An Era Ends Before It Even Begins

To paraphrase an oft-cited verse of T.S. Eliot’s, “this is the way the experiment ends.  Not with a bang but a whimper.”

The experiment was Geron’s highly touted clinical trial using human embryonic stem cells (hESCs) to treat patients with spinal cord injury (sci), for which the FDA gave approval in January, 2009.  The experiment certainly began with a bang, arriving with the usual media hype that human embryonic stem cell research (hESCR) has enjoyed over the years. 

“Some people think this is the dawn of a new era,” ABC’s Diane Sawyer gushed on Good Morning America.  The Los Angeles Times agreed with Sawyer’s talking points, similarly gushing that the trial was “ushering in a new era in medicine.” 

Well, that “new era” in medicine lasted not quite two years, which must be some sort of record for brevity in defining an “era.”  On November 14^th of this year, Geron announced it was shutting down its human embryonic stem cell program.  During this brief “era,” 5 sci patients received infusions of hESCs (Geron originally intended to treat 10 patients total for the trial).  While there were no serious adverse side effects, there has been no evidence of any benefits to the patients either. 

Geron cited financial difficulties as the reason for shutting down the program.  So how did market watchers react to that?

The Street.Com reacted by selecting Geron’s announcement to terminate its hESCR  program as one of the “Five Dumbest Things on Wall Street” for the week of November 18.  It deserves to be quoted in full:

“3. Geron's Bluto Moment

You think John "Bluto" Blutarsky from Animal House had it bad? He saw only seven years of college go down the drain. Biotech bust Geron squandered 21 years of shareholder hopes, dreams and dollars on a wasted education. Shares of Geron fell 21% to $1.74 Tuesday as a result of its decision to shut down its embryonic stem cell research program in order to focus on its experimental cancer drugs. John Scarlett, Geron's newly appointed CEO, insisted in interviews Monday that the company's decision to exit the stem cell business was not an indictment of the entire field but was more a company-specific business decision. Frankly, Scarlett, we don't give a damn how you spin it, but Geron will always be an embryonic stem cell company. For more than two decades, Geron has been sucking money from investors' wallets like a Hoover vacuum with the sole intent of turning embryonic stem cells into new tissue or organs. And now you want to drop it like a bad habit? And after all that preaching about how this technology will help paraplegics walk, cure diseases like diabetes and Parkinson's and prevent heart attacks -- not to mention an accumulated deficit of nearly $700 million -- now you want to try something new? No way, dude! You can't simply change your major like an aimless college student trying to delay graduation. Your parents -- or in this case, your shareholders and investors -- deserve better. Not that they have seen much of a return on their money so far. To date, only four paralyzed patients have received injections of embryonic stem cell-derived nerve cells into their spinal cords. And while no safety problems have been reported, Scarlett admitted that there were "no signs" the stem cell therapy was helping patients either. Still, that's no reason to abandon hope and to change course after all these years of trying. Remember, Bluto spent all those years in a filthy, idiotic fraternity and then went on to become a member of the U.S. Senate. Wait, maybe that's not the best analogy.  But you know what we mean.”

For years, Geron cynically manipulated investors with carefully timed but nonetheless deceptive media announcements that its hESC clinical trial for spinal cord injury was imminent.  Here’s a partial chronology of how Geron did this, as compiled by DNH founding member David Prentice, PhD: 

