Stem cells in a bottle

In an article in the Globe and Mail this past weekend, reporter Carolyn Abraham provided an interesting and under-reported glimpse into the cosmetics industry use of stem cells to market their products. She notes:

New regenerative medicine centre announced by Canadian government

Earlier this month, the Honourable Tony Clement, Minister of Industry, announced the establishment of the Centre for the Commercialization of Regenerative Medicine (CCRM) with a $15 million initial investment. The CCRM will be based in Toronto and is one of five new CECR’s funded through the Networks of Centres of Excellence program.

While stem cell research continues to make rapid progress and we are now seeing initial transition into the clinic, in relative terms the regenerative medicine industry is still in its infancy. This new Centre seeks to focus energy and resources into leveraging Canada’s research investment into a commercial presence in three emerging technology platforms that will be crucial to the long-term development of a Canadian regenerative medicine industry.

The closer cell based therapies get to the clinic, the more obvious and urgent become the more practical manufacturing and bioengineering issues relevant to delivering cells at scale to patients. Cell isolation and purity, expansion while maintaining function, batch-to-batch potency, and cryopreservation are critical issues that remain to be addressed. Systematic and repeatable manufacturing solutions need to be developed in partnership with industry. Consistent and repeatable delivery of cells at scale, especially cardiomyocytes and hepatocytes, is also being called for by the pharmaceutical industry to enable enhanced predictive toxicology testing, and screening for new drug targets. As a result, CCRM’s initiative to develop new technologies to enable and support GMP cell manufacturing facility will yield many practical clinical and commercial applications over the next five years.

The buzz about innovation

by Paul Krzyzanowski

Basic scientific research is a fundamental driver of improved quality of life that our society enjoys. However, it's tacitly acknowledged that the benefits of research sometimes don't materialize until some time has passed, with the finish line sometimes decades away. This length of time for an advance to be recognized as 'valuable' is extremely unpredictable -- so much so that it's one of the major points of dispute between those who conduct research for knowledge's sake and those eager to see the benefits of the research put into practices.  

Scientific advances and newly discovered techniques are always shared and copied by researchers, most of whom appreciate the time and skill required to learn how to do so. It's not always easy to replicate what someone else has done in another lab, even for someone considered to be a specialist in a subject area.

The business of scientific research

by Paul Krzyzanowski

One of the biggest choices graduate students and post-doctoral fellow face is whether to stay in academia or go into the business world.  

But what if the two weren't really that different?

Traditional advice about running a successful academic research group focuses on the development the Principal Investigator. A recent article by David A. Stone in The Chronicle of Higher Education splits the role of a PI into three: the scholar, the researcher, and the grant writer. The scholar generates and identifies good ideas to pursue and how to place them in well published papers, the researcher actually manages to get the work done, and the grant writer sells the potential of future research projects to funding agencies and foundations.

Can stem cells end the need for blood donors?

by Paul Krzyzanowski

In a previous post, Chris Kamel recently reviewed the Nature article about direct creation of blood progenitors from skin fibroblasts as discovered by Mick Bhatia's research group. The fascinating thing about this article is the potential for enabling autologous cell treatments with a reduced risk of iPS-cell-induced cancer.

Certainly, no one can deny that creating a clinically usable substitute for matched bone marrow from a person's own skin cells would be a phenomenal accomplishment. In my view, what this advance can really accelerate is work to produce methods of culturing human hematopoietic stem cells with the goal of producing artificial whole blood. Bioreactors are routinely used to expand hematopoietic stem cells and producing whole blood is only a (large) step away.

The demand for blood and blood substitutes is large and growing. According to the American Red Cross, approximately 15 million litres of blood were used in transfusions in 2006, and that's only taking the United States into account. This amount is expected to grow in the future, and with the individual components of whole blood having short shelf lives -- six weeks for red blood cells and only one week for platelets -- a constant supply of blood from donors is needed.  

Dr. Dana Devine, Vice-President of Medical, Scientific and Research Affairs at Canadian Blood Services said that cultured blood products might someday help part of this need. "There is a lot of transfusion research science currently ongoing worldwide " she said, noting that the use of skin derived stem cells to replace autologous blood cell collection might be possible for patients with adequate time to wait for cell culture (for example those undergoing elective surgery or chemotherapy), however “the tissue engineering and scale-up issues in turning these kinds of research scale studies into a cost-effective product remain a challenge.”  

The volume of blood required for some procedures is surprising: a liver transplant procedure might use up to one hundred units (45 litres) of blood, according to the Canadian Blood Services website. As less than 40% of the population is eligible to donate blood, those in need of rarer blood types may be out of luck if an appropriate donor hasn't recently come forward within the same geographical location.  

