BioScience Biz

Wisconsin’s $750 million biotech investment could use better vision

In 2004, the nation took notice as California and Wisconsin independently announced major investments in stem cell and biotechnology research. In California, voters approved Proposition 71, a massive $3B commitment over ten years to fund stem cell research. In Wisconsin, Governor Jim Doyle announced a $750 million state investment in biotechnology in order to help the state maintain a leadership position in the life sciences. Four years later, let’s take a look at what is going on inside Wisconsin and around the country to gauge just how well Wisconsin’s biotech leadership is holding up.

Home cooking—Wisconsin’s biotech investment

The cornerstone of Wiscon’s $750M biotech investment is the $150M Wisconsin Institute of Discovery (WID). WID is a partnership between the state, the Wisconsin Alumni Research Foundation (WARF) and a generous donation from John and Tashia Morgridge, each of which contributed $50 million to build a new public/private hybrid research building on the UW-Madison campus. Some of Doyle’s total came from the public sale of Blue Cross Blue Shield of Wisconsin, which had been in the works quite awhile before Doyle’s announcement. The total also includes $134M and $132M for new additions to the UW-Madison School of Medicine and Public health and to the Medical College of Wisconsin, respectively—funds that also had been raised much earlier and that included substantial private contribution.

By my count, of the $750M, $421M comes from non-state sources or is money that already was earmarked for medical school buildings when Doyle made his announcement, leaving about $330 as Wisconsin’s total commitment to life sciences since 2004—a tidy sum to be sure, but not as impressive as it was made to sound. This is about what California will spend on stem cells each year for the next ten years.

More revealing is what this money is buying. A significant portion clearly is going for bricks and mortar in order to expand and modernize the research infrastructure in Madison and Milwaukee. A substantial amount of the money from BCBS sale of BCBS goes for local public health and education efforts across the state. It is disingenuous to add this money into the total of a biotech initiative.

Even though ground has just been broken for the WID and the building won’t be finished until 2010, we can get a glimpse of the research the Institute will support from the $3M recently awarded for Discovery Seed Grants. These Seed Grants will support the following research:

• finding a diagnostic test for a common causes of infertility in women.
• understanding cognition and the effects of Ritalin in the brain.
• more efficient production of embryonic stem cells.
• finding new drugs that inhibit cancer cells from spreading to other locations.
• improved healing of persistent wounds.
• high-tech screening for drug candidates that can dock to critical disease-specific receptors on cells.
• developing micro-optical lenses that can be fine-tuned by environmental factors.
• finally, there also is a project to find improved ways to teach African American children from low income families to speak proper English.

While each of these projects, individually, are certainly very interesting and address important questions, it is hard to see any overarching theme in this disparate collection of projects. Was there any strategy behind selecting these projects other than that these were the ones that rose to the top of the pile of the potpourri of proposals that were received?

Case in point--as important as the research likely is, how teaching minority children to speak proper English fits into a biotech initiative is utterly befuddling. The micro-lens project may not have much life science relevance as well.

The impression from all of this is that the research component of Wisconsin’s biotech initiative lacks a critical focus that a rather small investment cannot afford. When competing with billion dollar initiatives, a smaller contender needs to clearly define its specific strengths, identify important opportunities related to those strengths and proceed in a focused fashion to capitalize on strength and opportunity rather than spread the largesse willy nilly. But, it appears that Wisconsin soon will have a fabulous, brand spanking new research facility staffed by a mish mash of researchers who will have little in common to talk about with each other.

For comparison, let’s take a look at what Wisconsin’s competition has been up to recently.

Looking Westward--California

While Wisconsin’s $3M in Discovery Seed Grants was given to 8 disparate research efforts, not all of which relate to biotechnology, the California Institute for Regenerative Medicine (CIRM) has so far approved 206 grants for more than $554M, all focused on stem cell research and regenerative medicine. These grants include money to support and train 169 new stem cell scientists and clinical fellows, 22 grants to launch the research of new faculty, funds for 73 seed grants to test highly innovative ideas, and awards for 28 comprehensive grants to senior stem cell scientists.

More importantly, on top of their stem cell meta-focus, the California initiative recently finished a round of grant awards strategically concentrated on developing new stem cell lines. The research programs supported by these California awards will go to find better ways to reprogram adult cells into stem cells and to develop clinical-grade stem cell lines that can be used to treat patients. Some of the projects will develop disease-specific stem cell lines in order to model cell development in Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and cardiovascular disease. This represents a beneficial mix of complementary projects so that the whole of California’s research initiative is greater than the sum of the individual projects.

California made 16 of these awards for a total of $23M, which comes to $1.44M/award compared to Wisconsin’s average of $375,000/award--26% of the California average.

Like the first round, the next round of CIRM research awards will also be strategically focused, but on forming disease-specific teams of researchers and clinicians to develop stem cell therapies for human illness. From the preliminary applications that have been accepted, these teams propose to develop stem cell therapies for diabetes, eye disease, osteoarthritis, wound healing, stroke, heart disease, muscular dystrophy, AIDS, Parkinson’s disease and certain blood diseases. CIRM indicates that successful proposals will include a plan for an investigational new drug filing with the FDA at the end of the four or five year project.

Wisconsin should especially take notice that these disease-specific team projects involve cross-functional teams of scientists and physicians, often from multiple California public and private institutions. The teams can also include partnerships with private biotech and pharma companies across the US, as long as the company has an office in California. Clearly, California is creatively leveraging its resources to not only support research, but also to ensure that the research is translated into business and moves into the clinic.

Compare California’s inclusive, collaborative team approach to Wisconsin’s singular focus on UW-Madison with the WID. While Wisconsin’s 8 Discovery Seed Awards do involve research teams, the teams only come from UW-Madison. These awards fail to take advantage of the growing private biotech sector in Southern Wisconsin and the scientific talent that can be found at other institutions across the state such as UW-Milwaukee, the Medical College of Wisconsin and the Marshfield Clinic.

In other words, California has purposefully focused its research efforts, while simultaneously encouraging broad public and private partnerships across the state. Wisconsin has done exactly the opposite by funding a broadly unfocused research portfolio restricted to a single institution.

California has positioned itself to get more “bang for the buck” than Wisconsin will for its investment.

It doesn’t stop there—the competition is getting more intense

In a 2004 press release, Governor Doyle said that California’s $3B stem cell investment, “…will not diminish Wisconsin’s role; if anything, there will be a synergy between our two states." However, time shows that California prefers to synergize elsewhere.