18 March 2002
University of California, Irvine Prof. Hans Keirstead announces he will ask university officials to seek the U.S. Food and Drug Administration's approval to test human embryonic stem cells on human patients with spinal cord injuries. Initially, Keirstead said he might be ready to take this step in about a year.
22 February 2004
"The company believes it will be cleared to start the first stem-cell therapy in human tests next year, possibly for spinal-cord injury."
1 December 2004
According to Geron CEO Thomas Okarma, the company is aiming to file an investigational new drug application with the U.S. Food and Drug Administration (FDA) requesting permission to begin clinical trials using glial cells derived from embryonic stem cells to repair damaged spinal cords in 2005 or early 2006.
5 February 2005
"Next year [Hans Keirstead] and his corporate partner, Geron, plan to try treating people who have recent spinal cord injuries, in what would almost certainly be the first human trial of any therapy derived from such cells.
19 April 2005
Thomas Okarma, Geron's CEO, is even less convinced that larger animal studies are necessary before testing Keirstead's technique in humans. During an interview at a conference, he said he believes the clinical trial could begin in mid-2006.
9 September 2005
"Geron plans to begin clinical trials on acute spinal cord injury treatment in early 2006, according to chief executive officer Tom Okarma."
7 November 2005
"[R]esearchers at Geron of Menlo Park want to take the next step - in people. They hope to get federal permission to inject those cells into damaged spinal cords. The procedure - which Geron intends to do next year - would be the first human tests of a treatment derived from human embryonic stem cells, the highly versatile body cells that can be coaxed into becoming almost any tissue in the body."
29 March 2006
Tom Okarma: We will complete our IND-enabling studies, which are now in process and still on track, and file our IND during the fourth quarter of this year, assuming the preclinical data continue to go well. That starts a 30-day review clock by the FDA, who then has 30 days to either accept our IND and allow us to proceed or, at that point, they have questions that we must answer before we can begin. We are on track for that. So, assuming they bless the IND, we would hope to be in the clinic in the first quarter of (2007).
17 June 2006
"I'm confident that we will be in the clinic next year with the first human ESC-derived product," said Tom Okarma, chief executive of Geron, at a conference in London last week.
27 July 2006
The company will apply for approval to start US clinical trials in 2007, using glial cells derived from human embryonic stem cells to treat spinal injuries.
4 August 2006
One company, in particular, Menlo Park, CA-based Geron, is taking the lead in developing experimental embryonic stem cell therapies and hopes to begin human trials next year.
9 May 2007
"The first clinical trial of embryonic stem cells is on track to start early next year on patients with spinal cord injury. Geron, the California-based biotechnology company, will carry out the study on accident victims in six trauma centres across the US."
20 July 2007
"Geron Corporation in Menlo Park, California, expects to start clinical trials of a therapy for spinal cord injury early in 2008, according to spokesperson David Schull."
31 October 2007
Geron, based in Menlo Park, Calif., has been using rats in its experiments of a potential treatment for spinal cord injuries. Geron has already met with the FDA and will submit its plans for human testing to the agency by the end of this year, according to Sion.
13 November 2007
Geron's development plan for the product calls for the filing of an Investigational New Drug (IND) Application with the U.S. Food and Drug Administration and, pending the agency's review, initiation of human clinical trials in 2008.
13 November 2007
Geron's development plan for the product calls for the filing of an Investigational New Drug (IND) Application with the U.S. Food and Drug Administration and, pending the agency's review, initiation of human clinical trials in 2008.

15 May 2008
The Geron Corporation announced Wednesday that its plans to begin the first clinical trial using embryonic stem cells had been delayed by federal regulators. While companies typically do not announce when they submit an application to begin a trial for an investigational new drug, the F.D.A.'s action means Geron must have submitted its application in the last 30 days, Mr. Benjamin said.

17 October 2008
But the FDA is nearing the end of its review process and may lift the hold and allow clinical trials to commence within the next three months, Okarma told The Scientist.

20 October 2008
A clinical trial that would test the use of embryonic stem cells to treat spinal cord injury could begin within three months.

In sum, Geron’s behavior over the years is emblematic of the way hESCR proponents have tried to advance their cause: year after year after year, promise major medical breakthroughs with, in the end, little or nothing to show for it. 

In addition to the market, other observers saw other forces at play in the demise of Geron’s hESC trial.  According to Datamonitor Expert View: “Although many would say that Geron's decision reflects the worsening economic environment, in which biotechnology companies are increasingly struggling to raise capital investment, Datamonitor believes that the underlying reasons for the announced divestment actually relate to clinical and intellectual property roadblocks facing Geron's stem cell programs... Geron's divestment highlights the potential pitfalls associated with specific types of stem cell technologies - namely, embryonic stem cells (emphasis added).”

In marked contrast, Datamonitor went on to observe, “adult stem cell therapies continue to race ahead.” 

