A framework for development

This one day conference focused on the interface between academic research and the commercialization of the fruits of stem cell research. The San Francisco-based linkurl:Women?s Technology Cluster;http://www.wtc-sf.org/ , whose mission is ?to increase the number of successful women-led companies in the life science, high technology, and clean technology sectors and to leverage their influence,? was the organizing sponsor. They apparently sponsor over thirty events a year to promote that mission. The symposium started with two keynote speakers, who gave overviews of stem cell science and then the rest of the day was made up of short presentations by panel discussion participants on their perspectives on the roles of the various parties to scientific business opportunities ? that is academic institutions, venture capital and other sources of revenue and businesses that are willing to take the risk on of collaboration. There were a variety of speakers from other countries ? Germany, Holland, Singapore, Canada, and England which added to the broad ranging perspectives that were discussed.In general, the overarching themes of this meeting were: 1) Who is going to pay for this research? ? Not venture capital ? at least for stem cell-based therapeutics. Look for alternative business plans with shorter timeframe revenue stream ? Not the linkurl:US Federal government;http://www.the-scientist.com/article/display/15758/ ? Europeans have restrictions, but at least they can work in the area ? That leaves private donors/angel investors, institutes such as CIRM, consortiums and networks of companies and institutes that are working together to fill the gap between basic research and industry 2) What can we do to encourage creative problem-solving in this area? Can we: ? Fund Rhodes scholar-like stem cell fellowships ? for study in labs where cutting edge work is being done ? Change the IP/royalty ownership model ? in Sweden the IP is owned by the professor, not the university, which leads to more small companies being spun out ? Minimize exclusive technology licensing ? Broaden the royalty payouts to others, besides the inventors (to incentivize others on the team) ? realizing cash from stock options is not short-term enough to be a real incentive ? Establish an incentive prize. X Prize Foundation ? the group that funded the $10 million prize to jumpstart the personal space flight industry has proposed the idea of putting together a similar prize for solving stem cell challenges 3) Collaboration, collaboration, collaboration. The critical dependence that this field will have on high degrees of collaboration for the following reasons: ? Cost and complexity of research ? Length of time needed to move business opportunities to a position of fundability ? Scarcity of cell lines ? want to minimize the number of replicative experiments (besides confirmation). Consortiums to characterize and bank the current cell lines and any new ones that are being developed ? Competing/blocking IP issues ? due to the complexity of the research it is anticipated that there will be a plethora of enabling technology advancements that will likely be patented ? there was much discussion around the importance of minimizing the exclusive licensing of ?upstream? enabling technologies, that would block the widespread adoption of important new methodology ? (what would have happened if the Cohen/Boyer patent had been exclusively licensed to one company!) ? Complementary skill sets ? so many different technologies will be required to move this research forward that those who collaborate well with experts in other fields will be the most successful in moving quickly. ? Importance of developing a common ethical framework within which all parties can play 4) The variety of different business opportunities available: ? Not just cell transplant ? that?s the furthest off ? Human cell-based toxicology screening ? e.g. rodent, dog and primate cardiomyocytes and liver cells are key cell types that pharmaceutical companies currently use to evaluate compounds prior to nomination for drug development, as human cell lines are very difficult to work with ? this would be a huge market ? Identification of endogenous growth factors/hormones that might stimulate stem cell differentiation or proliferation to potentially develop as treatments for cancer and tissue repair, respectively ? High throughput screening in stem cell systems to look for compounds that will induce differentiation or proliferation of stem cells, as above 5) The unknowns of the field ? related to risk management (particularly from a business funding perspective). It is well recognized that funding institutions such as venture capital and big pharma are highly risk averse (still having a hangover from the late 1990s) and are asking for higher risk premiums than asked for in the past ? money?s not cheap anymore! ? The signals required to differentiate cells reliably and appropriately ? The genetic and epigenetic stability of stem cell lines ? What the FDA is going to expect in terms of production, manufacturing, toxicology ? How are these going to be stored at the site of use ? hospitals. Universal dose? Timing will be an issue in many treatmentsUndercurrents ? comments made as asides or mentioned without going into much detail, but were there: 1) The increasing technological gap in stem cell research between the US and the rest of the world ? the US?s publication rate is decreasing while outside the US publication rate is increasing 2) Abdication of the US government in participating in the debate 3) linkurl:Korean somatic cell nuclear transfer fraud;http://www.the-scientist.com/news/display/22933/ situation ? effect that this is having on the field. This still hasn?t worked in humans yet. One point that was made several times is the observation that one can liken stem cell therapy to two of the most