For example, the Canadian Institutes of Health Research announced in a recent press release that it will join forces with California to focus on cancer stem cell research. Toward this end, Canada pledged $100M ($98.9M USD) to the Cancer Stem Cell Consortium, a partnership of academic, business and government agencies, which will work with CIRM.

On top of that, CIRM is actively seeking partnerships with the US federal government as well as with other nations in order to turn their ten-year commitment into a sustainable venture. Indeed the CIRM is working on a deal with the Australian state of Victoria and last year, the Canadian   province of Ontario ponyed up $30M for cancer stem cell research linked to CIRM. 

 Now look Eastward—Maryland, Massachusetts and New Jersey

Wisconsin does not only have to worry about competition from California--Massachusetts,  Maryland and New Jersey have or are planning major financial forays into the biotech field. In mid-June, Maryland Governor, Martin O’Malley announced a plan to provide $1.1B over the next ten years in state incentives in the form of tax credits and grant programs for the state’s biotech industry, while the state’s pension board will invest an additional $500M, bringing the total to $1.6B. The goals are to build a biotech center, finance capital projects and to make equity investments in start-up biotech companies—and intriguing and innovative idea.

It used to be that angel and venture investors covered this earliest and critical stage in biotech development that is euphemistically called the “valley of death”--a nod to the difficulty researchers have commercializing their ideas. But recent trends show that investors are increasingly reluctant to invest in nascent companies—they want to see prototypes and experienced teams in place before plunking down their money. Therefore, equity funding from states promises to meet an increasingly critical need for commercializing emerging biotechnology and this tactic could very well generate a nice return for Maryland —if it is approved by the state legislature.

Not to be outdone in the state bidding war for biotechnology, Massachusetts Governor Deval Patrick recently signed legislation to allocate $1B over ten years to fund the State’s life sciences industry. This includes $250M in tax incentives to support the growth of biotech companies, the same amount to fund research and $500M in infrastructure.

Patrick said it takes "political will and courage to make those long-term commitments" and admitted that his state's funding commitment is, in part, a defensive measure to ensure that Massachusetts’ universities, companies and research institutes retain top scientists and biotech companies.

Patrick’s candid admission underscores the intensity of the competition for science talent and resources in which Wisconsin wants to successfully contend. Further underscoring the high stakes in these biotech funding wars, Patrick claimed that over the next ten years, Massachusetts' support of the biotech industry will create 250,000 new jobs. In this light, it is illustrative that Massachusetts’ commitment to the biotech industry heavily factored into the decision of the regenerative medicine company, Organogenesis, Inc, to expand it operations in the state rather than elsewhere.

Meanwhile, in New Jersey, legislation was introduced in late June to establish an pioneering public-private vehicle for state funding of stem cell research with venture capital. A press release said that the bill will allow private investors to contribute up to $500M over five years to fund such research. To encourage participation, investors would be granted tax credits equal to their investment, but only if a funded research project failed to repay the loan. In order to obtain funding, researchers would submit loan applications to the state’s Economic Development Authority. Both non-profit and academic labs would be able to apply for a stem cell research loan.

What’s a state in fly-over country to do?

Clearly, Wisconsin has a very credible biotechnology research enterprise thanks to the huge bioscience community at UW-Madison. The state’s biotech footprint is even more impressive when private biotech companies and institutions other than the UW-Madison are included. Despite this research muscle and recent infusion of state money, Wisconsin is missing a narrow and critical opportunity to capitalize on its strengths because it lacks the vision and creativity seen in the efforts of other states.

Wisconsin could learn from California and make a much more resolute effort to strategically focus on developing specific biotech strength, be it stem cells or something else. Wisconsin also could learn from California, Massachusetts and New Jersey about creative leveraging of public and private resources to boost, not only academic biotech research, but biotech business as well. After all, the best research, if not translated into successful businesses, does nothing for the people, the state or the economy.

On average, across the country, every new biotech job generates almost 6 additional jobs in the community. Salaries in the biotech industry average a whopping 68% higher than other private sector jobs. This is the return that Wisconsin can expect to realize by wisely investing its resources in biotechnology. However, the latest data show that Wisconsin falls below average in both of these metrics, yet we have an above average per capita infusion of federal research dollars.

Wisconsin clearly has room to realize a better return on its investment.
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© 2008 Steven S. Clark, PhD. Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, Steven S. Clark, nor other authors, do not assume, and hereby disclaim, any and all liability for any loss or damage caused by errors or omissions, whether such errors or omissions resulted from negligence, accident, or other causes.

Articles contained herein, are meant to be distributed freely to interested parties. However, any excerpts from any article must credit BioScience Biz.

The brave new world of stem cells and human cloning

One of the great promises of embryonic stem cell research is being able to use human cloning to derive stem cells that carry genetic defects associated with myriad maladies. These cells can be used to study the development of tissues that are affected by genetic abnormalities and used as tools for testing new therapies for intractable genetic diseases.

The way that this works is that a researcher derives an embryonic stem cell line from someone with, say Parkinson’s disease. These stem cells can be coaxed into developing into the dopamine-producing neurons that are defective in patients with the disease. Then, a number of different things can be done. For instance, the development of these diseased neurons can be compared to the development of normal neurons in well controlled environments and, hopefully, yield new information on the origins and progression of the disease. Alternatively, the Parkinsonian neurons can be used to test new approaches for treating the disease.

Thus, cloning and derivation of disease-specific stem cells promises to be a powerful and novel tool for studying certain types of cardiovascular disease, certain cancers such as neuroblastoma, Alzheimer’s and Parkinson’s disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), metabolic problems such as diabetes, and so on.   

Ethical concerns of cloning human embryos notwithstanding (I am working on a column on this topic that will be posted at a later date), a confounding technical problem is where will researchers find the eggs necessary for the nuclear transfer cloning procedure (the procedure used to clone Dolly, the sheep)? Obtaining human eggs is done routinely at in vitro fertilization clinics, but it does involve hormonal manipulation of young women and a somewhat invasive procedure to harvest the eggs. Who would volunteer for this just so a scientist can do lab research? How many eggs will we need to all the research scientists want to do and are there enough women donors to supply the research needs?

Researchers in England are taking a new approach to deal with the problem of egg supply. They propose to undertake nuclear transfer cloning using eggs from pigs and chromosomes from a human with the desired disease in order to create animal-human hybrid stem cells. A UK regulatory agency recently licensed a laboratory to create human-pig embryos in order to study heart disease.

