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.

Top 10 Positive Stem Cell Developments in 2014

top ten listA lot has happened in 2014 in the stem cell and regenerative medicine field and so much of it has been good news.

These positive developments are often the result of many years of creative, hard work by amazing teams of researchers.

Here is my top 10 list of these exciting advances.

  • 1. First IPSC study in humans by team led by Masayo Takahashi.
  • 2. and 3. Major Diabetes advances: ViaCyte starts stem cell-based clinical trial for Diabetes and multiple teams of researchers make human beta cells with some encouraging functions, which may prove very important in the future as a basis for treatment.
  • 4. Ocata therapeutics‘ clinical trials for vision impairment continued on track with encouraging published results.
  • 5. Stem cell gene editing cures “bubble baby” disease (SCID) in some infants.
  • 6. BioTime and its subsidiaries make substantial progress with multiple clinical trial pipelines including Asterias’ push on OPC1 for SCI.
  • 7. Human therapeutic cloning of ES cells moves rapidly forward.
  • 8. Engineering resistance to HIV in stem cells by UC Davis team in the journal Stem Cells and a team led by Cowan and Rossi at Harvard (reported in Cell Stem Cell paper).
  • 9. Young blood reverses aging in mice. Is it at least in part a stem cell-mediated phenomenon?
  • 10. CIRM launches CIRM 2.0  with warp speed grant funding mechanism.

Did I miss any in your top 10? Tell us in the comments please.

Note: The author has a small long-term stake in Ocata.

Cloning Factory in China Has Familiar Partner: Hwang Woo-Suk

Cloning of animals is becoming a big, global business.

It turns out that this reproductive cloning of animals goes well beyond making duplicates of pets for sentimental customers at $100,000 a copy. Cloning of livestock by agribusinesses is becoming fairly common. Some are also trying to de-extinct woolly mammoths by cloning too, something that I oppose (see top 5 reasons why it might be a really bad idea) even though admittedly it sounds pretty cool.

More broadly, factory-scale production of copied animals is an expanding business. A familiar face in the human therapeutic cloning world (where the goal is to make ES cells) is getting more involved in this industrial-scale animal cloning: Hwang Woo-Suk. Hwang is well known for past bogus research on human therapeutic cloning research trying to make embryonic stem cells and other ethical transgressions.snuppy

Today he is far more associated with duplicating animals using reproductive cloning (aka “Star Wars” type cloning). For a handy diagram explaining the two types of cloning see here. Hwang cloned the first dog Snuppy years ago and now leads a Korean animal cloning company called Sooam.

China is an important emerging player in animal cloning and Hwang and Sooam are forging ties in that country. According to Nature, Hwang has been working with genomics researchers in China and now has opened a branch office for animal cloning in Shandong Province, China. Bloomberg reports on:

a partnership between Sooam and BoyaLife, a fast-growing Chinese biotechnology company with 28 subsidiaries and operations in 16 provinces. Sometime early next year, ground will be broken for a 667,000-square-foot research laboratory on a spectacular plateau of yellow grass and scrubby pines facing the Yellow Sea.

BoyaLife leading scientist Xu Xiao-chun was quoted by Bloomberg that “The point is to expand cloning in China…In China we do things on a massive scale,” he says. “But we want to do all this not just for profit, but also for history.”

Currently Sooam on its own can clone a few hundred dogs a year, but perhaps with the partnership with BoyaLife, they could expand to thousands of dog, pig, and cow clones as well as perhaps other types of animal clones each year.

cloned babiesI don’t necessarily have a problem with animal cloning per se, but I do wonder if it could be taken to an extreme where ethical issues arise and in addition the work done by these animal cloners also sometimes extends uncomfortably into the human arena.

For example, according to its website BoyaLife also operates the largest human stem cell bank in the world.

There’s definitely something disconcerting about one-stop shopping for both animal reproductive cloning and banking of human stem cells?

And Hwang remains quite interested in human stem cells and cloning as well. According to Nature, “Woo Suk Hwang intends to return to human therapeutic cloning.”

