BioScience Biz

FDA puts brakes on Geron stem cell trial--again

Last week the New York Times reported that the FDA put a clinical hold on Geron’s pioneering human embryonic stem cell (ESC) trial—before the first patient could be enrolled. In what was to be the world’s first clinical test of ESCs, Geron planned to differentiate the cells into neurons that can be injected into the spinal cords of paralyzed patients. However, the FDA requested more information after reviewing dose escalation data from pre-clinical animal studies.

This is the second time the FDA has delayed the Geron ESC clinical trial. Back in January, the FDA lifted an 8 months hold, allowing Geron to proceed with plans for the experimental injection of ESC-derived nerve cells into the spines of 8-10 paralyzed patients in attempt to repair the neural damage. The FDA was concerned over the safety of the protocol since the presence of any contaminating, undifferentiated ESCs could form tumors called teratomas.

In an announcement released Friday by Geron, the company explained that a recent animal study of the GRNOPC1 ESC therapy revealed the presence of “microscopic cysts in the regenerating injury site.” Fortunately the cysts were only found in the injection site and were non-proliferating. That is significant since it means that the cysts were benign, nevertheless, the FDA wants to look more closely at this development. 

"We have submitted these data to the FDA and are in discussions with the agency to answer its questions and proceed with the clinical trial," said the company in the release.

What’s new in stem cell research and therapy?

Stem cells are being tested in cardiovascular disease, stroke, diabetes, eye disease, Parkinson’s and to grow cartilage in damaged joints. Stem cells are also being made from blood, attached to sutures and authorities in Hungary crack down on unethical “stem cell tourism”.  Read about these and other recent advances in stem cell science here…

Science and ethics in the embryonic stem cell debate

The Medieval philosopher, Boethius, tackled the esoteric question of what is a human and came to the conclusion that “human is born of human”. There is a certain circular, facile truth in this conclusion that reminds one of the modern right-to-life refrain that “life begins at conception”—an argument that seems as unsatisfying as any argument that has been reduced to a cliché. It is repeated so often and so glibly that the basis of the argument goes unexamined and unchallenged. 

This “life begins at conception” reasoning, leads to a casuistic rhetoric where harvesting embryonic stem cells (ESCs) from a five day old human embryo called a blastocyst, for the purpose of treating human ailments, is akin to killing a living adult in order to harvest his organs to transplant into someone else.  But how do we cross the chasm of logic to believe that a blastocyst is the moral equivalent of an adult human?  This is an unexamined and unspoken conclusion that looks very different in the light of modern biology.

Before exploring the premises underlying the right-to-life position let me acknowledge that at this point, some will ask, why revisit this debate?  Haven’t embryonic stem cells been rendered unimportant in the face of the research success of adult stem cells and in view of the fact that we can now reprogram adult cells to become stem-like, thereby avoiding the destruction of embryos to harvest ESCs?

Not so fast.

The fact is that we are rapidly driving, some would say careening, toward the day when ESCs will be used to treat patients. Despite the exciting advances in stem cell alternatives, ESCs still play a role that adult and reprogrammed adult cells cannot supplant—yet.

"...FDA recently approved the first ESC clinical trial..."

The FDA recently approved the first ESC clinical trial to treat patients with spinal cord injuries. The California Institute for Regenerative Medicine that oversees the $3 billion stem cell investment that came out of Proposition 72 in 2004, recently awarded grants specifically for supporting research leading to FDA applications to use ESCs for experimental therapeutics. A medical doctor in India claims to have treated a quadriplegic with human ESCs, with modest results.  Doctors in other countries make similar claims, raising the specter of unregulated “stem cell” tourism and unfettered treatment of patients with insufficiently tested ESC therapies—unregulated clinical trials in reality.