In fact this is the third animal-human hybrid embryo license to be issued by the British Human Fertilisation and Embryology Authority. In an article just published in the British newspaper, The Telegraph, an HFEA spokesman said it had just approved an application from the Clinical Sciences Research Institute, University of Warwick, for the creation of hybrid embryos. This effort at the University of Warwick is led by Professor Justin St John. "This new license allows us to attempt to make human pig clones to produce embryonic stem cells," he said.

"We will take skin cells from patients who have a mutation for certain kinds of heart disease (cardiomyopathy, which makes the heart lose its pumping strength) and put them into pig eggs after their chromosomes have been removed. We will then make embryos so that we can attempt to derive embryonic stem cells which will allow us to study some of the molecular mechanisms associated with these heart diseases.

"Ultimately they will help us to understand where some of the problems associated with these diseases arise and they could also provide models for the pharmaceutical industry to test new drugs. We will effectively be creating and studying these diseases in a dish.

"But it's important to say that we're at the very early stages of this research and it will take a considerable amount of time. There is still a great deal to learn about these techniques and much of our early work will involve understanding how we can make the hybrid cloning process as efficient as possible."

The study is aimed at understanding the way the cell’s power-producing structures, called mitochondria, are passed from egg to embryo. Mitochondria contain their own small genetic program that produces many of the proteins these organelles need to power cells. Therefore, in the hybrid stem cell, the mitochondria will mostly come from the pig egg, and the researchers will do experiments in order to ensure that the trace of human mitochondria takes over, not least because it is designed to work with human nuclear DNA.

"The key thing we are doing is trying to create stem cells without any animal mitochondria in them. So even though these hybrid embryos normally have…animal mitochondria, we are hoping to create hybrid embryo cells that would have human chromosomes as well human mitochondrial DNA." The reason is that, as the team puts it, "mixing of these two diverse populations of mitochondria can be detrimental to cellular function."

Other research teams in Newcastle and London are also creating human-animal hybrid stem cells. The former have already created hybrids with cow eggs to study genetic regulation in early development, the latter made hybrids with a range of species to generate stem cells from people with neurodegenerative disorders.  Meanwhile, Chinese researchers in Shanghai have reported success in creating human-rabbit hybrid stem cells.

Such research is not allowed in the US, at least in federally-funded labs. But, this does not seem to stop this field from going forward world-wide. Are we in a brave new world, or are we making a Faustian bargain?

Read more on human-hybrid stem cells:

Hybrids: separating hope from the hype

Questions answered on animal-human embryos

Embryo research: a source of hope or horror?

Is drinking red wine the same as going on a diet?

Research says maybe so.

When considering factors that affect health, most people think about fatty diets, sun exposure, smoking, alcohol consumption, etc. But, research clearly indicates that one of the most important factors in quality of health is the simple calorie, which seems to one of the last health factors that people mention.

Everyone knows that obesity is associated with myriad health problems from cardiovascular disease, diabetes and stroke. Recent studies also link obesity to neurological problems such as Alzheimer’s disease. Obesity is caused by several factors including poor diet, sedentary lifestyle as well as genetic and metabolic issues. Certainly, caloric intake is a factor in obesity, but compelling research in rodents has shown that even a diet that does not lead to obesity may play an amazing role in age-related loss of function in the skeletal muscle, brain and especially the heart. When animals are restricted in caloric intake, but allowed normal levels of nutrients, vitamins, etc, their lives are significantly prolonged and their bodies retain a youthful physiology much longer than animals fed a regular diet.

I’ve seen the research data of caloric restriction on the musculature of the heart and the results almost gave me chest pains thinking about what my heart must look like in middle age.

Studies in several labs, including one recently reported by UW-Madison’s Tomas Prolla and Richard Weindruch, show that mice that are fed a component of red wine called reservatrol, along with a regular diet, showed healthier physiologies than mice who were not fed reservatrol. Significantly, the mice fed reservatrol and a regular diet, were as healthy as the mice on the calorie-restricted diet. In other words, feeding reservatrol to mice mimicked the beneficial effects of caloric restriction.

Both, Weindruch and Prolla, admitted to taking reservatrol supplements. But is this a good idea? Read more about this line of research here.

Quintessence moving forward despite discouraging data from competitor

A few weeks ago, I wrote that folks at Madison-based Quintessence Bioscience eagerly anticipated the outcome of a Phase IIIb clinical trial that Alfacell, a major East Coast competitor, would soon release on an anti-cancer therapeutic compound, Onconase™. Quintessence’s lead drug candidate, QBI-139, is very similar to Onconase™ and has not yet been clinically tested.

The results of the Onconase™ trial were just released and Quintessence Chairman and CEO, Ralph Kauten, said that he is “…disappointed that the results of the Onconase™ clinical trial were not an overwhelming success.”

Kauten shared with me a communication that Quintessence sent to its shareholders about the Alfacell trial. In it, they had this to say:

“Alfacell has released data indicating that their first-in-class drug, Onconase, failed to meet the primary endpoint in the Phase IIIb confirmatory trial in malignant mesothelioma. The trial compared the combination of Onconase plus doxorubicin to doxorubicin alone. The primary endpoint was an increase in overall patient survival. Alfacell’s initial analysis of the data showed no statistically significant improvement for evaluable patients receiving the combination of Onconase and doxorubicin.”

In other words, Alfacell tested the combination of Onconase™ plus the standard chemotherapy drug, doxorubicin, to doxorubicin alone in order to test whether Onconase™ would increase the survival of patients with mesothelioma, an extremely difficult to treat cancer that usually is associated with asbestos exposure. After the data were analyzed, there was no consistent difference in the two therapeutic regimens, which means that adding Onconase™ made no significant difference in the survival of the patients.

However, when the data were more closely examined, it appeared that a subset of patients who had failed the standard chemotherapy regimen for mesothelioma, showed a small, but statistically, increase in survival when treated with Onconase™. On this basis, Alfacell plans to submit an application to the FDA for using Onconase™ as a “second-line” therapy for mesothelioma patients who fail the standard chemotherapy. It is unclear how the FDA will respond to this parsing of the data. In the past, they have been averse to such sub-group analysis, but there are indications that this attitude may be changing, so Alfacell is forging ahead with the New Drug Approval process.

