Geron Explains Delay in Trial

Bloomberg.com, August 27, 2009

In January of this year, to great fanfare and widespread publicity, the U.S. FDA (Food and Drug Administration) gave approval to the Geron Corporation for the commencement of clinical trials with human embryonic stem cells (hESCs). The trials, originally scheduled to begin this summer, were to be the first official U.S. government-approved clinical trials ever conducted with hESCs. On August 18, however, the FDA imposed a halt on the trials, even before the first patient could be enrolled.

Although Geron declined to offer a detailed comment at that time, representatives of the company have now finally issued a formal explanation. According to Geron officials, the FDA halt is the result of "non-proliferative cysts" that were found in preclinical animal studies.

Although the precise, scientific interpretation of "non-proliferative cysts" is highly debatable, nonscientists in the general public seem to be pacified by Geron's extremely unscientific choice of words.

In actuality, this explanation contradicts initial reports in which Geron representatives attributed the FDA halt to "escalated dosage" that Geron scientists had reported in preclinical animal studies. (Please see the related news article on this website, entitled "Embryonic Stem Cell Trial Delayed", dated August 18, 2009, as originally reported in The New York Times). Now, however, "non-proliferative cysts" would seem to be a different explanation which is altogether entirely separate from "escalated dosage".

For those people with a modest understanding of scientific laboratory procedures, this latest statement by Geron does nothing to clarify matters at all, but, on the contrary, merely seems to obfuscate matters further. For the less scientifically inclined, however, any explanation at all would seem to be enough to restore full confidence and enthusiasm.

According to San Diego based WBB Securities analyst Stephen Brozak, "I think it provides people with a reasonable explanation. Everybody was afraid of the T-word, teratomas, and it clearly wasn't that."

In fact, the results are not clear at all, and indeed, people have good reason to be cautious of "the T-word", since teratomas are, by definition, a required characteristic not only of embryonic stem cells but of all pluripotent stem cells in general. Since pluripotency is defined as the ability of a cell to differentiate into tissue from all 3 germ layers (the ectoderm, the mesoderm and the endoderm), the formation of a teratoma remains the universal laboratory standard by which embryonic and other pluripotent stem cells are identified. If a cell in the laboratory forms a teratoma, then it is, by formal definition, recognized to be a pluripotent stem cell - and this includes not only embryonic stem cells but also the more recently developed iPS (induced pluripotent stem) cells. Conversely, if a cell cannot form a teratoma in the laboratory, then it is recognized as not being pluripotent.

A very specific type of tumor, teratomas are known for their extremely hideous appearance since they often contain not only bones and organs but also hair and teeth. They appear, in fact, to be just like an embryo, though highly physiologically disorganized, as if all the bones and organs had been disassembled and randomly rearranged. Although teratomas are benign, in the sense that they do not metastasize, they can still pose a serious health hazard and can even be fatal if left untreated. A metastatic, malignant counterpart does exist, known as a teratocarcinoma, and in fact when early teratomas are first detected in the laboratory it is impossible to know at such a primitive stage whether the tumor is the benign or the malignant version. It is therefore a realistic possibility that pluripotent stem cells can cause the formation of malignant teratocarcinomas as well as the benign teratomas.

Since embryonic stem cells (ESCs) are required, by the formal definition of pluripotency, to cause the formation of teratomas, a major concern with medical therapies based upon ESCs is that such therapies should, logically and predictably, also form teratomas in the patients who receive such therapies. Indeed, exactly how, or if, one might be able to flip off the cellular and molecular "switches" that cause pluripotent cells to form teratomas remains a hotly debated point among stem cell scientists.

By sharp contrast, however, adult stem cells are not pluripotent and therefore are not capable of forming teratomas, unlike ESCs and iPS cells. Although such a lack of pluripotency was originally seen as a disadvantage of adult stem cells, it is now widely acknowledged to be a major advantage and one of the primary reasons why adult stem cells have already been in clinical use as clinical therapies, safely, for years, without even one teratoma ever being reported as a side effect.

Geron did not offer a detailed elaboration of the precise features of these "non-proliferative cysts" which were found to form in laboratory animals who received Geron's novel, proprietary ESC therapy. Teratomas, of course, being nonmalignant, could also be described as "non-proliferative"; furthermore, teratomas are often routinely referred to as "cysts", especially within the medical community itself. It is not uncommon, for example, when teratomas form naturally on or around the ovaries, for a gynecologist to tell the patient that a "cyst" needs to be surgically removed, when in fact the "cyst" is a teratoma. Nevertheless, "cyst" is the more common, colloquial term that is more often used in casual discourse between doctor and patient.

It is not surprising, therefore, that many scientists remain skeptical about Geron's claim that these "non-proliferative cysts" are not, in fact, the dreaded "T-word", teratomas. There are also many scientists who are wondering why it took Geron so long to issue a formal explanation, thereby apparently deliberately perpetuating the initial reports which cited "escalated dosage" as the reason for the FDA halt. Especially when the formal explanation that is now released to the press consists of such a simple, and simplistic, reason as the appearance of "non-proliferative cysts", many scientists are left wondering why it was exactly that Geron took so long to get around to releasing this explanation to the public.

Allowing separate, independent laboratories to analyze the cysts, and to check specifically for the differentiation of cells into all 3 germ layers, could settle the skepticism once and for all. It could also clarify the apparently erroneous perception, carelessly propagated throughout the public, that "escalated dosage" had something to do with the FDA's reason for halting Geron's clinical trial. Thus far, however, Geron has indicated no interest in allowing such a clarification.

Meanwhile, it would appear as though financial analysts are not necessarily scientists, and Stephen Brozak, among others, have now given Geron the new rating of a "strong buy" precisely as a result of Geron's own description of "non-proliferative cysts". Consequently, shares of Geron's stocks rose 25 cents, or 3.6%, to $7.18 at the close of trading today - up significantly after having fallen 10% as a result of the FDA halt that was announced on August 18.

According to Joseph Pantginis, an analyst at Merriman Curhan, "I believe that since the worst case scenario did not occur, investors are relieved." In fact, it is not at all known whether or not "the worst case scenario" did or did not occur. Until independent laboratories can check specifically for cells from all 3 germ layers, it cannot be known with any reliability or certainty whether or not these "non-proliferative cysts" are teratomas. Such a stance has nothing whatsoever to do with Geron in particular but rather it is a fundamental premise of the scientific method in general, which is founded upon repeatability and independent verification, without which, claims are meaningless - regardless of who makes such claims and regardless of whether the claims pertain to medical science or to the physics of planetary motion or to any other natural phenomenon.

Nevertheless, Pantginis was quick to add that Geron is not completely out of the woods just yet, as he points out that, "The potential timing of a release of the clinical hold is a complete black box and cannot be projected."

After all, the U.S. FDA actually employs scientists, some of whom might want to see further, independently verified evidence for the absence of cells from all 3 germ layers in these "non-proliferative cysts", before any proclamation about teratomas can be made.