As we rapidly approach the era of stem cell therapy, or regenerative medicine, if in fact we are not already there, the debate over whether this technology represents a “brave new world” or a Faustian bargain will only intensify and I believe it will do so very soon. At the moment, this debate seems to be in a latent period due to the recent discovery that adult cells can be reprogrammed into stem cells. Opponents of ESC research hope that this advance will negate their ethical concerns about destroying human embryos in order to obtain stem cells. After all, if you can pluck a skin cell from someone’s arm, put it in a broth and, presto, pull a stem cell out, why would anyone need or want to do research with stem cells obtained from an embryo? But, the inconvenient truth behind these reprogrammed cells has not been fully explained. The fact is that they, too, have the potential to develop into persons. A scientist at MIT reprogrammed a mature mouse blood cell into a stem cell and used it to derive a whole new mouse. Very recently, two groups in China reported doing the same thing beginning with mouse fibroblasts and ending up with cloned animals. Let us consider how this ability of these so-called induced pluripotent stem cells (iPS) affects the whole stem cell debate.

Unpacking the right-to-life argument

I’ll begin by unpacking the right-to-life argument that “life begins at conception. It is abundantly clear that when a sperm fertilizes an egg cell, a cellular entity is created that can grow into a fully developed person. So, in a sense one can indeed claim that “life” begins at fertilization. But this argument assumes, and leaves unstated, that society is, therefore, obligated to give the same level of respect to a fertilized egg as it gives to an adult human. 

"...when is society obligated to give full respect to human life."

Thus, the underlying ethical argument here really is not about “when life begins” (indeed there is no precise time where this happens—it is a process lasting a couple of days), but about when is society obligated to give full respect to human life. This is the essential ethical issue on which the whole debate should focus. 

Let me illustrate the idea this way: We all agree that a living woman deserves our full moral consideration; society cannot legitimately take her life or deny her other life-related freedoms without good cause, such as committing a crime. On the other hand, neither a live dog nor a clearly dead human elicit the same level of consideration from society. This means that simply being alive, as in the case of the dog, or simply having a human body, as in the case of the corpse, do not provide a sufficient basis for assigning the full moral consideration that we give the woman. It follows that there is something inherent in the adult woman that we all readily recognize, but that we, equally readily, do not see in a live dog or a dead person, which tells us she deserves a greater level of moral respect.  This inherent worth in the woman that we all innately recognize is the crux behind making sense of the embryonic stem cell debate.

Viewed in this way, the question with ESC research becomes this: does a blastocyst that was created by a human (through in vitro fertilization) and that lives in a petri dish and lacks a brain, personal history, personality or any recognizable human trait is the moral equivalent of a living adult human that enjoys all these attributes?  Do we innately recognize something in the blastocyst, like we do in the woman, which compels us to assign full moral recognition to a five-day old sphere of cells that is no larger than a period at the end of a sentence?

At this juncture, some will argue that the fertilized egg possesses a completely novel human genome that denotes a unique genetic human being, and that this makes it deserving of full moral consideration by society. But, this argument has this major problem; certainly, genetic makeup is necessary and sufficient for determining that an embryo is Homo sapien, but genetic makeup, no matter how unique, is not sufficient for determining moral standing. If it was, then skin cells, which have the same genes as the fertilized egg from which they came, should also have equal moral standing with the fertilized egg.  

"...to acknowledge that a fertilized egg has potential to become a person means
that, in fact, it is not a person at that time."

It also could be argued here that an important difference between a fertilized egg and a skin cell is that the former has the "potential" to develop into a mature human person, while the latter does not. But there are problems of both semantics and logic with this contention.  For instance, "potential" describes something that can, but has not yet come into being. In other words, to acknowledge that a fertilized egg has potential to become a person means that, in fact, it is not a person at that time.

Furthermore, it is not logical to assume that “potential” confers any a priori obligation--while I may have the “potential” to become President, that obligates no one to play “Hail to the Chief” when I enter a room. So, based on potential, there is no compelling reason to afford a blastocyst the same obligation we offer the adult woman.

Conditional potential of stem cells

It also is important to understand that a thing’s “potential” can be altered by circumstance. Thomas Aquinas, the great Catholic theologian and philosopher, made this argument about “potential” many years ago. He explained that for potential to be present, a thing must have the capability of realizing that potential. Thus, a piece of paper has the potential to be burned, because it is burnable. Conversely, a bucket of water does not have the potential to be burned because it is not capable of being burned.