As I asked before, should there be cause for concern at Quintessence over these less than encouraging results from a competitor? As before, folks at Quintessence remain very committed to moving QBI-139 into clinical trials, probably sometime this summer. In their communiqué to shareholders, Quintessence went on to explain the following:

“Failing to meet the primary endpoints in the Alfacell Phase IIIb trial certainly makes approval of Onconase more challenging. However, Onconase still has significant potential to be approved as a second line treatment for malignant mesothelioma. While this change would mean a smaller market for the drug, our opinion has been and continues to be that any successful FDA approval of Onconase paves the way for general acceptance of RNases as cancer therapeutics.”

“Quintessence continues to make progress toward filing an IND and initiating a Phase I clinical trial for QBI-139. The majority of the data supporting the IND has been collected and analyzed and GMP manufacturing is underway. We are currently negotiating contracts with the clinical trial site as well as a contract monitoring group. We look forward to demonstrating the clinical benefit of QBI-139 in patients with cancer.”

The FDA’s response to Alfacell will be critical for the future of RNase-based therapies that Alfacell and Quintessence are developing. As I wrote in an earlier article, it is an unfortunate fact that if a drug is tested on the wrong disease and fails, it can be very difficult to resurrect its reputation in order to test it on another, more appropriate, disease. When a drug gets a bad reputation, it becomes much harder to garner enthusiasm from those who would fund the new study—investors and NIH grant reviewers.

Although, it may turn out that that testing Onconase™ on mesothelioma was a bad decision on the part of Alfacell, it was an interesting strategic decision that they made. Mesothelioma was chosen for the initial clinical trials because of its intractability to therapy, which allowed Onconase™ to be granted fast track status and orphan-drug designation by the FDA. This means that Alfacell was able to get Onconase™ into advanced clinical trials much sooner than it would have via conventional investigational drug approval procedures.

Mediocre therapeutic results against a cancer that no other therapy has shown much success against, does not mean that RNase-based therapies will not be effective against other types of cancers. As I pointed out earlier, there is good reason to believe that Quintessence’s lead RNase therapy, QBI-139, is superior to Onconase™.

For these reasons, Quintessence should and will continue to move forward with QBI-139 and focus on more common and easier to treat cancers than mesothelioma.

FDA delays embryonic stem cell clinical trial

 Geron Corporation, the Menlo Park, California-based company had sought permission from the U.S. Food and Drug administration to begin a human trial to test its GRNOPC1 stem-cell compound in patients with spinal cord injuries. In a press release dated yesterday, Geron anounced that they received oral notice from the FDA had delayed the Investigational New Drug application the company filed in order to begin clinical trials.  This delay does not mean that the IND was rejected, but until Geron receives the official letter, it will not known why the application was delayed or how long it will take to rectify the issues the FDA has.

Geron worked with the FDA over the last four years leading up the filing of a 21,000-page IND application.  Read the full press release here.

Madison's stem cell frontier, By Steve Clark

In an earlier column about the recent Stem Cell Symposium held on the Promega Campus, I extolled the exciting frontier of stem cell basic science that was on display; however, it was just as interesting to catch up with local stem cell researchers who attended the Symposium. I caught a glimpse of the current status of stem cell science in the Madison area.

Other health benefits of embryonic stem cells

For instance, I ran into Tim Kamp, an MD in the UW-Madison Department of Cardiology who, along with Professor Jamie Thomson, recently developed a reliable way to derive human heart cells from embryonic stem cells (ESCs).

About four years ago I first met Kamp in his UW-Madison office to learn about his research. At that time, researchers knew that when given the chance, human ESCs haphazardly differentiate in tissue culture into all the different tissue types and Kamp, using a microscope, had been able to find among the clutter of different cells a few well developed heart cells that actually were beating! You can see a short video clip of one of the beating heart cells here.

Using a steady-handed robot, Kamp inserted a very fine probe into a beating heart cell and measured its depolarization or the exchange of ions across its membrane, which constitutes the electric current that causes heart muscle to beat. With this, he recorded an “EKG” on a single human heart cell that changed as expected when he added to the culture, a drug often given to heart patients.

Currently, animal models are the best way to measure pharmacological effects of drugs on the heart—an important but insufficient model since 30% of drug failures are due to cardiotoxicity. Clearly, we need ways to test drugs on human heart cells, but until the advent of ESCs, there was no reliable way to obtain and grow them in the lab. Now, being able to derive functional heart muscle cells from ESCs provides a important option for testing drugs on real human heart tissue, thereby improving the safety and efficacy of new drugs. At least this was Kamp’s goal four years ago when I talked with him in his office.

Things seem to be progressing well. A couple of years ago, Kamp and his co-workers launched the local biotechnology company, Cellular Dynamics International, in order to bring this technology to fruition. In early March, Roche Palo Alto reached an agreement with CDI to begin using their ESC-derived heart cells for testing the cardiotoxicity of candidate drug compounds.

Using ESCs to derive fully functional mature cell types for testing potential drugs and toxins directly on human tissues is an under-appreciated and poorly communicated application for ESCs, but one that will soon be widely employed in the pharmaceutical industry. Thus, human ESCs will likely play an important role in human health, even if they are never used to directly treat human disease.

Kamp indicated that similar screening methods are being developed for other tissue cell types derived from human ESCs.

Treating neurological diseases

A few years ago, I attended a seminar by UW-Madison neuroscientist, Clive Svendson, who showed a video clip of patients with Parkinson’s disease before and after treatment with a nerve cell factor known as GDNF. The result was a dramatic slowing of disease progression in treated patients.

As encouraging as this therapy was, it remains highly experimental since GDNF cannot cross the blood-brain barrier and must be delivered by cannula—a thin tube inserted deep into the brain area affected by Parkinson’s disease—not an attractive long term option.

Furthermore, GDNF therapy only retards the progressive loss of dopamine producing neurons that is characteristic of Parkinson’s disease; it does not reverse the process. Therefore, this will not likely benefit patients with advanced disease who have lost too many of these critical cells. This is where the hope of stem cell therapy merges with the other great therapeutic hope—gene therapy.

For instance, ESCs alone are not likely to be much of a benefit for patients with Parkinson’s, because stem cell-derived dopamine-producing neurons transplanted in the brains of Parkinsonian patients likely will suffer the same fatal fortune as their endogenous predecessors. But, combine stem cell regeneration of the neurons with in situ production of GDNF via gene therapy technology and you just may be able to sustain dopamine-producing cells for the long term. Or so the hope goes.

