Patients talk stem cells. The FDA listens.

By Jeanne Loring

Last Tuesday I visited the FDA headquarters in Maryland, for a meeting called Public Meeting on Patient-Focused Drug Development for Huntington’s and Parkinson’s Diseases. The FDA holds about 6 meetings on different diseases each year, inviting patients and advocates to speak while a panel of FDA directors listens. The FDA representatives at this meeting included Billy Dunn and Eric Bastings, (Director, and Deputy Director, respectively, Division of Neurology Products [DNP], Office of New Drugs), Susanne Goldstein (Medical officer, DNP), and Theresa Mullin (Director, Office of Strategic Programs). All of these people are from the Center for Drug Evaluation and Research (CDER), which is the branch of the FDA responsible for evaluating new drugs. Biological therapies, including stem cell therapies, are evaluated by another branch of the FDA, the Center for Biologics Evaluation and Research (CBER). These CDER members will not be directly examining stem cell therapies, but it’s still useful for them to be aware of them – and they may have friends at CBER.

Summit for Stem CellsThe morning session, on Huntington’s disease, was both disheartening and inspiring: disheartening to hear about how horrible the disease is, and how it affects families – inspiring to see how hope still lives among the stricken and their family members. There are no treatments- none. HD is caused by a trinucleotide repeat in an essential gene that changes its function; the man next to me introduced himself as “a 43 CAG”, which means that he has 43 repeats of the trinucleotide CAG, enough to cause moderate pathological symptoms. His son, he said, is a 46.

Jenifer RaubThe afternoon was for Parkinson’s disease. I was there with two members of the Summit for Stem Cell Foundation, which is supporting development of a patient-specific stem cell therapy in my lab in collaboration with Dr. Melissa Houser at Scripps Clinic: Sherrie Gould, a nurse practitioner who treats PD patients is the heart of the foundation, and Jenifer Raub (pictured in photo from the meeting at left from Jeanne Loring) is a patient who speaks eloquently about the impact of the disease on her and her family. Jenifer was one of 5 patients who were chosen to speak directly to the FDA on a panel about therapies. If you want to add your own comments, the FDA is taking comments until November 23 at this link: http://www.regulations.gov/#!documentDetail;D=FDA-2012-N-0967-0747 .

Jenifer’s words will appear in the transcript and are far more meaningful than anything I could say- here is some of what she said:

“My Name is Jenifer Raub. …I have Parkinson’s disease….Every day is a struggle with the ups and downs of Parkinsonian symptoms and at the end of each day I am exhausted and frustrated.

I never know what tomorrow brings. Another day filled with the same unpredictability – Can I stand? How much pain will there be? How long will the medications that are working today continue to do so???

Acceptance of this instability is often frustrating. I heard a lot of frustration in persons here today…I have days I’m reminded of the fact that the medicines I take will not be effective forever. Parkinson’s disease is progressive. Those are the days I look at my children and grandchildren and wonder: How long will the medications be effective? How much time do I have?

My life has a new definition of “normal”. Parkinson’s disease has redefined my family, friends and marital relationships. There is NO cure for Parkinson’s disease today.

And, yes, I have looked for alternate treatments for my condition. I do not want to be dependent on medications for the remainder of my life… I strongly believe that there is great promise in the NEAR future for stem cell therapy for the treatment of Parkinson’s disease -specifically induced pluripotent stem cells, which are patient specific and DNA matched…Stem cell therapy in Parkinson’s disease has a 30 year history. Decades ago studies were done using fetal cells. Those participating in those studies are now dying of natural causes and the dopamine cells at the time of death were still viable! Fast forward 30 years – today a simple skin cell can be made into a pluripotent stem cell and consequently a dopamine producing neuron…. [Summit for Stem Cell hopes to file an application with the FDA in 22-36 months. I know the risks and side effects of the medications I take. I know the risks of stem cell therapy. I am willing to take the risk rather than acquiesce to Parkinson’s disease. Let me – Let US have the right to take the risk and the right to choose HOW we fight the symptoms of Parkinson’s.

I fight EVERY day to move. I am fighting for a life with my family…I want a future with the simple joy of being with my husband, my children and my grandchildren. I want to see my grandchildren graduate college. I want to attend their weddings and I want to meet their children and kiss their foreheads.

Time is limited for someone with Parkinson’s.

MY time is limited.