Certainly we now know that water can be given the potential to burn, but only under specific electrolytic conditions that separate oxygen and hydrogen from the water molecules. So, the conditional circumstances in which water exists determine its potential to be burned.

In the laboratory, human ESCs are harvested from a blastocyst that has only lived in a tissue culture dish. As long as a blastocyst lives in the petri dish, it has zero potential to become a person. This can only happen if someone intentionally inserts it into the womb of a woman who has been hormonally manipulated to mimic pregnancy. Only after these human efforts, like the human efforts needed to make water burnable, can the tissue culture organism then acquire the potential to become a person. 

From animal cloning, which is now a common practice, we know that under the proper conditions, we can reprogram adult cells back to an embryonic state where they acquire the ability to grow into an embryo and a fully functioning animal. Therefore, modern science tells us that, like a blastocyst that lives in a petri dish, a blood cell that lives in your veins has conditional potential to develop into a person. Since we do not confer any special moral status to a blood cell what then compels us to confer such status to the blastocyst that was created in a laboratory and that lives in a petri dish or frozen in a liquid nitrogen tank? After all, they both have similar conditional potential to become a person.

Thus, like genetics, “potential” is not a sufficient basis to compel us to confer the same moral status to a fertilized egg that we reserve for a living person. 

At what point do we give a developing embryo full moral consideration?

It, admittedly, is very hard, if not impossible, to know when we ought to bestow full moral protection to a developing human embryo. But, I submit that we can know when the embryo does not enjoy the same consideration we give to an adult. To illustrate this point, consider this thought experiment—you walk past a building and see a fire raging inside.  Moreover, you also see a man struggling to get off the floor and escape the conflagration. You see that he is lying next to a tank that you know contains thousands of frozen human embryos.  What would you do if you only had time to make one trip into the burning building? 

"Most of would opt to rescue the man..."

Most of us would opt to rescue the man indicating that we recognize a greater moral responsibility to one anonymous living adult person than we do to a tank full of nascent persons. Indeed, most of us would opt to rescue a dog before the tank of embryos. In other words, we do not innately view thousands of five-day old embryos as moral equivalents to a single fully formed person any more than we view a live dog as the moral equivalent of the woman. To do so, we have to conjure up a special respect for embryos that is based on the imperfect arguments discussed above.

Unfortunately, poor Boethius, a Christian, ran afoul of the Visigoth rulers of Rome and was executed in an especially gruesome way. They wrapped a rope around his head, inserted a stout stick and twisted it until his skull burst. I suspect that when the right-to-life community becomes aware of the ability of reprogrammed adult cells to become people, the debate will flare once again generating Boethian-sized headaches on both sides.

© 2009 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.                                     

More stem cell trial problems for Osiris Therapeutics

Clinical trials can be vexing, just ask anyone associated with Osiris Therapeutics, a leading stem cell therapeutic company. The company recently announced that their mid-stage, Phase II trials to treat chronic obstructive pulmonary disease (COPD) with adult stem cells (called Prochymal) did a great job reducing inflammation, but failed to improve pulmonary function. The 62 patients enrolled in the trial will be followed for two years in order to assess possible long term effects of the therapy.  Nevertheless, these results reveal how complicated and unpredictable clinical trials can be. 

COPD is really a combination of two maladies, chronic bronchitis and emphysema, rolled into one diagnosis. The disease commonly is caused by smoking, which triggers an abnormal inflammatory response in the lung in some individuals. In the larger airways, this inflammation causes chronic bronchitis, while in the microscopic lung sacks called alveoli, the inflammatory response causes emphysema, which is the destruction of the lung tissues where oxygen and carbon dioxide are exchanged. The result of this double inflammatory whammy is to limit the flow of air to and from the lungs causing shortness of breath. COPD is poorly reversible and usually gets progressively worse over time. In 1990, COPD was the third leading cause of death worldwide.

"...anyone would have predicted a priori that reducing lung inflammation would translate to improved lung function."