A similar idea is being tested in Svendsen’s lab for treating amyotrophic lateral sclerosis; also know as ALS or Lou Gehrig’s disease. Like Parkinson’s, ALS is caused by the progressive and irreversible loss of certain critical neural cells in the brain. Svendsen’s lab has developed rat and primate models of ALS and using human fetal-derived neural stem cells, in conjunction with gene transfer technology, have successfully implanted fully functional, GDNF producing neurons in brains of these ALS animals. The results are very encouraging at this point--they see long-term survival of the transplanted cells and sustained production of GDNF, and these correlate with resolution of symptoms.

This is not the first example using ESCs to successfully treat human diseases in animal models, but ESCs have not yet made it into the clinic. Human trials will likely begin in the next year or two and the FDA is now considering how to best monitor them for safety and efficacy--not a trivial undertaking, but, stay tuned.

Moving stem cell science along

At the symposium I also had the chance to connect with Eric Forsberg, the recently appointed Director of WiCell. This is the non-profit spin-off from the Wisconsin Alumni Research Foundation (WARF) that provides support for stem cell researchers at UW-Madison.

According to Forsberg, WiCell, not only maintains the National Stem Cell Bank, it also engages in outreach activities and provides core services for stem cell researchers that are not found elsewhere on the UW-Madison campus. Forsberg pointed out that WiCell is also happy to provide such support and training for private stem cell companies in order to foster the development of cell-based medicine in Wisconsin..

Forsberg hopes to soon partner with the Waissma Center on the UW-Madison campus to begin a trial run to grow clinical-scale batches of ESCs under the cGMP conditions that are required in order to use the cells to treat patients. The Waissman Center has the cGMP facilities to produce biological materials for clinical use.

This will be a proof-of-principle endeavor designed to show that ESCs can be produced in clinically relevant quantities while maintaining their state of differentiation. Unforeseen problems, the bane of any biotechnology research, will be identified and resolved during this trial run so they will be ready when the time comes to quickly move ESCs into clinical trials.

We rapidly approach the day when ESCs will be used in experimental therapies of human diseases. Probably the first trials will use blood or bone marrow products derived from ESCs as a donor source for marrow transplantation or red cell transfusion.
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© 2008 Steven S. Clark, PhD. Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, Steven S. Clark, nor other authors, do not assume, and hereby disclaim, any and all liability for any loss or damage caused by errors or omissions, whether such errors or omissions resulted from negligence, accident, or other causes.

Articles contained herein, are meant to be distributed freely to interested parties. However, any excerpts from any article must credit the BioScience Biz Blog.

The stem cell frontier, 2008, on display, By Steve Clark

Cut a flat worm in two, the tail will grow a new head and the head a new tail. Cut it right down the middle, it will grow a mirror image. How does it know what to grow?

Flies can re-grow damaged tissues. Small fish can regenerate heart muscle. Why can’t humans?

In a developing infant, how do human embryonic stem cells know to grow into heart, muscle, liver, neurological and other cell types at the proper time and in the proper place?

These questions are at the center of science’s brave-new-world of stem cell biology and were the topic of the recent 3^rd Annual Stem Cell Symposium. The science was deep and detailed, and enormously enthralling. It was an intellectual playground of exciting ideas and fabulous potential.

The overriding lesson from the conference is that the mechanism by which stem cells regulate how and when they replenish themselves vs develop into different tissues is conserved in species as divergent as worms, flies, fish and mammals. This is fascinating for developmental biologists, but it also has a profound practical impact for eventually using stem cells to treat human disease. Let me explain how.

A primer on stem cell science

Consider for a moment what needs to be accomplished for an immature stem cell to differentiate into, say a beating heart cell. First, there needs to be a stimulus that initiates this program, telling the stem cell to specifically move along the cardiac muscle developmental pathway. The stem cell must then begin expressing heart cell genes while repressing the expression of all other genes that could cause it to become liver, blood, kidney and all other cell types. Quite a tall order!

Once the stem cell develops into a mature beating heart cell, it remains that type of cell. Mature cells, like zebras, cannot change their stripes. We never see a heart cell become a skin cell and vice versa. Cellular development is unidirectional and this has been one of the central tenants of developmental biology.

Then along comes Scottish scientist, Ian Wilmut, who did an experiment in the mid-1990s that no self-respecting developmental biologist would attempt since we all “knew” that cell development only moved in one direction.

What Wilmut did was to remove the nucleus from an egg cell and replace it with the nucleus from a fully mature cell taken from a different animal. Keep in mind that this donor nucleus had already been directed to express only those genes of the tissue it was taken from and to repress the expression of genes from all other tissues.

Wilmut then transferred this engineered egg into the womb of a pseudo-pregnant sheep, where the engineered egg should have died. Instead, a sheep was born that was a genetic twin of the nucleus donor sheep and the world was introduced to the first cloned animal, Dolly.

This is the type of research result that causes a scientific paradigm shift. For the first time, we realized that the genetic program of a fully developed adult cell, when placed in the proper environment, can be reprogrammed to relinquish its adult cell properties and return to its undifferentiated stem cell state, capable of developing into a fully grown sheep. 

Around the same time that Dolly was born, University of Wisconsin-Madison scientist, Jamie Thomson, published his seminal studies demonstrating the ability to grow monkey and human embryonic stem cells (or ESCs). These, of course, are the immature cells derived from five day old embryos that are able to develop into all tissues of the adult body. The way that ESCs are harvested kills these embryos making ESC research highly controversial. It would be great to be able to obtain such embryonic stem cells without having to destroy a functional human embryo.

Fast forward ten years to the conference where Professor Thomson gave an update on his recent report that he can reprogram adult cells to become stem cells without having to transplant cell nuclei. Looking at recent research from different labs, he noted that only a few regulatory genes are needed to maintain cells in their nascent developmental stage. As the research presented at the conference illustrated, these regulatory genes work across different species, so this mechanism is highly conserved in biology.

Thomson used routine gene transfer technology to induce expression of three different regulatory genes in the cells of mature fibroblasts and, amazingly, the mature cells were re-programmed to become stem cells! What Wilmut was able to do by transferring a cell nucleus to an enucleated egg can now be done in a petri dish and without the egg cell.

At the conference, Thompson explained that these “induced pluripotent cells” or iPCs seem to behave exactly like ESCs. Think about the implication of this observation: it means that mature cells from an adult can be re-programmed back to the stem cell state where they are able to generate anew, all tissues of the human body.

What next for stem cells?