Give me a chance to choose. Give all of us a choice. I would like to ask the FDA to consider supporting and furthering this new and revolutionary field of regenerative medicine that will change therapies and treatment for not only Parkinson’s disease but for so many diseases that there is NO cure for today.

Thank you for your time…I appreciate you listening to me…”

Overview of Yamanaka Talk at #ISSCR2015 by Heather Main

Heather_MainISSCR day one

By Heather Main

The day of plenary is the most enjoyable in my view. You don’t need to make the choice between sessions and the judgement on the viability of shifting sessions versus staying put and listening to the slightly less relevant.

ISSCR 2015 plenary was, as to be expected, full of the big names, the affectionately known Rusty (Fred Gage), Jonas Frisen (one of the smartest MD PhDs I have ever met) and of course Shinya Yamanaka. In deciding which talk I wanted to highlight it is somewhat cliché to go for the Nobel Prize winner but I just can’t help it, he is just such a great guy.

I first met Shinya at Karolinska Institutet, Stockholm, Sweden, when he was giving a presentation (no doubt an interview for his Nobel Prize). In association with this trip he was interviewed in our lab space where he divulged that he got into research as he didn’t think he was a very good orthopaedic surgeon, he wanted to do something where he could help people!

So, I was very pleased to see that his ISSCR 2015 talk was divided into 3 sections;

  • immune matching of pluripotent cells
  • differentiation and purification of desired cells types
  • pre-clinical testing of stem cell therapies

What this tells me is that Shinya is truly devoted to helping people. That he is not just thinking about the first step or the last step of stem cell therapies but the entire process, each step as important as the next and the previous. It is not enough that he has a Nobel Prize and could spend the rest of his career studying the mechanisms of reprogramming, he wants to drive his technology to the patients. What a star!

The first part of the talk outlined his work into HLA haplotype matching with regard to homozygous individuals. With a current Japanese focus, just one donor homozygous for the most common HLA haplotype would be sufficient to provide immune matched cells to 10% of the Japanese population. 10 homozygous donors with other common haplotypes would cover 50% of the population and 140 homozygous donors would cover 90%. With 1:1000 individuals showing a homozygous phenotype AT LEAST 140,000 individuals would need to be HLA screened, with this number falling drastically short on the fact that a specific repertoire of HLA haplotypes would be needed. So Shinya and his team are scanning the blood donor and cord blood bank stocks to find their golden donors. A huge task, with huge reward.

For differentiation and sorting Shinya’s team have developed a method called miRNA switch. The technique is mainly aimed at those cell types for which we do not have good cell surface markers for FACS sorting. Basically expression of two fluorescent proteins indicates transfected cells, which upon differentiation to the desired cell type, will lose expression of one of the fluorescent indicators under the control of a cell type specific miRNA. These single positive cells can then be sorted or selected with chemical resistance. Simple and elegant though may require significantly larger numbers of cells, dependant on transfection efficiency.

Finally, my favourite iPSC master showed data from a pre-clinical study into Parkinson’s Disease transplantation of Corin+ dopaminergic neurons. For this section Shinya was very careful to acknowledge his collaborator Professor Jun Takahashi, and continued through the section to present the work as ‘he did’ rather than ‘I did’ or ‘we did’. In the study they were able to show that sorted iPSC derived Corin+ dopaminergic neurons transplanted into monkey brain gave functional recovery of Parkinson’s Disease and survived for at least one year without a reduction in graft size and without tumor formation. Interestingly, whether the original iPSC were from diseased or non-affected individuals, similar rescue was seen, arguing for autologous therapies from the diseased individual. These results were setting up for the exciting step of testing these human cells in human clinical trials beginning within the next 2 years.

While Shinya may be the big name, his humility and genuine desire to make a change in the lives of patients is a great inspiration. His continued dedication to the cause in light of his earth shattering appearance onto the stem cell stage is a testament to a great guy. Japan is definitely the space to watch for a dedication to stem cell therapies (including liberal regulatory standards), and I’m sure along with Shinya they will continue to drive the field forwards both at the basic and clinical level.

Yamanaka Interview on Clinical Use of Pluripotent Stem Cells

Dr. Shinya Yamanaka

Dr. Shinya Yamanaka.                                           Photo from CiRA, Kyoto University

I invited Nobel Laureate Shinya Yamanaka to do an interview on the future of clinical translation of induced pluripotent stem cells (iPSC).