Given the central role of inflammation in the pathogenesis of COPD, anyone would have predicted a priori that reducing lung inflammation would translate to improved lung function.  But, this is like believing that the baseball team with the most hits will automatically win the game. It is not uncommon for such surrogate measurements of efficacy to fail to predict the final outcome—the full game must still be played and the clinical trial done before the outcome can be certain. 

Osiris is also testing Prochymal for its ability to treat other inflammatory diseases, so the reduced inflammation seeing in the COPD trial might be a good omen for these other maladies, even if Prochymal is of little benefit to patients with COPD. Unfortunately, however, last month Osiris was forced to discontinue enrollment in a phase III trial to treat the chronic inflammatory bowel condition known as Crohn’s disease. The reason for this, according to the company, is that patients on the placebo arm of the trial were doing unexpectedly well and interim data analysis indicated that this response would make it impossible to show a benefit of the Prochymal therapy. After examining the data with the FDA, it was concluded that  that there was a potential “systematic design flaw” in the trial that “might be related to the fact that patients responding to the initial stem cell therapy were eligible to participate in a second, longer-term trial evaluating Prochymal as a maintenance therapy. Because the current standard for determining response of Crohn's patients to therapy is largely subjective, there may have been response bias to meet the eligibility requirements for continuation of therapy in the longer-term maintenance trial”.

Prochymal is a preparation of mesenchymal stem cells obtained from the bone marrow of healthy donors and specially formulated for intravenous infusion. In addition to Crohn’s disease, Prochymal also is being tested in two other Phase III studies to treat both acute and steroid-refractory graft-vs-host diseases (or GvHD). The FDA granted Prochymal Fast Track status for these and Crohn’s diseases and both the FDA and the European Medicines Agency granted Prochymal Orphan Drug status for GvHD. In addition to the COPD trail, Osiris is also conducting Phase II Prochymal trials for the treatment of acute myocardial infarction and type 1 diabetes.  The therapy also is being developed as a potential treatment for acute radiation syndrome.

"...the company has a lot riding on Prochymal and can ill afford any further
clinical trial snafus." 

Osiris also has another stem cell product in the pipeline, called Chrondrogen, which is being tested for its ability to regenerate cartilage. Last November, Genzyme paid Osiris $130 million upfront and promised up to $1.3 billion more in milestone and other payments to gain commercialization rights to Prochymal and Chondrogen outside the U.S. Osiris retains the rights to market these products in North America.  Clearly, the company has a lot riding on Prochymal and can ill afford any further clinical trial snafus. 
______________________________
© 2009 Steven S. Clark, PhD, some rights reserved.  Articles contained herein, are meant to be distributed freely to interested parties. However, any use, including excerpts from any article, must credit Steven S. Clark and provide a link to the original article published in BioScience Biz.

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.

PRESS RELEASE: First human embryonic stem cell therapy trial approved by FDA

California's Menlo Park-based Geron Corporation announced today that the U.S. Food and Drug Administration (FDA) granted clearance of the company's Investigational New Drug (IND) application for the clinical trial of the world's first human embryonic stem cell (hESC)-based therapy in patients with acute spinal cord injury.

Geron plans to initiate a multi-center Phase I clinical trial that is designed to evaluate the safety of the therapy in patients with spinal cord injuries.

"The FDA's clearance of our...IND is one of Geron's most significant accomplishments to date," said Thomas Okarma, Ph.D., M.D., Geron's president and CEO. "This marks the beginning of what is potentially a new chapter in medical therapeutics - one that reaches beyond pills to a new level of healing: the restoration of organ and tissue function achieved by the injection of healthy replacement cells. The ultimate goal for the use of (the stem cell therapy) is to achieve restoration of spinal cord function by the injection of hESC-derived oligodendrocyte progenitor cells directly into the lesion site of the patient's injured spinal cord."

"The neurosurgical community is very excited by this new approach to treating devastating spinal cord injury," said Richard Fessler, M.D., Ph.D., professor of neurological surgery at the Feinberg School of Medicine at Northwestern University. "Demyelination is central to the pathology of the injury, and its reversal by means of injecting oligodendrocyte progenitor cells would be revolutionary for the field. If safe and effective, the therapy would provide a viable treatment option for thousands of patients who suffer severe spinal cord injuries each year."