As Geron’s great new era of medicine was closing with a (media) whimper, the Discovery Institute’s Wesley Smith noted the media’s double standard in the way it covered Geron’s failure vs. advances with adult stem cells.

“You would think Geron’s failure would be very big news,” Smith wrote in the Weekly Standard.  “Instead, it turns out that the mainstream media pay attention only when embryonic stem cell research seems to be succeeding—so far, almost exclusively in animal studies.  When, as here, it crashes and burns, it is scarcely news at all.”

Citing, for example, the attention the Los Angeles Times gave to the FDA’s approval of the Geron trial in January 2009, and then again when the first patient actually received a transfusion of hESCs in October, 2010, Smith noted: “During the same period, however, the paper did not report the encouraging results of early human trials of treatments for spinal cord injury developed using adult stem cells.”

On that Good Morning America show cited above, Sawyer asked Sean Morrison, PhD, a researcher at the Howard Hughes Medical Institute: “What about it, Dr. Morrison? Do you think it could have been done with adult stem cells?”

Morrison replied: I don't think there's any adult stem cell that's ready for use in clinical trials that could be used to do what Geron is doing with these [embryonic] cells.”

How to explain such a remark?   Ignorance?  A willingness to mislead?

In 2005 – four years before the FDA approved Geron’s trial – Dr. Carlos Lima of Portugal published a report in the peer-reviewed Journal of Spinal Cord Medicine showing positive results from a “pilot clinical study” that used adult stem cells derived from olfactory mucosa to treat sci patients  (Lima subsequently published a second study on the use of olfactory mucosa derived stem cells to treat sci patents in the peer-reviewed Neurorehabilitation and Neural Repair, 9/30/09). 

Even earlier, in 2002, reviewing the positive results of using such stem cells in animal models, the Federation of American Societies for Experimental Biology declared : “These results are the most dramatic functional and histological repair yet achieved after complete spinal cord transaction in mammals, and they open new avenues in the search for treatment of spinal cord injuries in other mammals, including humans.”

Finally, and perhaps most important, a word about the patients.  They are the ones who have been the most ill-served by all the media hype surrounding Geron’s “new era” of medicine and hESCR in general.  They have also been ill served by the corresponding willingness of the media and even many researchers to downplay the very real and ongoing advances with adult stem cells.   

There is still great hope and promise for stem cell research to help patients. 

As the Geron example shows, don’t go looking for human embryonic stem cell research to fulfill it.  That hope and promise are being realized with adult stem cells.

Simpler, Better

The New Scientist recently ran a rather remarkable editorial, “In praise of stem cell simplicity.”

“We should keep all avenues of stem-cell research open but be grateful when simpler alternatives emerge,” the editorial asserts.  Pointing to recent advances using adult and induced pluripotent stem cells (iPSCs), the article says these “could spawn novel, personalized stem-cell treatments that, if not simple per se, are simpler than what has gone before.”

Not only are these advances simpler (compared to using human embryonic stem cells (hESCs) to try and treat disease), but “[w]hat marks these treatments out is that they are eminently practical and ethically unquestionable. This is in stark contrast to much previous work, which has focused on human embryonic stem cells, or hESCs.”

Drawing out that contrast, the article notes that hESC research has always been ethically questionable.  It then refers to the so-called “breakthrough” in October using cloning to produce human stem cells.  However, the article notes, the process still required eggs, an embryo was still killed and the resulting stem cells were genetically malformed, “rendering them useless for medical uses.”  Three strikes and that so-called breakthrough is out.

The article specifically refers to two advances demonstrating how non-embryonic stem cell research is simpler than and superior to hESCR.  “Diabetic rats cured with their own stem cells” tells how researchers transformed brain stem cells that had been extracted through the nose into insulin producing cells in the pancreas.”  The researchers did this “without genetic trickery.”

The second advance tells how scientists used stem cells taken from a baby’s own amniotic fluid to repair congenital defects such as holes in the diaphragm.

So it would certainly appear clear that non-embryonic approaches to stem cell research are turning out to be simpler and more effective in terms of actually producing therapies than hESCR.  Despite these advantages, however, the article concludes by calling for all avenues of stem cell research to continue.  For instance, the article notes, iPSCs are reprogrammed using a virus and the reprogrammed cells do not yet match embryonic stem cells.