This convergence of animal reproductive cloning, human therapeutic cloning, stem cell technology, and powerful genomics technology (all separately on their own arguably having the power to do positive things) nonetheless is a potentially explosive combination that could have troubling repercussions.

More specifically, I am most concerned that this confluence could help pave the way to human reproductive cloning.

Think that’s hyperbole?

Think again.

As animal cloning becomes more widespread as well as accepted as normal by society and as human therapeutic cloning (the ES cell type, but the technology of which can also be used to help in the pipeline to actually clone people) advances as it has in the past year, human cloning may not be so far-out or far-off.

I would note that some folks are talking more and more from a practical perspective about cloning human beings. For example, fertility clinics are starting to talk about using human cloning as a “treatment” for infertility as well. Talk of human cloning also ranges from cloning children that parents have lost to illness (a question I’m increasing getting from readers of this blog who are parents who have suffered this tragedy) to cloning superstars such as John Lennon, Elvis, and others.

I would also remind you that human cloning is legal in the US. The FDA says it has regulatory authority over it, but realistically that doesn’t mean much.

Heck, what if someone went ahead and tried to clone people, what could go wrong? A lot.

This is a cutting edge, rapidly evolving area of biomedical science that will be fascinating even if also somewhat unnerving to watch in the coming years.

Cloning is cloned again: New Nature Paper is 3rd on Human SCNT

A new human therapeutic cloning paper is out today, the third in a matter of months. This one is from the lab group of Dr. Dieter Egli published in Nature demonstrating production of nuclear transfer embryonic stem cells (NT-ESCs) from an adult human somatic donor via somatic cell nuclear transfer (SCNT).

This human SCNT paper follows on the heels of a similar paper (Chung, et al.) from Bob Lanza’s group published in Cell Stem Cell and the pioneering Mitalipov human SCNT paper (Tachibani, et al.) in Cell in 2013.

Together these three papers have proven that human therapeutic cloning to make patient-specific ES cells is absolutely the real deal and that it presents a new therapeutic option based on stem cells in the years and decades to come.

This Egli group paper, Yamada, et al., is entitled “Human oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cells”.

Yamada Extended Data SCNT

So what’s the scoop on this new Yamada human SCNT paper?

The main conclusions fit with those of the previous Tachibani and Chung papers. Oddly enough, one of the most important sets of data is tucked away as Extended Data Figure 8 (see above) that nicely summarizes the paper’s data.

There are some additional technical data that may prove useful for additional labs to make NT-ESCs by therapeutic cloning of human somatic cells such as surprisingly the inclusion of fetal bovine serum (FBS; see the figure above, the far right two columns showing that addition of FBS seems to really boost the process of making NT-ESC lines.

This team also made NT-ESC from a Type I Diabetic patient highlighting the future clinical potential of this technology.

What about the bigger picture?

As I mentioned in a previous post providing broader perspectives on translating human NT-ESCs to the clinic there are some key challenges and I list the top 5 hurdles. I called human therapeutic cloning to make NT-ESCs the stem cell story of the year for 2013.

It’s still a very big deal in 2014. The two new 2014 human SCNT papers just raise the intensity of this story to another level. It will be a fascinating story to continue to follow.

Hannah near-perfect reprogramming voted as iPS cell paper of 2013

iPS cell poll 2013

I recently did a poll asking readers of my blog to vote on the iPS cell paper of the year for 2013.

The vote kind of seesawed at the beginning, but in the end with 100 votes cast the paper by the Hannah lab on near-perfect iPS cell production won out (see votes at left).

In second place was the Deng lab paper on all-chemical reprogramming. I suspect that just a couple years ago, this paper would have won by a landslide, which I think shows that priorities have changed.

I wonder if I had made the poll “the top reprogramming paper” of 2013, would Shoukhrat Mitalipov’s SCNT hESC paper in Cell have top the charts?

My own choice for iPS cell paper of the year? Yamanaka’s one on how to identify defective iPS cells.

Any other papers on iPS cells that you think deserve honorable mention?