The Stem Cell Clinical Program

Patients eligible for the Phase I trial must have documented evidence of functionally complete spinal cord injury with a neurological level of T3 to T10 spinal segments and agree to have the cells injected into the lesion sites between seven and 14 days after injury. Geron has selected up to seven U.S. medical centers as candidates to participate in this study and in planned protocol extensions. The sites will be identified as they come online and are ready to enroll subjects into the study.

Although the primary endpoint of the trial is safety, the protocol includes secondary endpoints to assess efficacy, such as improved neuromuscular control or sensation in the trunk or lower extremities. Once safety in this patient population has been established and the FDA reviews clinical data in conjunction with additional data from ongoing animal studies, Geron plans to seek FDA approval to extend the study to enable access to the therapy for as broad a population of severe spinal cord-injured patients as is medically appropriate.

Preclinical Evidence of Safety, Tolerability and Efficacy

Geron submitted evidence of the safety, tolerability and efficacy of its hESC therapy, GRNOPC1, to the FDA in a 21,000-page IND application that described 24 separate animal studies requiring the production of more than five billion GRNOPC1 cells. Included in the safety package were studies that showed no evidence of teratoma formation 12 months after injection of clinical grade GRNOPC1 into the injured spinal cord of rats and mice. Other studies documented the absence of significant migration of the injected cells outside the spinal cord, allodynia induction (increased neuropathic pain due to the injected cells), systemic toxicity or increased mortality in animals receiving GRNOPC1.

In vitro studies have shown that the GRNOPC1 hESC therapy is minimally recognized by the human immune system, which allows a low-dose of immunosuppression drugs.

Also included in the IND application were published studies in animals that showed that administration of the GRNOPC1 hESCs significantly improved movement of animals with spinal cord injuries when injected seven days after the injury (Journal of Neuroscience, Vol. 25, 2005). Histological examination of the injured spinal cords treated with GRNOPC1 showed improved axon survival and extensive remyelination surrounding the rat axons. These effects of GRNOPC1 were present nine months after a single injection of cells. In these nine-month studies, the stem cells were shown to migrate and fill the lesion cavity, with bundles of myelinated axons crossing the injury site.

Production and Qualification of GRNOPC1 hESCs

GRNOPC1 cells are produced using current Good Manufacturing Practices (cGMP) in Geron's manufacturing facilities. Geron's cell production process and clean-room suites have been inspected and licensed by the state of California. The cells are derived from the H1 human embryonic stem cell line, which was created before August 9, 2001 and is on the list of former President Bush's approved human enbryonic stem cells. Studies using this line qualify for U.S. federal research funding, although no federal funding was received for the development of Geron's therapeutic product or to support the upcoming clinical trial.

Induced pluripotent stem cells steal the limelight from embryonic stem cells, by Steven S. Clark

Recent stem cell headlines are all about how adult cells can be reprogrammed into induced pluripotent stem cells (iPS), which was recently hailed as the biggest scientific breakthrough of 2008.  All of this attention to iPS cells and hardly a word about embryonic stem cells (ESCs)—have ESCs lost their luster since scientists figured out how to reprogram adult cells back to the primordial stem cell state?

In reality, iPS cells have been around longer than ES cells.  In cloning the sheep Dolly in 1996, Scottish scientist Ian Wilmut took a single adult cell and injected its nucleus into a sheep egg from which the nucleus had been removed.  The cellular environment of the egg reprogrammed the nucleus of the adult cell so that it was able to give rise to Dolly. 

Last year, the laboratories Jamie Thomson at the University of Wisconsin-Madison and of Shinya Yamanaka, from Kyoto University, reported that this reprogramming could be done by simply expressing only three or four genes in an adult cell.  More recently reprogramming has been used by Harvard professor, Kevin Eggan, to derive iPS cells from patients with ALS (Lou Gehrig’s disease) and by UW-Madison professor, Clive Svendson, to derive iPS cells from patients with another neurodegenerative disease, spinal muscular atrophy (SMA).  Both iPS cell lines were then used to grow the defective neurons in the lab giving the scientists their first access to the very cells that caused the respective neurodegenerative diseases.  This creates a powerful research tool that will enable researchers to study the disease process and find ways to halt it. 

