Aaron Cathcart was told by his doctor that he barely had a year to live, because his heart was so weak that he would not be able to survive surgery. That was over two years ago.

On June 26th of last year, however, Mr. Cathcart received autologous adult stem cell therapy in which his own adult stem cells, derived from his own bone marrow, were administered directly into his heart during open-heart surgery. Prior to receiving the therapy, his heart had an ejection fraction of less than 20%, whereas a normal ejection fraction range is considered to be between 55% and 75%. Three months after receiving the adult stem cell therapy, his ejection fraction had improved to 36%, and by January it had improved even further to 41%. Now, he no longer needs a defibrillator and is almost within the normal range for a healthy ejection fraction.

As Mr. Cathcart now describes, “It used to be that I couldn’t walk a couple hundred feet in the yard without getting pains. I couldn’t go out if the weather dropped below 50 degrees because my heart would strain in the cold.”

Since stem cell therapies are still plodding their way through the multi-year, highly expensive and lethargic FDA clinical trial process that is required for government approval of such therapies in the U.S., most stem cell therapies are not yet available in the U.S. at all, except through FDA-approved clinical trials. In fact, this is exactly how Mr. Cathcart discovered the therapy, since he was fortunate enough to find a clinical trial with adult stem cells that was being conducted not far away from his hometown. The company TCA Cellular Therapy was seeking patients who had suffered heart attacks but had never undergone heart surgery, conditions which applied to Mr. Cathcart and which made him eligible to participate in the trial. The therapy utilized autologous adult stem cells which were taken from each patient’s own bone marrow, expanded in the laboratory and then administered back to each patient according to his or her particular medical condition. Although such therapy usually eliminates the need for surgery, in Mr. Cathcart’s particular case the doctors determined that heart surgery was necessary due to the advanced pathology of his heart, so his own adult stem cells were injected directly into the dead tissue of his heart during bypass surgery.

Embryonic stem cells were never used in the therapy, due to the numerous medical risks and dangers that embryonic stem cells pose, not the least of which is the formation of teratomas (tumors). By sharp contrast, adult stem cells pose no such risks.

As Mr. Cathcart explains, “People hear ‘stem cells’ and they think ‘killing babies’. People are not distinguishing between the two. These were my own stem cells they used. Everyone’s body has them, and if you increase them in concentration, they can repair your body much better than normal.”

The company TCA Cellular Therapy, which is headquartered in Covington, Louisiana, is focused exclusively on the research and development of adult stem cell therapies, not embryonic stem cell therapies. Their latest successes in the treatment of various cardiac conditions hold great promise for the safe, effective and ethical treatment of diseases that afflict a growing number of people each year. In 2005 alone, it was estimated that over 35% of all deaths in the United States were related to cardiovascular disease, and every day approximately 2,400 Americans die from complications of this “silent killer”. Additionally, over 6 million people in the U.S. alone are believed to have blood-flow problems to their legs, which is a contributing factor to cardiovascular disease.

TCA Cellular Therapy owns two patents for proprietary autologous adult stem cell processes and products that are derived from the patient’s own bone marrow, and currently the company is in four separate FDA-approved Phase I and Phase II clinical trials, for the use of autologous bone marrow-derived stem cells in: 1/ the treatment of infarcted myocardium during bypass surgery, 2/ the non-surgical rescue and repair of cardiac muscle following acute myocardial infarction, 3/ the treatment of severe limb ischemia and 4/ the treatment of severe coronary ischemia. Further clinical trials for spinal cord injury and ALS (amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease) are still pending FDA review, and future protocols are currently being designed for the treatment of Parkinson’s disease and idiopathic cardiomyopathy with autologous adult stem cells.

During a conference call for institutional investors held Monday by Summer Street Research Partners, an independent health care research firm, a spinal surgeon and stem cell researcher offered a negative and cautionary view of Geron’s research. Subsequently, TheStreet.com decided not to disclose the doctor’s name due to privacy concerns, “since the call was not intended for public dissemination.” The doctor stated, however, that he has no financial ties to Geron, nor does he own, nor has he shorted, any of Geron’s stock. Nevertheless, the doctor pointed out that the highly publicized upcoming clinical trial for which Geron recently received FDA approval is clinically dubious because the entire rationale for the study is “based on a single experiment in 8 rats.”

In a highly controversial ruling, the FDA granted approval to Geron in January of this year to begin the first clinical trials ever to be conducted in the U.S. with human embryonic stem cells. The clinical trial will administer human embryonic stem cells to patients who have been paralyzed from the waist down with spinal cord injury. Since the primary objective of Phase I clinical trials is to test safety, efficacy will not be tested until years later – assuming, that is, that safety can be proven, although this remains the subject of widespread speculation. Without concrete evidence of safety, the proposed therapy cannot advance to further clinical trials.