UW-Madison stem cell researcher, Clive Svendson, moderator of the conference, believes that the next major advance will be the ability to develop iPCs by simply changing the environment in which adult cells are grown in the lab, which could be accomplished in about a year. This means that we would not have to insert several genes into a cell’s DNA, which has significant risks and is not a trivial procedure. Thus, it soon may be very easy to take cells from your skin, put them into a defined tissue culture environment and develop stem cells that contain your precise genetic makeup. No embryos would be destroyed and no clones would be created in the process, mitigating most of the ethical concerns.

Svendson opined that this could lead to a big boost in the tissue banking business as people store tissues when they are young for making stem cells if they should need them later. This would be necessary because, as Thomson explained, chronologically young cells are more efficient at being reprogrammed than cells from older animals. One can envision that it could become routine at birth to store placental tissue, the youngest tissue readily available that is genetically identical to the newborn baby.

As exciting as the science was at the conference, there remain some problems to deal with before these stem cells are used in the clinic. First, as with ESCs, undifferentiated iPCs form tumors called teratomas. Therefore, we need to develop a fail-safe way to completely separate or incapacitate contaminating stem cells from the functional tissues grown from them before we put them into patients. According to an article I posted here earlier, the FDA recently convened a meeting to grapple with this problem in anticipation that clinical trials will begin in the near future.

Next, even if we can use stem cells to regenerate damaged tissues, we still need to continue research into the causes of degenerative diseases because simply replacing the dying cells without dealing with what causes them to die may only be a short term fix.

Potential ethical issues may still arise

Finally, and potentially an explosive issue, there remains an ethical question regarding iPCs that no one seems to have addressed. When a mature cell is reprogrammed, how far back does it go? Do iPCs only have the potential to develop into different body tissues, or can an iPC, if given the chance, form an embryo? Of course, if the iPC cells are more like fertilized eggs than stem cells, then all bets are off--the ethical issues will arise again.

I asked both Svendson and Thompson about this and both admitted that this idea had not been tested. Svendson even owned up that no one in the field wants to test it. They do not want to know the answer because it could be very inconvenient.

My prediction

Carl Gulbrandsen, Director of the Wisconsin Alumni Foundation, shared with me that reading Thomson’s paper on reprogramming adult cells to derive embryonic iPCs made him “tingle”. Mr. Gulbrandsen does not seem to be the tingly type, but his response to Thomson’s results was not inappropriate—they are that amazing and significant.

As a scientist, I have learned to be cautious about making predictions. However, I venture one prediction here that I believe has a very good chance of being realized: Professor Jamie Thomson will, in the not-to-distant future, be awarded the Nobel prize for his outstanding work that has created a whole new field of stem cell biology and invigorated the practice of regenerative medicine. While I am at it, you can bet that he will share the prize with Ian Wilmut.

Any takers?
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This post was first published in-part by the Wisconsin Technology Network News

 

© 2008 Steven S. Clark, PhD. Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, Steven S. Clark, nor other authors, do not assume, and hereby disclaim, any and all liability for any loss or damage caused by errors or omissions, whether such errors or omissions resulted from negligence, accident, or other causes.

Articles contained herein, are meant to be distributed freely to interested parties. However, any excerpts from any article must credit BioScience Biz.

Madison biotech company happy to ride the coattails of competitor, By Steve Clark

Madison, WI based Quintessence Biosciences is developing a cancer therapy that targets cancer cell RNA.  Since current cancer therapies target DNA or proteins,  this is a very novel approach to treating cancer.  While Quintessence plans to enter initial clinical trials this summer, its major East Coast competitor, Alfacell, has just finished its second Phase III trial on a similar product.  Read my column, Biotech Takes, to find out why Quintessence is enthusiastic about Alfacell's success.

Predicting success in emerging biotechnology, Part 2. By Steve Clark

An investor recently asked me to compare the technology behind two early-stage biotech companies he was thinking of investing in. Both companies had novel therapeutic products at similar stages of development and the investor wanted to know which company’s product had the greater chance of success.

In an earlier article on this topic, I cautioned that predicting success of a technology is impossible. Therefore, in my analyses, I look for scientific limitations that might portend failure of a new technology.

Here, I illustrate another way to evaluate emerging biotechnology—science-focused market analysis. I contend that one needs to assess the market, not only from a business perspective, but also with a scientifically critical eye in order to fully appraise the risks of a new technology. Let me use a real example to illustrate how this works.

Two companies, A and B, are at similar stages of developing novel therapies for treating cancer of the prostate (CaP). Prostate cancer is very difficult to treat successfully; hence, enormous efforts are underway to develop better therapeutic options. The competition is stiff.

In order to fully appreciate the market potential for these products, we first need to understand the biology and treatment of CaP.

Treatment options are limited for CaP 

When CaP is detected, usually surgery or radiation is used first to reduce the size of the cancer (step 1 in the figure). At this stage, cancer growth depends on androgens, or male hormones produced in the testes; therefore, after surgery or radiation, men are often chemically castrated in order to retard the re-growth of any remaining cancer cells (step 2 in the figure). Despite this treatment, the cancer invariably returns and slowly progresses to a more aggressive malignancy.

CaP progression obviously means that androgen depletion no longer prevents the tumor from growing. The first indication of cancer progression is increasing blood levels of PSA (prostate specific antigen), a protein which is secreted by prostate cells. At this stage in the disease, there is no therapeutic option and one simply waits (“watchful-waiting”, step 3 in the figure) until the slowly re-growing cancer develops into end-stage carcinoma (step 4). Increasingly, patients with end-stage CaP are treated with chemotherapy, but this offers minimal, if any, results.

Experimental therapies of the two companies

Because CaP is so difficult to treat, many experimental therapies are in various stages of development and mostly target the end-stage metastatic disease. It is in this milieu that companies A and B are working to develop new therapies.

Company A is developing a naturally occurring biological product that enters cells and kills them by preventing gene expression. For unknown reasons, the product selectively kills advanced-stage cancer cells and not normal cells. Therefore, this product is targeted for potential treatment of end-stage CaP.

This experimental product has stiff competition from the plethora of other experimental cancer therapies under development. Nevertheless, it is likely that multiple therapies that have different mechanisms of action will be needed to successfully treat end-stage CaP. This means that the uniqueness of Company A’s product is a significant advantage; however, the stiff competition also means that, in order to marketable, this product will need to show as good or better efficacy and side-effects than other current and emerging therapies.