“Clinical trials” using iPS cells

The benefits of iPS cells don’t stop there.  Madison, Wisconsin-based Cellular Dynamics International (CDI) recently produced one of the world’s first commercial stem cell products, ESC-derived cardiomyocytes.  These are functional heart cells that CDI produces and sells to pharma companies for drug and toxicity testing.  But CDI also has a robust research effort to efficiently produce iPS cells, possibly without having to introduce exogenous genes into the adult cells.

“We have a large scale research activity to create a vector-free methodology for no integrated DNA (in the iPS cells),” said Chris Kendrick-Parker, Chief Commercial Officer at CDI.  The company is now filing patents and Kendrick-Parker was not at liberty to say if CDI has developed a DNA-free method for inducing iPS cells.  However, he did say that the company is “looking at all options.”

Kendrick-Parker believes that CDI will soon switch exclusively to using iPS cells to develop heart and other cell types for sale to pharma and researchers.  The advantage of iPS cells he said is that they can be used to produce adult tissues from people representing different ages, ethnic types and sexes as a way to model the human heterogeneity in tissue culture.  This way, “drug companies can actually recapitulate (in tissue culture) what happens in clinical trials,” Kendrick-Parker said.   

For this to happen, Kendrick-Parker says that CDI and other companies will use iPS technology to make a library of iPS cells from a wide range of people in order to reflect the genetic heterogeneity of the population.

Most investigational or even post-market drugs fail due to liver or cardiotoxicity in a subset of people, which is “why pharma is so interested in these (iPS-derived) models,” said Kendrick-Parker.  The cells should allow drug makers to identify organ-specific toxicities before clinical trials begin, thereby saving much time and money bringing a new drug to market, only to have it fail.  For example, having iPS-derived cardiomyocytes from a large patient population might have identified, early on, the cardiotoxicity of Vioxx, saving Merck & Company a great deal of money getting the drug to market and in subsequent litigation fees.

iPS cells in the clinic?

But what about using iPS cells to directly treat disease?  After all, they have been widely touted as the great ethical hope for stem cell therapy since they don’t involve destroying human embryos. 

Currently, iPS cells are made by expressing a few genes in an adult cell, which turns back the cells' developmental clock to an embryonic-like state from which they can become any of the body's 220 different cell types. Yet, the genes used to reprogram adult cells are, themselves, associated with cancer, so iPS cells made this way will not be used clinically.

However, last November, Thomson opined that in about six months, it will be possible to make iPS cells without having to resort to oncogenic gene expression.  While this will eliminate the immediate problem to using the cells clinically, they still face significant hurdles before being used to treat specific diseases.  In fact, Thomson also suggested that there may be problems with iPS cells, saying that there are “dark clouds on the horizon”.

Eric Forsberg, Director of the WiCell Research Institute, explained that reprogramming of adult cells is extremely inefficient, meaning that for some reason, it is only the rare adult cell that can be successfully re-programmed.  This suggests that other unknown factors affect the ability of each cells’ genome to be reset to an embryonic state. 

Researchers also know that reprogramming is incomplete.  The genome clock is not completely reset and this Incomplete reprogramming likely plays a role in the health problems that cloned animals have—Dolly had arthritis and was euthanized due to progressive lung disease.  This raises the possibility that tissues developed from reprogrammed iPS cells might not function normally.

Forsberg pointed out that the extent to which a person’s genome is reset can vary from person to person and this could mean that each person will require an individualized reprogramming regimen in order to create iPS cells for therapeutic use.  But, it is unlikely that the FDA would approve such an individualized protocol—they like uniformity and conformity in therapeutic protocols, not different protocols for different people

Thus, while iPS cells provide enormous potential for learning how human disease develops and progresses and for cost-effective development of new and safer drugs, they are still a long ways from the clinic.  In fact, ESCs will likely find clinical use before iPS cells do.