In the days immediately following the FDA’s announcement, Geron’s stock soared from $5 a share to more than $48 a share, but such dramatic gains were quickly sold and the stock has steadily fallen ever since then, plummetting to a low of $3.79 on March 5th. According to Adam Feuerstein of TheStreet.com, “Even President Obama’s lifting of the federal research ban on stem cell research Monday failed to provide more than a marginal lift to Geron’s stock price, which closed Tuesday at $4.27”, up a mere 1.4%.

As Mr. Feuerstein further explains, “Wall Street’s health care investors, most notably biotech-focused hedge funds, have been more inclined to steer clear of Geron or short the company’s stock. Geron’s short interest has risen from 8 million shares to 17 million shares over the first two months of the year. Conference calls for Wall Street health care investors with experts critical of Geron’s research, like those held by Summer Street Research on Monday, explain why. The doctor on the Summer Street conference call, a spinal cord injury expert who has also conducted stem cell research, was skeptical about Geron’s study because there is very little animal data to support the theory that a therapy derived from [embryonic] stem cells will benefit patients with severe spinal cord injury.”

Indeed, as the doctor stated, “The fact that Geron’s entire study hinges on this one experiment in eight moderately injured rats is tenuous in terms of efficacy.”

This laboratory experiment upon which Geron’s upcoming clinical trial is based, was conducted by Dr. Hans Keirstead of the University of California at Irvine, using 8 rats in whom spinal cord injury had been deliberately inflicted in order to induce hind-leg paralysis. Rats that were treated with Geron’s human embryonic stem cell product saw a partial return of some function to their paralyzed legs after 7 days, but all of the rats were considered to have “moderate” spinal cord injury. However, when the start of treatment was delayed for more than a week, and also when the experiment was conducted on rats with severe spinal cord injuries, Geron’s therapy had no effect. The human patients who will participate in Geron’s clinical trial will not have moderate spinal cord injury, but instead they will have been chosen for the clinical trial because they suffer from severe spinal cord injury.

According to the doctor who spoke during the conference call, “We don’t know what will happen when these cells are placed into a human, which is the reason immune suppression is required. The risk is that these are not patients you would otherwise want to have on immune suppressants because the severity of their spinal cord injuries, the trauma they’ve suffered, their surgery and wounds make them more susceptible to infection.”

In Geron’s upcoming Phase I clinical trial, human embryonic stem cells will be injected directly into the spinal cords of the human patients. Ordinarily, after undergoing any type of transplantation, immune suppression is required for the remainder of the patient’s life, but the patients in Geron’s clinical trial will be removed from immunosuppressive drugs after 42 days, at which time there is a high risk of immune rejection by the patients’ bodies to the stem cells. In and of itself, this type of immune rejection has the potential to be life-threatening. As Mr. Feuerstein adds, “Another safety concern is the risk that the cells in Geron’s therapy may grow uncontrollably and form tumors on the spinal cord,” to which the doctor from the conference call further adds, “If one patient gets a tumor from the Geron therapy, it will be catastrophic.”

While the CEO of Geron, Tom Okarma, has tried to downplay expectations of efficacy by reminding the public that none of the patients are expected to be instantly cured from the Phase I clinical trial, it is a bit more difficult to dispel concerns about safety.

Despite the fact that Geron’s preclinical data is based upon only one experiment with only 8 rats, Geron’s FDA application nevertheless included a staggering 22,000 pages of data. Although such an unwieldy number might impress those who are uninitiated in “the scientific method”, Mr. Feuerstein points out that such an enormous FDA application “has not stopped some experts from questioning Geron’s science.” One such expert is Dr. Evan Snyder of the California- and Florida-based Burnham Institute for Medical Research, who wrote in an article that was published in the January 30th issue of the journal Science that, “There’s a lot of debate among spinal cord researchers that the preclinical data itself doesn’t justify the clinical trial.” Similarly, in the January 23rd edition of The New York Times, Dr. John Kessler, a neurologist and director of the Stem Cell Institute at Northwestern University, wrote, “We really want the best trial to be done for this first trial, and this might not be it.”

As every investor knows, financial markets are forward-looking, and the price of any particular stock at any particular time is a measure of confidence in that company. In Geron’s case, as with all other biotechs, the financial details are inextricably tied to the scientific details. Precisely for that reason, therefore, at least at this particular moment in history, institutional investors are growing increasingly wary of Geron because of the serious words of caution that are echoed throughout the medical and scientific communities.