As well known medical procedures, blood transfusions serve two major purposes. One is to replenish volume from blood loss after trauma or during surgery, while the other is to restore the oxygen carrying capacity of the circulatory system. Most volume-expanding blood substitutes are more or less salt solutions, which don't restore the oxygen carrying capacity provided by red blood cells. The products that actually do restore this capacity are divided between perfluorocarbons and various hemoglobin solutions, the latter usually derived from bovine blood.

However, development of bovine hemoglobin products hasn't been easy. None are approved for general use, and those undergoing clinical trials today are in no way guaranteed to gain approval. Up until recently, Biopure was a company producing Oxyglobin, a viable oxygen-carrying product approved for veterinary use, but primarily pursuing approval for a similar product for use in humans called Hemopure. Failing to get approval, the company began to run out of funds in early 2009 and filed for bankruptcy soon thereafter. Some may also recall the Canadian company Hemosol (Now Hemosol BioPharma) formed in the 1980's to commericialize Hemolink, a human hemoglobin based oxygen carrier. Like Biopure, Hemosol filed for bankruptcy in 2005, and both were examples of firms developing their products over the span of two decades or more. Many other blood substitutes like these have been pulled from trials due to safety concerns, including vasoconstriction and pain accompanying their transfusion. 

Producing blood from stem cells may finally be the technology that becomes successful in this space, as erythrocytes (red blood cells) can be produced from human iPS cells. These laboratory studies are establishing principles to show that red blood cells can be generated on a larger scale, and raise the possibility that, in the future, problems of limited blood supplies being available may be reduced or nearly eliminated.  "Though we currently don't have ongoing shortages of blood products in first world blood systems" said Dr. Devine, "there are significant shortages in the developing world."

"However, for the foreseeable future, we still need blood donors to make the system work."

 

The Royal Society and the philosophy of openness: Are we moving backwards?

by David Kent

One of the most memorable moments of my PhD training was at a 2006 Keystone conference where Shinya Yamanaka presented a little something called Pluripotency and Nuclear Reprogramming. He carefully presented the transcription factor screen that would culminate in the first re-programming of a skin cell into a pluripotent stem cell (iPS cells). It was in the mouse, but as the publication trail shows, human iPS cells were not far behind. Having full knowledge of how important this discovery was and how simple the technique was to replicate, Yamanaka had elected to present the transcription factors used in the screen as letters "A" through "X" instead of the actual gene names. While the room certainly stirred as people realized the therapeutic possibilities of such a technology, a more impressionable moment for me was a rather saucy comment that popped up in the question period: 

“This is great Shinya. You know… our lab has also worked with factor M and have obtained very similar results – what are the other factors?”

After a good-natured chuckle, the audience quickly realized that the factors were not to be named that day and we all went back into the dark waiting for the research paper to be published. 

Let it be put on the table that I have an enormous amount of respect for Shinya Yamanaka and his team of scientists – they uncovered something amazing with iPS cells that will certainly drive much future scientific research. But this single event of holding back data stopped the emergence of the iPS field dead in its tracks for months. I realize why it was done, and I recognize that there was a pretty reasonable chance that the discovery would be poached by someone else – so fair enough, right? I filed these feelings away, until…

Late last month I attended a Royal Society Meeting entitled What’s Next for Stem Cell Biology where Kazutoshi Takahashi (the lead author on the original Yamanaka study) gave an excellent talk on the newest developments in his research which highlight a gene that potentially distinguishes “good” iPS cells from “bad” iPS cells (i.e.: prospectively identifying those lines that are likely to cause tumor development). Which gene was up there on the big screen?  Gene X. 

Of all the places to present a “gene X” – the Royal Society venue seems particularly egregious. A society with a 350 year history of openly discussing topics of scientific interest with one of its five priorities being to “increase access to the best science internationally” seems a likely advocate against such blatant acts of non-disclosure? However, it seems the organizers and scientist participants were perfectly okay with this brand of discussion – not even a cheeky question this time.

Again, I understand the reasoning behind keeping your cards close to your chest – but surely something is wrong with the system if we have to wait for months and months of reviews and publication before getting such information into the hands of other scientists. Have we entered (and embraced) an era of scientific research where one’s career path is tantamount to moving science forward? If so, I think we desperately need to question our motives for being in medical research in the first place.

Colleagues with whom I have shared these views shrug their shoulders and tell me it’s better to have a funded lab and hold back research than to have no lab at all (which apparently is the fate of those unfortunately “scooped”). I’m not convinced though. To me, when you are confident in the results that you observe, it behooves you to share them with the research community despite any amount of you-might-not-get-a-lab rhetoric. Hopefully we’ve not traveled too far down this path to avoid turning back.