Embryonic stem cells after a decade of hope…or was it hype? By Steven S. Clark

As we reach the ten year anniversary of UW-Madison Professor, Jamie Thomson’s, discovery of how to grow human embryonic stem cells (ESCs), one wonders whether this has been worth the controversy that ensued over the destruction of human embryos in order to obtain the stem cells.  After all, no therapies have come from the discovery, so were opponents correct that this research was not only unethical, but also irrelevant?

While there have been no headline-grabbing ESC-based therapies, the technology is surely changing the way that medicine will be done.  This was illustrated by recent events in Madison, including the World Stem Cell Summit held last September and a more recent celebration of the ten-year anniversary of Thomson’s discovery, put on by the Wisconsin Academy of Arts and Sciences.  The Anniversary event featured keynote talks by Thomson and Michael West, CEO of BioTime, Inc., and founder of Geron, a West Coast stem cell company.

Thomson sounded his usual cautionary note, saying that it will be very difficult to use ESCs to directly treat disease.  But, he also said that even if they never make it into the clinic; ESCs will profoundly affect the future of medicine.  ESCs give us laboratory access to human tissues that we had not been able to get at before.  This lets scientists see what goes wrong with the specific cell types that cause Parkinson’s and cardiovascular diseases, diabetes and other maladies.  This, Thomson said, will lead to the development of new drugs and therapies to treat and prevent such diseases.  

Thomson also explained that the different cell types that can be derived from ESCs enables researchers to directly test new drugs on different human tissues.  He suggested that this will both dramatically reduce the number of animals used in drug and toxicity testing and allow more precise assessment of new drug efficacy and toxicity.  

This was put into perspective at the Stem Cell Summit, by John McNeish, head of Pfizer’s Regenerative Medicine efforts. He said that 10-16% of all new drugs fail during Phase I clinical trials alone due to cardiotoxicity.  Many more drugs fail due to liver, kidney and other organ-specific toxicities.  Overall, about 92% of new drugs that enter clinical trials fail due to lack of efficacy or to toxicity, according to the FDA’s web site. This means that potential drug toxicity is inefficiently measured in current animal models, making drug makers gamble early on that their new drugs won’t show organ-specific toxicity—a gamble that they lose nine times out of ten.  ESC technology, therefore, promises to provide tissues on which to test and eliminate potentially toxic drugs much earlier in the development pipeline, potentially saving billions in drug development costs, according to the FDA.  

ESC-derived research tools are entering the marketplace

Thomson and others from the UW-Madison, recently founded Cellular Dynamics International, or CDI, to grow different tissues from ESCs.  According to Tim Kamp, a UW-Madison cardiologist and CDI co-founder, the company now sells heart cells to Roche and Covance for drug testing purposes.  CDI grows the heart cells in-house and then sells them as research tools. Thus, they retain control of the ESCs and the developmental process, while providing a renewable stream of cellular tools that researchers can purchase.  At this time, CDI only markets heart cells, said Kamp.  But, according to Chris Kendrick-Parker, CDI Chief Commercial Officer, the company has agreements with, or is talking to the “all of the top 20 pharma companies” to provide cells for toxicity testing.

Besides CDI, the Menlo Park biotech company, Geron Corp., and San Francisco’s Vistagen Therapeutics also use ESCs to produce cells from the heart, pancreas, liver and other organs for similar purposes.  The European company, Cellartis provides AstraZeneca with ESC-derived liver cells for toxicity testing, but only at very low numbers that are not useful for high-throughput-screening of new drugs.  Cellartis also provides Pfizer with embryonic cells to test for birth defects.  Clearly, ESCs as drug testing and research tools is a growing international market, which Pfizer stem cell expert, John Hambor, said at the Stem Cell Summit, currently stands at $1.5 billion and is predicted to grow 20% annually in the foreseeable future.

Clinical trials on the horizon?