successful recent technologies, replacement protein therapeutics (e.g. erythropoietin and growth hormone) and monoclonal antibodies, which can be loosely grouped together as therapeutic approaches that manipulate normal components of the body that are missing or underactive in disease. This was compared to the much less successful gene therapy approaches (they also lumped in antisense and RNAi technologies), in which introduction of foreign chemical agents is the therapeutic approach. Obviously, the jury is still out on the relative success of stem cell therapeutics versus gene therapy. One could argue that the most successful therapeutics are small molecule drugs, which are foreign agents ? not endogenous component replacements. The important point though, is to remember to pay attention to all the places where other approaches have gotten hung up ? regulatory, production issues, etc. Notes on talks: One very interesting thing was Stanford University lecturer?s linkurl:Chris Scott?s;http://www.the-scientist.com/article/display/15594/ presentation where he discussed the observation that not only are biochemicals (growth factors and hormones) involved in differentiating stem cells into specialized cell types but that biomechanical regulation has an effect on differentiation of specialized phenotypes as well. For example, a multipotent osteoblast, when grown under conditions of longitudinal strain will become fibrous tissue, while if grown under pressure, becomes cartilage, under mild tensile strain they will become bone and if grown under pressure and tensile strain will become joint tissue. This definitely adds to the complexity of signaling systems that will need to be understood prior to reliable derivation of stem cells that consistently differentiate into the desired tissue. Obviously there is much to be done to understand the variety of signals that regulate cell differentiation and specialization. During the noon keynote seminar, Susan Bryant, dean of the School of Biological Sciences at UC Irvine, described interesting research on regeneration in the salamander limb in which it has become clear that there are differentiation signals in fibroblasts, that differ depending on where in the limb the cells are derived from, that are required to recapitulate the normal regeneration of an entire, normal limb. If one damages the skin of a salamander and removes the underlying stromal tissue, a limb will not develop. However if a nerve is moved to the site of skin damage a limb bud will form (but not grow) and if one adds fibroblasts from two radially different locations on the limb, an entire normal limb will develop, while fibroblasts from one location will not stimulate this regeneration. Recent data from Pat Brown?s group at Stanford has done gene expression studies on fibroblasts from different locations within the body and found that they have very different gene expression profiles, indicating that there are biochemical signals that participate in the ?patterning? of tissue ? however, little is known about what those signals are. This underscores both the size of the task of understanding this signaling biology, but also the importance of understanding how that biology fits together to make a tissue with highly complex three dimensional structure. Companies in stem cell news: Exelixis ? program looking at the Notch pathway (also Wnt and Hedgehog), which is critical for the self-renewal process of stem cells. They have a collaboration with Genentech in this area and together they are looking for small molecules, proteins and/or antibodies that would regulate Notch activity up or down thereby influencing the proliferative or differentiation process in the cells. NovoCell ? Cadaver islet cell transplants for type 1 diabetes as ?proof-of-concept? for cell transplant therapy, currently in Phase I/II Cellerant ? Three approaches with differing levels of risk: 1. sorted purified hematopoetic stem cells ? for treatment of patients that wouldn?t previously have benefited from bone marrow transplants ? breast cancer and lupus patients after myeloablative therapy, this reduces chance of graft versus host disease 2. common myeloid progenitor cell transplant ? to boost hematopoeisis, allows increased chemotherapy doses 3. discovery program looking for progenitor cells behind blood cancers ? to develop therapies to attack the stem cell source of the cancer. StemCells Inc ? Currently in Phase I/II with human neural stem cells for Batten?s disease, a disease characterized by the absence of an enzyme which leads to paralysis and death Primer on the Science of Stem Cells The definition of a stem cell is a cell that divides asynchronously, such that one daughter cell is a specialized cell and the other daughter cell is ?self-renewing? ? that is, it gives rise to another daughter cell which is self-renewing. There are loosely, three different type of stem cell: ? Pluripotent stem cell ? can give rise to any one of the approximately 200 cell types found within the body ? Multipotent stem cell ? can give rise to a more restricted (and usually tissue-specific) set of cell types (e.g. hematopoetic, neural) ? Restricted stem cell ? can give rise to one or only a few differentiated cell types (e.g. gut, germ cell) The rule of thumb is that the more different cell types that a stem cell can give rise to the earlier it comes in the lineage process ? thus embryonic stem cells (those derived from a blastocyst) are pluripotent, cord blood stem cells (from the umbilical cord) are multipotent, giving rise to the entire blood cell lineages, both myeloid (erythrocytes, neutrophils, macrophages?) and lymphoid ( T and B cells, NK cells?), and adult stem cells are the most restricted of all ? gut and skin stem cells only being able to give rise to a few cell types of those tissues.

A framework for development

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