Monday morning musings: stem cell stocks, ISSCR, grants, CRISPR, New Book, & more

Wake up, it's Monday

What’s on your mind on this Monday morning? Are you caffeinated enough yet? Depending on where you live it may even be time for dinner, bed, or already early Tuesday.

Here’s some musings…

To get safe and effective stem cell treatments to patients in a responsible, compliant manner you need commercial efforts and that in almost all cases means biotechs.

Doing this blog for 5+ years has made it really sink in just how crucial the commercial side is to all of our shared goals. This means that things like stocks, patents, etc. are really important for us all to think about including academics, patients, students, and more. Of course stocks are very important more directly to investors too.

I’m not a big investor overall and my only stock in the stem cell biotech world now is Ocata ($OCAT) in which I have a very small holding (consider this a disclosure). I like the company’s scientific leadership and its technology. Throw in some promising clinical trials for an area of huge need like macular degeneration and it’s hard not to get excited about Ocata. However, even as Ocata rang the bell at NASDAQ last week, the OCAT stock price has been getting its bell rung this year and in particular more recently it has dropped off a (small) cliff. I don’t claim to understand the subtleties of stock investing super well, but one gets a sense that the company is at a sensitive moment in its history right now. The above issues as well as some rumors and intangibles give a feeling of change in the air.

Of course Ocata is not alone. The stem cell  sector is super volatile and the stock prices of other stem cell companies routinely take beatings. For instance, StemCells, Inc. has had a pretty awful time of it lately on the stock front and things seem pretty dicey right now for them. I hope it can turn around. By the way, this post is clearly not financial advice.

More broadly in this area I suppose we can just hope for the best in terms of trial results and financials holding up during tough periods of time. This has been a tougher year than I had imagined on this front for the field. Stay tuned for more posts on stem cell stocks soon. Still it was good to see many stem cell biotechs at ISSCR making presentations of largely encouraging data.

Speaking of ISSCR, I wasn’t there myself, but the sense I got from some attendees is that it was fairly upbeat. Again, seeing more biotechs presenting talks than in the past is very encouraging. I believe that the more diverse that ISSCR can become the better. Stay tuned also for one or two more posts on ISSCR Stockholm including possibly more from Heather Main (see her posts here). It’s looking like Heather may become a more regular contributor to this blog, which I think would be awesome.

Grants are on everyone’s minds even more now than in historical times in science (i.e. meaning a few decades ago). In my 2+ decades in science in various positions I’ve never seen it quite this bad. These days it seems like I’m always working on at least one grant and sometimes several simultaneously. It eats up a lot of time, focus, and energy, but that seems to just be the new reality.

I consider myself lucky to have gotten one foundation grant funded recently. Even so we’ve all got constant worries on grants. I also recently participated again in another NIH study section, which is always a lot of hard work, but a huge learning experience.

CRISPR science has moved at warp speed, but there is also rapidly growing focus in the life sciences on policy issues related to CRISPR-Cas9 technology, particularly in 2015. The next 6-12 months are likely to prove crucial in determining the path forward including possible action by Congress, the NAS, and more.

In addition to participating in the dialogue, I am also currently finishing a new book on human genetic modification that will probably come out late this year or in early 2016. I hope that it educates and sparks more dialogue without getting me in too much hot water. Stay tuned for some previews/teasers on this book in the next month or two.

There’s been a lot of talk lately about the “postdoc crisis” of there being too few academic positions for postdocs, postdoc training periods being too long, etc. This problem has been growing over the years, sometimes the same possible solutions get trotted out, and people wring their hands, but nothing substantive changes. I don’t have some kind of miracle solution, but it is something we should all be thinking about. What might be some creative solutions?

US Congress Wants FDA to Consult Religious Experts and Ban Human Embryo Genetic Modification

Crystal_Structure_of_Cas9_in_Complex_with_Guide_RNA_and_Target_DNAThe US Congress recently held its first hearing on human germline genetic modification.

The meeting included CRISPR-Cas9 pioneer Jennifer Doudna (see video here) on the panel. See image of Cas9 structure from Wikipedia. CRISPR-Cas9 is a powerful, strikingly efficient tool for genetic engineering of cells and whole organisms.

Now Republican congressional leaders have included a provision in the current spending bill that would block editing of viable human embryos and could interfere with important research.

Concern over a possible reactive move by Congress on human embryo editing has been building so this was not exactly a shock, but is still a concern. The National Academy of Sciences and its Institute of Medicine (IOM) have taken on the task of holding a meeting more broadly on the issue of heritable human genetic modification and issuing a report.