However, the process of producing iPSCs has vastly improved in the relatively short time since they were first discovered in 2007.  Researchers have used a particular RNA viral vector that carries no risk of integrating into the host genome, to produce iPSCs that have no foreign gene insertions and that are viral/factor-free.  The researchers reported that “the resulting iPSCs expressed human embryonic stem cell markers and exhibited pluripotency.”  Another study has found that proteins produced by iPSCs and human embryonic stem cells (hESCs) are 99 percent similar.  According to one of the researchers the study suggests that iPSCs and hESCs are quite similar.  “According to some measurements, the protein production of an embryonic stem cell was closer to that of an IPS cell than to a second embryonic stem cell. “

As the Do No Harm Coalition has frequently pointed out, in 1999, when President Clinton’s National Bioethics Advisory Committee (NBAC) first recommended federal funding for hESCR, it did so conditionally: “In our judgment, the derivation of stem cells from embryos remaining following infertility treatments is justifiable only if no less morally problematic alternatives are available for advancing the research…The claim that there are alternatives to using stem cells derived from embryos is not, at the present time, supported scientifically. We recognize, however, that this is a matter that must be revisited continually as science advances.” (Ethical Issues in Human Stem Cell Research, Volume I, p.53, emphasis added).

In other words, they recognized that, given the ethical problems associated with hESCR, it should not be undertaken if viable alternatives exist.  

Such viable alternatives exist.  Advances in non-hESCR to treat disease are many, ongoing and well documented in the peer-reviewed literature.  It’s time that proponents of human embryonic stem cell research revisit, in the light of scientific advances, their earlier premature judgments on the need to pursue such destructive research.

Are they really still bothering with That?

In 2007, the world was introduced to induced pluripotent stem cells (iPSCs).

With this breakthrough, Somatic Cell Nuclear Transfer (SCNT) -- more commonly known as cloning -- suddenly looked to be the Dodo bird in the field of stem cell research and regenerative medicine.

But human cloning for research has staged a mini-comeback recently, attended by the usual media hype that always seems to accompany any development in embryo-destructive stem cell research. 

In a 10/6/11 article published in Nature, scientists reported that they had, for the first time, successfully generated a line of stem cells from a cloned human embryo.

Numerous media outlets hailed the news as a “major breakthrough” for stem cell research that had, according to CBS, “scientists buzzing.”  “May lead to cure for Parkinson’s and diabetes” declared the (London) Independent. 

But for all the buzzing and talk of cures on the horizon, the stem cells harvested from the cloned embryo were therapeutically useless.  Dr. Scott Noggle, co-author of the Nature article announcing the “breakthrough” admitted as much: "These cells are not therapeutically relevant at the moment," he stated.  The cells were, in fact, abnormal, given the way that Noggle and his colleagues carried out the SCNT procedure. 

Typically, the SCNT procedure entails removing the nucleus from an egg, thus removing its genetic material.  The nucleus from the donor’s somatic cell is then inserted into the enucleated egg and stimulated to begin development of the cloned embryo. This is the process used to create Dolly the sheep, but it has never been successful in producing a viable human embryo.

The success reported in Nature changed this procedure by inserting the nucleus of the donor’s somatic cell into an intact egg, i.e., an egg that still contained its nucleus.  While  viable (for purposes of harvesting stem cells) embryos were produced, because the egg’s nucleus was not removed the embryos were abnormal, as they contained an extra set of chromosomes, as did the stem cells harvested from those embryos.  Thus, the cells could serve no therapeutic purpose.  "These are grotesquely abnormal cells, so they have no clinical applications. Even scientifically they are of questionable value," said Maureen L. Condic, an associate professor of neurobiology and anatomy at the University of Utah.

In truth, news of this supposed “breakthrough” came across as tired and stale, especially in light of the fact that scientist are currently producing patient specific, fully pluripotent  stem cells without having to create and destroy embryos -- iPSCs .  