Michael West is more optimistic than Thomson that ESC-based therapies will soon happen.  He cited the very high interest in the technology shown by several biotech and pharmaceutical companies as the driving force that soon will propel ESCs into the clinic.  

Some biotechs already are pushing hard to begin clinical trials of ESC-based therapies. For instance, last Spring, Geron submitted an Investigational New Drug application (IND) to the FDA for permission to undertake the first ESC clinical trial to treat spinal cord injuries.  According to a company press release, the trial had been in the works for four years, but the FDA issued a Clinical Hold because they have not yet established ensure safety and efficacy guidelines for ESC-based therapies.  According to an article last May in the science journal, Nature, there also is speculation that President Bush’s objection to ESC research helped force the FDA to put the trial on hold.

Geron also is planning ESC clinical trials for heart disease, while Advanced Cell Technology in Los Angeles has indicated that it is close to submitting an IND to use ESCs to treat macular degeneration.  San Diego’s Novocell, with funding from Johnson & Johnson, is preparing for ESC clinical trials to treat diabetes.

So, ten years after Thomson’s discovery, ESCs are just now entering the market as research tools for drug and toxicity testing and clinical trials loom on the horizon.  At this point, the holdup is so the FDA can figure out how to monitor the trials.  Furthermore, with the Obama administration, political constraints on the FDA to approve ESC-based trials will likely be removed next year. 

Europe says no to stem cell patents

The UK's Guardian reports that "the European Patent Office has refused a patent covering the use of human embryonic stem cells on the grounds that it would be contrary to 'public order or morality.'" Referring to it as a "landmark ruling," the article goes on to say that if the patent had been granted, observers feared it would thwart companies engaged in developing hESC-based technologies. Robin Lovell-Badge, head of stem cell biology at the National Institute for Medical Research, is paraphrased in the article as saying that "the ruling would make it easier for biotech companies to operate in the EU compared with the US, where similar patents on the use of human embryonic stem cells have been granted."

The brave new world of stem cells and human cloning, by Steven S. Clark

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?

Treating stroke, Parkinson's and other brain diseases with stem cells

Brain repair using genetically engineered embryonic stem cells could offer novel treatments for stroke, Alzheimer's, Parkinson's and other neurological conditions, after encouraging preliminary tests.

Scientists at the Burnham Institute for Medical Research in La Jolla, California, have, for the first time, genetically programmed embryonic stem cells, which have the potential to turn into any type, to become nerve cells when transplanted into the brain, according to a study in The Journal of Neuroscience.

The research showed that mice afflicted by stroke showed "tangible therapeutic improvement" following transplantation and none developed tumors, which had been a major setback in prior transplants.

The team was led by Prof Stuart Lipton, who treats patients with these disorders. "We found that we could create new nerve cells from stem cells, transplant them effectively and make a positive difference in the behavior of the mice," said Prof Lipton.

"These findings could potentially lead to new treatments for stroke and neurodegenerative diseases such as Parkinson's disease."

Prior to this research, creating nerve cells from embryonic cells in a reliable way had been problematic and sometimes cells would seed tumors. Prof Lipton tackled these problems by inducing the stem cells to make a protein called myocyte enhancer factor 2C (MEF2C), which turns on specific genes that drive stem cells to develop into nerve cells.

"We need to have a reliable source of nerve cells that can be easily grown, differentiate in the way that we want them to and remain viable after transplantation," said Prof Lipton.

"MEF2C helps this process first by turning on the genes that, when expressed, make stem cells into nerve cells. It then turns on other genes that keep those new nerve cells from dying. As a result, we were able to produce neuronal progenitor cells that differentiate into a virtually pure population of neurons and survive inside the brain."

The next step was to show whether the transplanted "progenitor" cells became nerve cells that integrated into the existing network of nerve cells in the brain. Performing intricate electrical studies, the team showed that the new nerve cells, derived from the stem cells, could send and receive proper electrical signals to the rest of the brain. The team found that mice which received the transplants showed significant behavioral improvements, although their performance did not reach that of normal control mice.
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Excerpted from an online article by Roger Highfield in the Telegraph on 6/24/08.