He provides some intriguing new insights into the iPSC field and the broader stem cell arena.

PK: The Takahashi Team’s active Clinical Study using iPSCs to make RPEs to treat Macular Degeneration has generated a great deal of excitement. Can you please share your perspectives on the importance of this work and the team involved? 

SY: This is the first study to apply iPSC technology to human care. This is a very important study, because if it succeeds it will show that iPSCs can be safely used in humans and also their potential for cell transplantation treatment. We collaborated with Dr. Masayo Takahashi of RIKEN CDB by evaluating the safety of the iPSCs and iPSC-derived cells that were used for the cell transplantation. She is an excellent researcher, and I am not surprised that her team is the first to have succeeded in this transplant.

PK: Any cutting edge investigational clinical work such as this has some risks. Could you please comment on the potential risks in this iPSC trial? Are there some elements here such as preclinical data, the number of cells used, or the target tissue of the eye that lower risks?

SY: One of the major concerns is whether transplanted cells such as the RPE sheets will cause tumors. In our collaboration with Dr. Masayo Takahashi’s team, we evaluated the safety of iPSCs and iPSC-derived cells by genome and epigenome analysis. While we minimized the risk to a level acceptable for clinical trials, we really cannot confirm how the cells will respond until we actually do experiments with humans, which is why this project is so important. One advantage of treating age-related macular degeneration is that it is easy to detect any abnormalities in the eyes, which is why the disease is a good starting model for iPSC-based treatment.

PK: As the inventor of iPSCs did you imagine 7-8 years ago that a patient in a clinical study in 2014 would already have received an iPSC-based treatment? How was this rapid translation from bench to bedside possible?

SY: I was surprised that after the announcement of human iPSCs in 2007, Dr. Takahashi told me that she would bring iPSC to the bedside within five years. I thought it possible technically speaking, but doubted it could be done so soon, since we needed to improve the technology and get government approval. It took 7 years, which is remarkable considering the work required. Both the accomplishment and the speed at which it was achieved are testaments to Dr. Takahashi’s leadership and her strong team.

The rapid transition is because many bright and passionate people are in the iPSC field. The funding and infrastructure provided by the Japanese government is also a major factor, as these have encouraged excellent scientists to enter the field.

PK: We are also starting to hear more about Dr. Jun Takahashi’s Team’s important work towards using iPSCs to treat Parkinson’s Disease. Can you please tell us more about that?

SY: Prof. Jun Takahashi’s team at CiRA is working on cell therapy for Parkinson’s disease, aiming to transplant iPSC-derived dopaminergic neural progenitor cells into PD patients’ brains. Early results suggest this treatment can be effective, and his team has established the protocol for transplantation. They are now focusing on validating its safety using monkey models. We hope his work will soon reach the operating room within the next few years.

PK: What other clinical applications of iPSC technology are in the works and that might begin clinical studies in the next few years?

SY: There are two major clinical applications of iPSCs, namely regenerative medicine and drug discovery. CiRA has a number of researchers working on either or both. For regenerative medicine, Prof. Koji Eto at CiRA is working on generating platelets via iPSCs, and we expect this will also proceed to clinical research in a few years. Besides work at CiRA, a team at Keio University has a plan to conduct clinical research on patients with acute spinal cord injury in four to five years, while Osaka University and Keio University hope to transplant iPSC-derived cardiac myocytes into patients with heart diseases within a few years. CiRA is collaborating with these teams as well.

Regarding drug discovery, you may have heard recently of CiRA’s Prof. Noriyuki Tsumaki’s paper about statins effects on bone growth, which was published online in Nature last month.

PK: Some in the media are taking about a certain tension between clinical iPSC work in Japan and clinical iPSC work in the US. Do you believe such a tension exists and if so, why? What does it mean for the iPSC field overall?

SY: I am not sure what “tension” means. I understand that both competition and collaboration exist between the US and Japan.

PK: How do you view hESCs today? Are there hESC clinical trials or potential applications that are of particular interest? What is your view of the argument by some that hESC are no longer needed?