An Israeli boy who suffers from a rare, often fatal genetic disease known as ataxia telangiectasia (A-T) has developed a tumor that was directly traced to the fetal stem cell therapy that he received. No known cure exists for A-T, which causes degeneration of the brain regions that control movement and speech, and people with the disease usually do not survive past their teens or twenties. Consequently, when the boy was 9 years old, his family traveled to Moscow so that he could receive an experimental therapy consisting of intracerebellar and intrathecal injections of human neural fetal stem cells – derived from aborted human fetuses – which were then injected into the boy’s brain and spinal cord as a treatment for his A-T. Even though he received two more treatments with the fetal stem cells at the ages of 10 and 12, he still had not shown any improvement by the age of 13 and in fact the severity of his disease had progressed to such an extent that he required a wheelchair. When he began having headaches, tests conducted at the Sheba Medical Center in Tel Aviv revealed a multifocal brain tumor pressing against both his brain stem and his spinal cord, which biopsy revealed to be a glioneural neoplasm. The tumor was surgically removed in 2006 when the boy was 14 years old, at which time cytogenetic and molecular analysis of the tumor revealed it to be of the same tissue as the fetal stem cells, and was therefore caused directly by the fetal stem cell therapy. Among other tests, genetic analysis revealed that some of the cells of the tumor had originated from a female donor and were comprised of 2 normal, healthy copies of the gene in which mutations cause the A-T disease, and which therefore did not match the boy’s own genotype containing abnormal copies of the gene.

Had this tumor not been discovered and surgically removed, it certainly would have been fatal and the boy would have died – not from the A-T disease, but from the therapy which was meant to treat the A-T disease. Indeed, one of the most serious concerns with embryonic and fetal stem cells is that they might constitute “therapies” which are worse than the diseases that they are meant to treat. This particular example with a boy suffering from A-T offers strong evidence to justify exactly such a concern. The boy is being closely monitored for any other tumors which might also possibly develop over time, as a lingering yet direct result of the fetal stem cell therapy that he received.

The formation of tumors has long been one of the main concerns associated with embryonic and fetal stem cells, and the fact that this boy’s tumor was not detected until 4 years after his first treatment raises some new concerns. According to Dr. Marius Wernig of Stanford University, “Stem cell transplantations have a humongous potential. But if people rush out there without really knowing what they’re doing, that really backfires and can bring this whole field to a halt.”

As Josephine Quintavale of the public interest group Comment on Reproductive Ethics adds, “The risks of tumor formation in association with embryonic stem cells are widely acknowledged and one reason why there are very serious concerns about the proposed use of such cells in treating spinal cord injury in the US. It would appear from this report that fetal stem cells are similarly unstable. These are not areas of therapy we should be rushing into, whatever the ethical debates surrounding the use of embryo or fetal tissue per se.”

Dr. Stephen Minger of King’s College London further explains, “This is worrying and we have to be cautious. We need to have long term monitoring and follow-up of the patients who are given stem cells and rigorous regulation of centres providing cell therapy. Although this is just one case, it does show that we need to be careful about the cell population we are using.”

As we have often explained on this website, all stem cells are not created equal, nor do they behave equally, and important distinctions must be made between the different types of stem cells. Generally speaking, all stem cells fall into 2 broad categories: adult stem cells, and everything else. The latter category includes embryonic and fetal stem cells, while stem cells that are derived from umbilical cord and placental blood are categorized as “adult” stem cells. The relatively recently discovered endometrial regenerative cells (ERCs), which have shown to be particularly promising, also fall into the category of “adult” stem cells. It is important to understand that adult stem cells behave very differently from embryonic and fetal stem cells, with one of the major differences being the risk of tumor formation, which has long been known to be inherently problematic in embryonic and fetal stem cells, especially in regard to the formation of teratomas (a specific type of tumor), which is the definitive requirement of pluripotency; by sharp contrast, however, adult stem cells do not cause tumors because adult stem cells are not pluripotent, but are instead multipotent, at best. In the past, the lack of pluripotency in adult stem cells was seen as a disadvantage, although increasingly it is being recognized as a distinct advantage, since it eliminates any danger of tumor formation.

According to a warning issued by Dr. John Gearhart, a stem cell scientist at the University of Pennsylvania, “Patients, please beware. Cells are not drugs. They can misbehave in so many different ways, it just is going to take a good deal of time.”

Although this particular case of tumor formation was originally reported in the PLoS medical journal, a peer-reviewed open access journal published by the Public Library of Science, the story was subsequently republished in all major media outlets around the world. As the authors of the PLoS paper cautiously conclude, “This is the first report of a human brain tumor complicating neural stem cell therapy. The findings here suggest that neuronal stem/progenitor cells may be involved in gliomagenesis and provide the first example of a donor-derived brain tumor. Further work is urgently needed to assess the safety of these therapies.”