According to multiple sources including a great new piece in Nature News by Sara Reardonthe US House would also require the US FDA to consult religious “experts” as it weighs three-person IVF, a form of human genetic modification intended to prevent genetic mitochondrial diseases. Three-person IVF has been approved in the UK, but not in the US due at least in part to unresolved safety concerns. I have been one of the main scientists openly questioning whether three-person IVF is ready for prime time because of limited relevant pre-clinical data.

From Reardon’s article:

“The House legislation calls for another layer of review. It would direct the FDA to establish “an independent panel of experts, including those from faith-based institutions with expertise on bioethics and faith-based medical associations” to review the IOM report once released.”

I am concerned over the possibility of heritable human genetic modification including the future possibility of efforts at human enhancement. However, requiring that religious figures in a sense instruct the FDA or the biomedical community is the wrong way to go.

I’m also not a fan of the idea of legislation restricting the use of genetic modification technology. So I’m with Hank Greely of Stanford who said, “This step seems dumb…”.

To me the best approach instead would be a moratorium imposed promptly by the scientific community specifically on clinical use of human germline modification technology, while allowing in vitro research to occur on a limited basis with careful bioethics training, transparency, and institutional oversight (see my ABCD plan). Could someone violate such a moratorium? Of course that is possible, but a moratorium would at least reduce that risk and importantly serve to place any rogue efforts into an appropriate context both for the scientific community itself and the public.

Review of Biotech/Translational Talks #ISSCR2015: StemCells Inc, Semma, ViaCyte, & Le Blanc

By Heather Main

The path to the clinic is a slow and arduous activity, frustrating not only to the researcher and patient, but investors. Successful clinical translation of technologies requires a balance of science, streamlined translation and funding. To develop fantastic science and then realise the most important components cannot be adapted to the clinical environment is as disastrous as having a great product but no cash to get it past the post. The fruitful interaction of researchers, companies and clinics will save a lot of pain in streamlining technologies to patients. Thus, it was nice to see an ISSCR 2015 plenary session on stem cell therapies including companies StemCells, Inc. and ViaCyte, Inc. The topics were a good spread of autologous and allogeneic cell sources as well as therapies directed at inflammation and immune reactions versus integrative cell replacement technologies.stemcellsinc-logo

StemCells, Inc. presented progress in clinical trials with allogeneic neural stem cells in brain, spinal cord and eye disorders. As is the reality for companies giving talks some data and beautiful pictures is not disclosed. Though there were no revolutionary data sets on efficacy, what was clear was that grafts could persist 1.5 years post removal of immunosuppression (this was determined with HLA-mismatch begging the development of a Shinya Yamanaka style allogeneic HLA cell bank). It should not be a surprise that there were no amazing efficacy leaps in these first trials. There would be a lot of luck in getting the right cell, the right dose and the right transplantation method in the first go. Even the development of reliable measures of graft behaviour and efficacy will take time to develop and standardise.

Semma TherapeuticsDoug Melton was clear to state that they “haven’t (just) done an academic study”. That while they are not yet in the clinic and even though they present a more classical academic study, showing a complex defined differentiation and detailed functional analyses, that they recognise the importance of not just talking the talk but walking the walk. Doug presented their in-vitro beta-cell body technology that show functional characteristics equivalent to, if not better than, cadaveric islets. They were able to upscale this technology and are now on the prowl for encapsulation technologies to move into the clinical space, which will happen through their new start-up Semma Therapeutics.

ViaCyte New LogoIt’s always nice to hear an Aussie accent ;), giving additional benefits to listening to Alan Robins present the progress of ViaCyte in clinical trials of their pancreatic progenitor and encapsulation technologies. Following on from Doug, Alan made a couple of comments to assure the audience that there was a lot of vigorous science behind their technology, the curse of not being able to disclose and thus somewhat unfairly being seen as less careful. The ViaCyte technology is based on the major phase of expansion in pluripotent cells followed by mass differentiation and subsequent encapsulation. Interestingly in their pre-clinical animals studies the grafts were able to regulate insulin levels at the standard human blood concentrations, indicating not only functionality but also species specific functionality.

Katarina Le BlancKatarina Le Blanc presented her work on MSCs for GVHD, diabetes and vocal cord scarring. Somewhat disappointingly I heard the comments of someone leaving this talk with the all too common disregard that MSC technologies are inferior to pluripotent technologies rather than recognising them as complementary technologies. Katarina showed epithelial cell death and inflammatory markers were reduced with maximal effect at 3 weeks after IV injection for GVHD, even though they also prove that IV infused cells have mostly disappeared already at 3 days post infusion. She also showed that while coagulation and complement cascades are activated in response to IV infusion of MSCs blood clotting is not a common occurrence. The risk of clotting was cell number, dose and passage number dependent, which is a little scary when many autologous therapy clinics do not standardise the cell number they IV inject.