SY: Human ESC was a great discovery for regenerative medicine and also instrumental to the discovery of iPSC and the type of medical treatments we are aiming to apply iPSC. At the same time, the ethical issues that hESC possess mean that as iPSC technology improves, hESC will be less needed. Still, iPSC is a new technology, and its safety and efficacy still needs to be confirmed. In addition, there may be some therapies for which hESC are better than iPSC. Thus, I think basic and clinical research of hESC is also important and should be done in parallel with iPSC research.

PK: What excites you most about the stem cell/regenerative medicine field right now today?

SY: I am excited about the possible number of people treated with iPSCs. This field has great potential to provide treatments for currently incurable diseases. Hopefully, within 5 years, we will refer to Dr. Masayo Takahashi’s AMD work as just one of many patient studies using iPSCs.

PK: Where do you see the iPSC field and the broader stem cell field in say 5-10 years?

SY: It is pretty amazing how much it has changed in the past years, so predicting the next 5-10 years is very difficult. I certainly hope we will see more diseases being treated with iPSC and related technologies such as direct reprogramming. I also hope that iPSC will be used more widely and routinely in drug development.

PK: What advice would you give to young scientists today who are excited about a career in stem cells/regenerative medicine?

SY: Through biomedical research, you could help thousands of patients in the future. Stem cells provide unprecedented opportunities in stem cell therapy and drug development. Biology of stem cells itself is extremely interesting. I hope many young scientists will enter to this field.

Human clinical studies of iPS cells to treat Parkinson’s Disease coming very soon

Jun TakahashiA Japanese team of researchers led by Dr. Jun Takahashi, professor at Kyoto University is reportedly aiming to start in human studies of an induced pluripotent stem (iPS) cell-based treatment for Parkinson’s Disease (PD) as early as fiscal year (FY) 2014.

In Japan the FY runs from April 1-March 31 so FY2014 would begin in about 10 months.

That is still remarkably fast and encouraging in the battle against PD.

It also more broadly is an indication of the accelerating pace with which Japan is aiming to translate iPS cell technology to patients. Jun Takahashi (pictured above in CIRA photo) is part of the larger team working to make iPS cell-based therapies a reality for helping patients.

The Asahi Shimbun article reads:

“We hope to confirm the effectiveness and safety over the coming year or two before proceeding to the stage of clinical research,” Takahashi said during a lecture in Tokyo on June 6.

At Scripps in La Jolla, CA, Jeanne Loring leads another team, this one working with PD patients, working to apply iPS cell technology to treat PD.

I asked Jeanne about this new report of Dr. Takahashi’s plan and have the following quote from her:

I met Dr. Takahashi a few months ago at a CIRM workshop on Parkinson’s disease, and saw some of his very convincing work.  His experiments with transplanting cells in non-human primates supports the idea that dopamine neurons from autologous iPSCs are more likely to be therapeutic.  Since our project plans to transplant patient-specific iPSC-derived dopamine neuron progenitors, this is great news for us. In this case, I don’t feel like this is a competition, and I’m happy to follow in Takahashi’s footsteps.

Dr. Takahashi has published quite a bit on PD’s more generally including treatment of a monkey PD model using a hESC approach that was encouraging from a safety and efficacy standpoint.

I hope we can soon see some of Takahashi’s pre-clinical data on iPS cells for PD published soon so we can get a sense of the safety and other information.

Overall this seems like very good news for the stem cell field and Parkinson’s Disease community.

Jeanne Loring interview: optimism on clinical translation of IPS cells

Jeanne Loring

One of my favorite stem cell scientists is Jeanne Loring of Scripps. She does great science and when you ask her questions, she frankly states her opinions and is clearly a gifted educator at heart too.

Below is a Q&A interview I did with Jeanne on key issues of clinical translation of iPS cells. You will see that Jeanne is very optimistic about the eventual clinical use of iPS cell-based medicines.

My Qs are bolded and her answers are italicized. Enjoy!

1. While there is some disagreement over the exact number, it seems that  on average, each iPSC line has a very small number of mutations. Some  mutations are present in the somatic parental cells of origin of the  iPSCs, while others may occur rarely during the iPSC production process. What is your feeling for the functional significance, if any, of these genetic changes?

Jeanne: I think this is an attractive idea that turns out to just not to be true.  There were several reports that reprogramming causes mutations, but the studies were flawed because they didn’t consider the existing heterogeneity of the fibroblasts used for reprogramming.  The paper from Flora Vaccarino’s group at Yale has solved this issue, I think (Abyzov, et al, 2012. Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature. 2012 492:438-42).