Company B has two novel therapies in development. The first therapy is derived from a natural dietary product that surprisingly blocks the androgen receptor. This drug is targeted toward prostate cancer patients who have undergone androgen deprivation therapy, but show rising PSA levels without having yet developed androgen-independent metastatic cancer. Currently, “watchful waiting” (step 3) is the only clinical option available for these patients. So, this product is designed to throw another punch at the slowly growing cancer before it achieves full blown androgen-independence.

The second product that Company B is developing is based on careful understanding of the cell biochemistry that drives CaP progression. When androgen binds to its cellular receptor, many things happen in addition to stimulating growth of prostate cells. It is believed that a specific “side-activity” of androgen stimulation is responsible for turning normal prostate cells into cancer cells. Furthermore, this side-activity also likely drives the progression of CaP from a slow growing tumor to end-stage cancer.

Company B’s second product blocks this cancer-inducing side-activity without affecting any other activity of androgen stimulation. For this reason, the drug is targeted for patients who have not yet undergone androgen depletion therapy. The goal is to retard early tumor progression and avoid the androgen depletion regimen which comes with considerable side-effects.

Which technology do you invest in?

All things being equal (or at least as much as possible between two different early-stage biotech companies), the decision comes down to predicting which technology has a better chance at success, or as I wrote previously, the least chance of failure. Here, science-focused market analysis tells you that the product under development by Company A, while unique and with good potential, nevertheless will compete with current therapies as well as with the many new experimental therapies in development.

In contrast, the products being developed by Company B specifically target stages in CaP where there is no good therapeutic option currently available. The competition for these products is negligible, which means that even if they are marginally effective or have side effects, there likely will be a significant market for them.

The unique biomedical niche targeted by company B’s products means that the significant risk factors company A faces due to competition are not likely to be a problem for Company B. Hence, market analysis through a scientific lens favors investing in company B over company A.

The example described here provides a good illustration of how scientific understanding of emerging biotechnology can add significantly to your market analysis. So, don’t forget to include your technical advisor when doing market research.

This article was first published in part in the Wisconsin Tecnology Network News
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© 2008 Steven S. Clark, PhD. All Rights Reserved.

Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, neither Steven S. Clark, nor other authors,  assume, and hereby disclaim, any and all liability for any loss or damage caused by errors or omissions, whether such errors or omissions resulted from negligence, accident, or other causes.

Articles contained herein, are meant to be distributed freely to interested parties. However, any excerpts from any article must credit BioScience Biz.

 

Genetic Basis for Cancer: Oncogenes, by Steve Clark

The first clues that cancer has a genetic basis came from several independent observations. In 1914, the German cell biologist, Theodor Boveri, noticed that cancer cells often carried abnormal chromosomes as seen through the microscope. However, the fact that a specific chromosome abnormality was routinely associated with a particular type of cancer did not come until 1973 when Janet Rowley showed that chronic myelogenous leukemia (CML) cells carried a chromosome translocation in which the ends of chromosomes 9 and 22 were exchanged. Several other studies also showed that certain types of cancer could run in families, suggesting that the risk for specific cancers can be inherited. Then, in 1981 the laboratories of Robert Weinberg and Geoff Cooper showed that DNA from a human bladder cancer cell line could cause nonmalignant cells in tissue culture to become cancerous. This was the first direct demonstration that genes can cause cancer. A cancer-causing gene was called an “oncogene”.

Since the Weinberg and Cooper observations, dozens of oncogenes have been identified and characterized. It is now clear that oncogenes represent normal cellular genes that are either aberrantly expressed or functionally abnormal. Such normal cellular genes, called “proto-oncogenes, can be “activated” to become oncogenes through a variety of different molecular mechanisms.

RNA tumor viruses lead to the discovery of cellular proto-oncogenes.

In 1911, Peyton Rous reported that a class of RNA virus can cause tumors in animals. These RNA tumor viruses, called “retroviruses,” carry an RNA genome that, once inside a cell, is reverse-copied into DNA, which then is inserted randomly into the host cell’s genome. Some retroviruses are slow to cause tumors. After they infect and spread to a large number of cells, the  DNA copy of the viral genome, by chance, might integrate into a host cell’s DNA near or within a normal gene that plays an important role in cell growth. If this viral integration disrupts the expression or structure of the normal cellular gene, it could induce abnormal growth signals that cause this single cell to develop into cancer.

In contrast to retroviruses that take a long time to cause cancer, other retroviruses cause tumors to appear very quickly. In these cases, during the process of reverse-copying the viral RNA into DNA, RNA in the cells that is expressed from normal cellular genes is sometimes mistakenly copied into the viral genome. If this captured cellular RNA is from a gene that is important in stimulating cell growth, the recombined virus can transfer the captured cellular gene to many other cells where it then causes abnormal growth stimulation leading to the rapid development of a cancer.

Through molecular cloning, many genes that are activated by the insertion of retroviruses into the genome, or that are captured by reverse-copying of cellular RNA into the viral genome have been identified and characterized. Almost three-dozen such retroviral oncogenes and their related cellular proto-oncogenes are now known.

Proto-oncogenes can be activated in the absence of retroviruses.

The first human oncogene, called Ras, ultimately was identified in the Weinberg and Cooper experiments mentioned above. We now know that the protein product of the Ras gene serves as a “switch” that turns growth signals on and off. Normally, the activity of this Ras switch is tightly regulated in cells. However, single mutations (or “point mutations”) in critical sites of the Ras gene cause the Ras growth “switch” to remain constantly on, and this leads to cancer. Thus, some normal proto-oncogenes can become oncogenes by random genetic point mutation in cells.

Oncogenes also can be activated by structural changes in chromosomes known as “amplifications” or “translocations.” DNA amplification increases by several-fold a specific region of a chromosome. This can produce many copies of any genes that lie in the amplified region. If one of the genes in an amplified region is important in driving cell growth, its overexpression due to amplification could lead to uncontrolled cell proliferation and cancer. In the case of chromosome translocations, a proto-oncogene on one chromosome might be moved to another chromosome resulting in the gene’s structural alteration and/or aberrant expression. For example, in the translocation between chromosomes 9 and 22 that is found in CML, a proto-oncogene on chromosome 9, called c-Abl, is moved to chromosome 22 where it is fused to another gene called Bcr. Normally, c-Abl is a nuclear “tyrosine kinase,” which is an enzyme that adds a phosphate molecule to proteins at an amino acid called tyrosine. Phosphorylation on tyrosine regulates the function of certain proteins that play important roles in stimulating cell proliferation. The fusion of Bcr and c-Abl genes creates an oncogene, called Bcr/Abl, which makes a protein with highly elevated tyrosine kinase activity and that is found in the cytoplasm instead of the nucleus. These changes in the activity and cellular location of the c-Abl proto-oncogene lead to chronic myelogenous leukemia.