It’s great to see both academics and companies being recognised as the drivers of cellular therapies. Working in a stem cell company myself, I was surprised 2 years in a row to see talks from academics about skeletal muscle differentiation protocols that do not come close to our technology. It’s somewhat understandable that when it is not possible to disclose a lot of details of your research, the companies are often not taken seriously and are relegated to paid presentations during the lunch break. It is fantastic however, to see positive movement in reputable exposure for the companies attempting to drive research to patients.

Heather Main on Carla Kim & Hans Clevers talks on organoids at #ISSCR2015

By Heather Main

Organoids are pretty big in stem cells right now. The last couple of years have attracted a lot of media attention on mini lungs, mini brains, mini kidneys, mini guts and more, giving the impression that scientists know how to specify and organise cells into mini functional organs in the lab. Organoids have become a hot topic in a stem cell environment where our understanding of disease is limited by studying only cell autonomous effects in single cells. If Thursdays ISSCR 2015 plenary is anything to go by, 2 of the 5 talks were on organoids, the first from Carla Kim on lung organoids and the second Hans Clevers on gut and liver organoids.

Carla Kim started with a seemingly irrelevant summary of the fact that just about every cell type in the lung seems to have some sort of stem cell or regenerative capacity but then continued to discuss their work on formation of lung organoids from Sca1+ BASCs (Bronchio Alveolar Stem Cells). Culture of bodies from these sorted stem cells leads to a mixed population of organoids, 20% representing bronchiolar, 60% alveolar and 20% mixed structures. Carla’s research has now shown that Tsp1 increases the proportion of alveolar organoid formation. This is relevant to an increase of Tsp1 seen due to alveolar injury and works towards defining the reactions of lung stem cells to different types of lung damage. I must say however that what caught my attention from a purely human view was Carla’s movie on unidirectional mucin flow in bronchiolar organoids, demonstrating the level of complexity of these structure but also just giving you the school yard giggle of producing snot from pluripotent cells.liver organoid

Hans Clevers talk was such a mass of animation that you found yourself amazed that they have the funding for all of this and a little cheated at the same time that it is the animation that sticks in your mind rather than the data. Hans began with his gut organoids and then moved onto liver organdies (note added from Paul; see image of a liver organoid from one of the Clevers lab papers with the wonderful Meritxell Huch, Hans’ former postdoc as first author, who now has her own lab ).

It was fascinating to see that at least to some extent the gut organoids were capable integrating to gut tissue when transplanted in vivo. The animation showed the organoid splitting to expose its apical surface and then integrating into the tissue through its basal surface. It was unclear to me, but possible I just missed it, if the body was capable of integrating to normal tissue or if some type of damage was required to allow the basal surface to implant in the tissue. Hans also showed forskolin induced swelling of these bodies and rescue of swelling in CRISPR modified Cystic Fibrosis cells. As a progression Hans discussed their developments in liver organoids. These bodies were established from dissociation of liver, which left EPCAM+ bile duct cells that could be programmed to a stem cell state through Wnt and RTK regulation. These liver organoids were used to test responder behaviour of different individuals to drug treatments.

The organoid talks are always beautiful. They always have amazing staining patterns of impressive structural complexities, but what makes them any more interesting than a biopsy in understanding disease? Will they be more powerful for cellular therapies than single cell populations or transplantation of the relevant stem cell of origin? The cost of producing and culturing these organoids needs to be balanced against the benefit of the application over existing and alternative technologies. It was nice to see Hans’ application in responses to chemotherapy, which should be a field that would benefit out of such techniques. The cost to the patient of undergoing a cancer treatment that does nothing to the cancer but ravages their body is huge and will have implications in the number of other treatments that they are able to endure. Chemotherapy treatments themselves have a large financial cost not only for the drugs but the time in hospital, which would further validate the cost of organoid diagnostics.

However, it is not time to throw away autonomous cell studies. The direct effects of genetic diseases on primary affected cell types are essential to understanding the origin of disease. Treating secondary effects will not be as effective, or long-lived, as rescuing the primary effect. Organoids give a second level of understanding which will no doubt lead to increased complexity of autonomous ‘single cell’ cultures towards absolutely defining mechanisms for efficient targeting of therapeutics.

Back to the public, one may imagine that while being a little exciting these ‘mini organ’ studies also seems a little scary to the public and may make them scared of what else we are capable of if we are now growing mini functioning organs. What may need to be a little clearer, at least for the sake of the public, is that while different labs can produce structures with more or less complex hallmarks of structures within particular organs, at this stage we have very little understanding of the processes involved and thus have extremely limited control. It seems that both the starting cell and the culture conditions are important in driving the complexity of tissue formation, but the field is still quite primitive in understanding the complexity of the programs these starting cells undergo. We are also far from the public impression of growing ‘functional’ organs in the lab.

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.