We are all mosaics of cells with slightly different sequences, and the mosaicism shifts in dividing cells as they acquire sequence changes (note that I did not call these “mutations”). Since healthy people have this mosaicism, we assume that it is not harmful.

Another issue is the sequencing technology itself- there is an intrinsic error rate, and to confirm single base changes we need very deep sequencing and many replicate samples.  Most stem cell researchers are not also expert in genomics, so it’s easy to be misled.

2. iPSCs also exhibit epigenetic differences from hESCs. Is it known what if anything these differences mean for the biological behavior of the iPSCs? Given that the epigenome is inherently dynamic, is there concern that iPSCs could “drift” during preparation?

Jeanne: If you were asked, for a bet, to distinguish hESCs from iPSCs by their epigenomes, with one exception, I’m afraid you would lose.  The exception is the X chromosomes in female cells.  We females have two X chromosomes, while males have only one, so to balance the activity of the genome, we turn one of the two X’s off. When iPSCs are first generated from female cells, one of the X chromosomes remains inactive. About half the time, the inactive X in iPSCs becomes active over time in culture, becoming indistinguishable from female hESCs, which start out with two active X’s.  If you were given a set of male iPSCs and hESCs, and asked to distinguish them, you’d be completely out of luck. There are no other consistent differences between iPSCs and hESCs.

I should have asked you to bet on this before telling you the secret…perhaps I’ve missed my chance to win.  Actually, this is not a secret; those who are brave enough to tackle our admittedly dense opus on DNA methylation already know the answer (Nazor et al, “Recurrent variations in DNA methylation in human pluripotent stem cells and their differentiated derivatives”. Cell Stem Cell 10: 620-634. (2012)); it’s a tough read, so I think that most people are waiting for it to come out on video…

The approach is summarized in this quote from the paper:  “To obtain a comprehensive view of hPSC-specific epigenomic patterns, we collected 136 hESC and 69 hiPSC samples representing more than 100 cell lines for analysis. In order to establish expected variation in human tissues, we collected 80 high-quality and well-replicated samples representing 17 distinct tissue types from multiple individuals. Finally, we selected 50 additional samples from primary cell lines of diverse origin to control for any aberrations that may arise as a general, non-hPSC-specific, consequence of in vitro manipulation”.

Translation:  we looked at a LOT of cell lines and samples, not just a few.  Shinya Yamanaka points out in a perspective in the June 2012 issue of Cell Stem Cell that the consistent story from large studies is that iPSCs and hESCs are the same; from small studies, that they are different. If you look closely at a small number of cell lines, you are bound to find differences, between iPSC and hESC, as well as among hESC lines and among iPSC lines.  If you look at a lot of cell lines, those differences turn out to be insignificant.

3. In addition, it seems that iPSCs can possess epigenetic memories of their cell of origin. For example, an iPSC made from blood cells has been reported to be more adept at differentiating into blood cells versus an iPSC made from skin, which is better at making skin. Do these memories impact the therapeutic potential of iPSCs?

Jeanne: This is another attractive idea that doesn’t hold up well to examination.  I wonder how many people have actually tried this?  We (and others) have found that these “memories’ are inconsequential and transient.  The epigenome of iPSCs continues to stabilize as the cells are expanded, and by passage 10 or so, there are no persistent epigenetic memories of what the cells once were.

Our iPSCs derived from cartilage and melanocytes are no better than other cell lines at making their cell type of origin, and they all make all three germ layers just fine.  The paper just out from Doug Melton’s lab shows that a simple manipulation in the culture conditions, just adding DMSO, makes both hESC and iPSC lines lose much of their bias toward a particular form of differentiation (Chetty et al, “A simple tool to improve pluripotent stem cell differentiation” Nature Methods, online publication 14 April 2013).  The message is that if we have robust differentiation protocols, all pluripotent cell lines will differentiate into whatever we wish them to.

4. iPSCs can also have various other distinguishing features from hESC ranging from subtle differences in the transcriptome and metabolomes to other areas. Overall, do you view hESC and human iPSCs as essentially “bioequivalent”? In other words, are they functionally interchangeable? In regards to the first 3 questions above as well, in the end is the bottom line how the cells behave above and beyond all else?

Jeanne: I think that the preponderance of evidence is that iPSCs and hESCs are bioequivalent.