Can collaboration and commercialization co-exist?

by Tania Bubela

Increasingly, commercialization is a key requirement for securing project funding and support for scientific research. The field of stem cell research is no exception. But does this emphasis on commercialization, which necessarily involves issues of ownership and secrecy, come at the expense of another largely-encouraged element of scientific research, namely academic collaboration? This is a question we posed in a recent study, the findings of which were published on July 2 in Cell Stem Cell.

Using bibliometrics and network analysis to visualize academic collaboration patterns, we examined the impact of patenting behavior and involvement in startup companies on the number of co-authors of individual principal investigators (PIs) within Canada’s Stem Cell Network (SCN). We found that PIs involved in startup companies had about five times as many patents as those not involved. There was a negative relationship between the number of patents garnered and the degree of academic collaboration of SCN PIs. In other words, scientists with the lion’s share of patents typically had fewer academic co-authors and were less connected within the overall co-authorship network for stem cell research.

Above this key conclusion, our research showed some very positive facts about SCN. For one thing, most science researchers at SCN exhibited a high degree of collaboration (up to an impressive 828 co-authors in one case), within Canada and with international scientists—and many developed strong international profiles as a result. This is most evident in the fact that 14 of the 100 most highly-cited researchers in our sample of over 160,000 scientific publications related to the field of stem cell research were SCN PIs.

But what does our finding about the apparent competition between commercialization on the one hand, and collaboration on the other mean? Overall, it suggests that public funding to organizations such as SCN needs to balance incentives for patentable research with those offered for collaborative research. This is most important in the field of stem cell research where the development of marketable products and therapies is highly dependent on innovative, exciting multi-disciplinary, collaborative, international and largely academic research.

iPS cells can help speed traditional drug development

by Paul Krzyzanowski

Imagine that you've just discovered a novel drug that potentially solves a medical problem, one that accelerates wound healing in skin or can reduce the size of cancerous tumors. You can show the effects beautifully in your model tissue culture system and mice obviously respond to the treatment. You decide to call your technology transfer office and at the very last digit, you hesitate, and wonder whether the drug will show any adverse reactions in humans; one side effect can render it useless.

The likelihood of this scenario is quite high; an estimated 75% of drug toxicity problems are not detected until reaching at least preclinical stages of drug development, and only after large amounts of time, funds, and heartache have already been expended. The need for in vitro systems to test for human side effects is clear.

Both human embryonic stem cells (hES) and induced pluriplotent stem (iPS) cells can be coaxed to generate differentiated cells analogous to those in the human body. The Stem Cell Network's Mick Bhatia leads a recently awarded Ontario Government grant intended to identify novel compounds that can promote differentiation of pluripotent cells into different lineages. This work complements that of several other Ontario groups that are developing methods to create pancreatic islets, lung epithelial cells, cardiomyocytes (heart muscle cells), blood and endothelial cells, neural cells and retinal cells.

Two major goals of the project are to identify drugs promoting endogenous tissue repair and to develop tools to generate replacement tissues. However, differentiated cells that behave like their endogenous counterparts (both stem cell or otherwise) are also of use for traditional pharmaceutical development. Using derivative cells in toxicology screens can reveal higher order compound effects at cell or tissue levels instead of simply flagging drugs as being generally cytotoxic or non-toxic. So, the question of whether a potential drug compound inadvertently stops insulin secretion from pancreatic cells or disturbs cardiac rhythms can partially be answered in advance.

The benefits of using hES and iPS cells for this kind of screening have been noted by most of the larger industrial research companies, and many are pursuing either development of stem cell-based screening systems for their own research programs or for productization of screening technology. In 2006, Novocell (now ViaCyte) demonstrated conversion of hES into insulin-producing cells and in 2008 partnered with Pfizer in a drug discovery collaboration using this system. In the same year, GlaxoSmithKline partnered with the Harvard Stem Cell Institute to develop various stem cell-based screening technologies. The following year, Geron and GE Healthcare entered a deal to commercialize hES derived cellular assay products, and soon thereafter Cellartis and AstraZeneca extended their previous collaboration to continue developing hES derived hepatocytes (liver cells) and cardiomyocytes, specifically for developing products for compound screening, drug metabolism studies, and safety assessments.

These developments in toxicology screening suggests that in the not-too-distant future, broad based side-effect assays will become mandatory at earlier stages of pharmaceutical development, possibly prior to any interest being expressed by initial investors. Looking further forward, if conducting stem cell based toxicology screens becomes commonplace, this data might even be required to support claims in basic research publications.