It also says in an aspirational tone in the fine print, “However, we do believe in the healing power of stem cells and offer them to you in advance of any potential scientific discoveries that may prove their efficacy.”

Biomedical treatments should be, in my opinion, based on more than belief and should not be sold prior to proof.