I know that this is not yet the most prevalent opinion; attractive ideas are hard to shed.  Another recent example is the attractive idea that iPSCs will be rejected even if they are transplanted autologously (that is, to the identical strain of mouse, and by analogy, to the same person from which the iPSCs were derived).  One paper published in 2011 started this idea; two papers since then have refuted it very well. The good news is that if we’re patient, the real story eventually emerges.

5. What is your current preferred method for production of iPSCs for potential clinical use and why? The last time I talked to the FDA, they indicated to me (informally at least) that their experiences and regulations derived from oversight of hESC studies (Geron, ACTC) would provide a framework for their oversight of iPSC-based drug products assuming no genetic modifications invoked to make the iPSCs. Is that your impression as well?

Jeanne: There are two different ways to look at this:  what do WE think is the best, safest, method, and what does the FDA want us to do?  Unfortunately, the FDA will not tell us what to do, so we’ve decided, of course, to use non-integrating methods (Sendai or episomal vectors).

My personal view is that it’s also critical to do intensive molecular analysis of the cells: genome and epigenome- and correlate those data with the behavior of the cells.  For example, if we find that a particular duplication or mutation in the genome is consistently linked with bad behavior (like making tumors), then we can make sure that those cells are not used for therapy.

Stem cell genomics is one of my soapboxes:  we have all the tools we need for comprehensive genomic and epigenetic analysis of human pluripotent cells and their differentiated derivatives, and we should use them. My only caveat that the data MUST be interpreted biologically.  In other words, I would want researchers who are doing in depth analysis of stem cells to have great expertise in both genomics and in stem cell biology.

6. Can you tell us a little bit about your own lab’s clinically-oriented iPSC-based work?

Jeanne: We have active projects for both “disease in a dish” and transplantation therapy using iPSCs.  The work that is closest to a clinical application is our project to develop an autologous therapy for Parkinson’s disease.  A very long time ago I worked on fetal cell therapy for Parkinson’s disease; since the 1980’s, there have been multiple cases of successful transplants of human fetal dopamine neurons to PD patients.  Issues of fetal research aside, we think that our ability to quality control iPSC-derived dopaminergic neurons before transplant, which was difficult with fetal cells, will make this a much more consistently successful therapy.  Note that this work is fully supported by a patient group- Summit4StemCell.org. The stories of the 8 patients in the pilot study are on the web and are remarkable.

We have recently initiated a collaborative project on Multiple sclerosis that is supported by CIRM funding. Tom Lane of UC Irvine is working with my group to develop a stem cell therapy for this disease.

We’re also studying autism with a disease-in-a-dish approach, and have a small study on the possible role of stem cells in melanoma.  For the future, we have been developing an ethnically diverse collection of iPSCs that we hope will be useful in drug development, to identify drugs that are toxic to people with certain ancestries.

7. Finally, what is your perspective on the intellectual property (IP) area of iPSCs? I’ve been told that we should prepare for an iPSC patent war. Is that an exaggeration? More operationally and practically, does a  lab such as yours (or perhaps mine at some future date if we get to that  point with iPSCs) have to worry about who might own the IP rights to use iPSCs that your own lab might produce depending on how you make them?  How does a scientist navigate that legal and IP complexity?

Jeanne: Patents interest me.  Just last week, I visited the Supreme Court to watch the arguments about whether human genes should be patented.

Patents on fundamental things:  genes, human embryonic stem cells, iPS cells- allow the patent holder to have a monopoly, preventing anyone else from using whatever they’ve patented.

Patents are supposed to stimulate investment in development.  Why, as Justice Scalia said last week, would anyone have the incentive to study a gene and, for example, develop diagnostic tests, if they couldn’t prevent everyone else from working on that gene?

But patents also stifle competition and the advances that come from having many different groups studying the genes or cells.  One of the main reasons I returned to academia was so I could have freedom to study human ES cells without worrying about getting threatening letters from a patent holder, demanding that I either stop working on the cells or pay a steep licensing fee.

There will inevitably be problems commercializing iPSC-based therapies and assays, because at least three institutions own patents on aspects of iPSCs.  I’m paying attention to the patent “landscape”, but have decided to deal with those problems when they arise, and hope that the iPSC patent holders realize that the potential of these cells is too great to keep to themselves.  It would be better for all of us if the issue of stem cell patents never has to be decided in the Supreme Court.