Oncogenes cause cancer by “short-circuiting” normal growth control mechanisms.

Normal cell growth is controlled by the availability of growth factors, which are hormone-like molecules that bind to specific receptors that usually sit on the surface of cells. When this happens, the receptor initiates a signaling cascade from the cell membrane to the nucleus that ultimately tells the cell to divide. Many of the gene products in such signaling pathways are proto-oncogenes that can become oncogenes when activated by the different mechanisms described above. When a signaling proto-oncogene is activated, the signaling cascade becomes “short circuited” and cells behave as if they are continually in the presence of their growth factor.

For example, the v-sis oncogene from a monkey cancer virus known as the simian sarcoma retrovirus (SSV) comes from a gene that encodes platelet-derived growth factor, which stimulates growth of different cell types. Cells infected with SSV are, therefore, constantly bathed in the v-sis growth factor and stimulated to proliferate. Other oncogenes are mutated growth factor receptors where mutation leaves the receptor permanently “on” even in the absence of the growth factor. Two examples of mutated receptor oncogenes include v-erbB found in a bird retrovirus that causes various cancers and v-fms, which is carried by a mouse retrovirus that causes leukemia.

Inside the cell, components of the signaling cascade that connect cell surface growth receptors to the nucleus also can cause cancer when their activity is altered by mutation or overexpression. The Ras proto-oncogene that was mentioned above is an example of a signal-transmitting molecule that is found inside cells that can be mutated into an oncogene.

In the nucleus, normal growth signals trigger the expression and activity of yet other proteins, called “transcription factors,” that regulate gene expression needed for cell growth. Many of these transcription factors also are proto-oncogenes. Two examples of proto-oncogene transcription factors are c-Fos and c-Jun, both of which were first identified as retroviral oncogenes.

“Tumor suppressor genes” inhibit the development of cancer.

In 1983, Raymond White and Webster Cavanee, using a technique called “chromosome mapping,” learned that the loss of a small segment of human chromosome 13 was a recurring feature in retinoblastoma, a rare childhood cancer of the retina that can run in families. In this deleted region of chromosome 13 they discovered a gene that they named RB (for retinoblastoma), both copies of which were inactivated either by DNA deletion or by a mutation within the gene that destroyed its function. Interestingly, such inactivation of both copies of the RB gene occurs in about forty percent of all human cancers.

The product of the normal RB gene functions as a brake to cell division, so that loss of this brake can lead to unregulated cell growth. Another gene that also is associated with cancer when both copies are inactivated by mutation is the p53 gene, which acts as a “guardian” of the genome. This gene product induces a cell suicide program called “apoptosis” in cells with damaged DNA. Normally, this protects the body from cells whose DNA is damaged. However, loss of p53 activity allows cells with damaged DNA to grow and pass DNA mutations to their daughter cells, thereby contributing to the growth of tumors. A third type of gene that plays a role in cancer when it is inactivated is NF1. This gene encodes a protein that turns off the Ras growth signal mentioned above. Thus, loss of NF1 function is another way that the Ras growth signal can be left constantly on.

Since the discovery of RB, researchers have identified several additional genes in which both copies are inactivated due to mutation or chromosomal deletion. These genes normally block cell growth and prevent tumors from growing; hence they are called “tumor suppressor” genes. Since both copies of these genes need to be inactive in order to release cancer cells from growth inhibition, tumor suppressor genes act recessively. This contrasts to the oncogenes described above, where only one copy needs to be activated in order to promote cancer. Therefore, in contrast to tumor suppressor genes, oncogenes act in a dominant fashion.

Cancer usually arises after multiple genetic “hits.”

In 1971, Alfred Knudson, Jr. proposed that retinoblastoma resulted from at least two separate genetic defects. In families with a high risk of retinoblastoma, the first defect was inherited, while the second occurred sometime during childhood. This came to be known as Knudson’s “two-hit theory”. We now know that the “first hit” is the inheritance of a copy of chromosome 13 that carries a small deletion in the region that carries RB. The “second hit” occurs when a random mutation inactivates the remaining copy of RB in a single cell making the cell susceptible to unregulated proliferation.

Subsequent research has shown that most, if not all, cancer arises from multiple genetic events or “hits.” Bert Vogelstein and coworkers first showed this in colon cancer in the late 1980s. Colon cancer begins with a pre-cancerous stage, called a benign polyp. Left untreated, this will progress through successively more cancerous stages until it becomes an aggressive carcinoma. Vogelstein’s group found that the progression of colon cancer through these different stages was associated with the acquisition of genetic changes in oncogenes such as Ras, as well as in a number of different tumor suppressor genes including p53. Together, sequential activation of different oncogenes along with inactivation of various tumor suppressor genes drives the step-wise progression of pre-cancerous cells to highly cancerous tumors.

Bibliography:

Bishop, J. Michael. “Oncogenes.” Scientific American 246 (1983):80-92.

Cavenee, Webster K., White, Raymond L. “The Genetic Basis of Cancer.” Scientific
American March (1995):72-79.

Croce, Carlo M., Klein, G. “Chromosome Translocations and Human
Cancer.” Scientific American 252 (1985):54-60.

Varmus, Harold. “Retroviruses.” Science 240 (1988):1427-1435.

Weinberg, Robert A. “A Molecular Basis of Cancer.” Scientific American
249 (1983):126-142.

-- “Tumor Suppressor Genes.” Science 254 (1991):1138-1146.

This article was originally published in Genetics, vol 3, R. Robinson, ed.  2003.

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Steven S. Clark, Ph.D., a former professor and medical researcher at the University of Wisconsin School of Medicine provides consulting services for investors and biotechnology companies.  He encourages contributions to this page.  Email him with story pitches.
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© 2008 Steven S. Clark, PhD. All Rights Reserved.

Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, neither Steven S. Clark, nor other authors,  assume, and hereby disclaim, any and all liability for any loss or damage caused by errors or omissions, whether such errors or omissions resulted from negligence, accident, or other causes.

Articles contained herein, are meant to be distributed freely to interested parties. However, any excerpts from any article must credit BioScience Biz.