IPSCs are ordinary somatic cells, such as a skin cell, that have been reprogrammed into a fully pluripotent state, like an embryonic stem cell.  Among the great benefits of this breakthrough in reprogramming cells is that it gives researchers a ready and virtually unlimited supply of pluripotent stem cells without having to destroy human embryos.  Nor would women be subject to health risks and exploitation because of the large number of eggs necessary for research cloning.

Moreover, iPSCs are patient specific, i.e., they share the same genetic material with the donor of the reprogrammed somatic cell.  For many, the ability to generate patient specific stem cells for transplant was the holy grail of stem cell research.  The whole point behind cloning for research was to generate such cells by using SCNT to create an embryo that was the virtual genetic duplicate of the patient, and then destroy that embryo for his or her stem cells.    

With the advent of iPSCs, cloning for research became all but obsolete.  No less than Ian Wilmut, the scientist most associated with cloning for his role in creating Dolly the sheep, announced he was giving up on SCNT research to pursue iPSC research instead.  And the California Institute for Regenerative Medicine, established by voter referendum in 1997 with a 10 year, $3 billion budget and a mandate to give preferential funding to human embryonic stem cell research (hESCR), including cloning for research, has been noticeably stingy in grants given to the latter (in fact, the number of grants CIRM has given over the years to adult stem cell research projects has proven greater than those for hESCR and SCNT).

No doubt the idea of cloning will continue to provide fodder for science fiction writers and their fans well into the future.  And it will keep some researchers buzzing.

But the supposed potential of human cloning for research to be a practical, therapeutic tool to actually help treat patients, already seems like a thing of the past.

Actions Speak Louder Than Words

Late August saw another round of grants from the California Institute for Regenerative Medicine (CIRM).

CIRM, you may recall, was established by a voter-approved referendum in 2004, with a $3 billion budget (plus another $3 billion in interest) over 10 years.  Its mission was to fund stem cell research, with funding preference to go to human embryonic stem cell research (hESCR) and to human cloning for research. 

But as the late August grants (again) show, things have not turned out as anticipated. 

This round of grants is intended to encourage researchers to form teams in an effort to quicken the time frame for translating research into actual clinical trials.  As CIRM put it, the grants would encourage “the most promising approaches towards and into early phase clinical trials.”

So what are these “most promising approaches” to actually producing early phase clinical trials, especially in terms of CIRM’s mandate to give preferential treatment to hESCR and human cloning for research?

Well, projects involving adult stem cells were preferred over those utilizing embryonic stem cells – and by a whopping 3 to 1 margin. 

In total, CIRM handed out 19 grants amounting to $1.8 million in preliminary funding (a second round of grants will be worth up to $20 million each).  Of those 19, 16 involved the potential therapeutic uses of stem cells (other proposals addressed other research areas, such as proposals to study cancer stem cells).  Of those 16, 12 involved proposals to use adult stem and other non-embryonic stem cells to treat heart disease, Huntington’s and Alzheimer’s, among others. Eleven will use actual adult stem cells, while 1 will use non-embryonic induced pluripotent stem cells (iPSCs).

Only 4 of the approved grants were for projects using hESCs.  No grants were awarded to research using cloned human embryos.

This latest round of grants actually continues a pattern that has been developing for some time at CIRM. 

In October, 2009, a major round of CIRM grants totaling some $230 million went to 14 research projects – but only 4 of them involved the use of hESCs.  The rest, again, went to research using adult stem cells or more conventional approaches, such as drugs to treat cancer. 

The irony of an institute founded to give preferential support to hESCR and human cloning for research instead giving such extensive support to adult stem cell research was not lost to observers at the time.  

“In something of an irony, little of it is going to the reason the institute exists - to work with human embryonic stem cells,” the Knight Science Journalism Tracker commented.

The San Diego Union-Tribune noted: “One irony of the latest grants is that much of the work they support does not involve human embryonic stem cells, a contentious area because it requires the destruction of embryos. Bush administration funding restrictions on that work were a big reason the California institute was launched to begin with, but many of the current projects use less-controversial adult stem cells”.

And the New York Times said that the large number of grants to adult stem cell research compared to embryonic is a “tacit acknowledgment that the promise of human embryonic stem cells is still far in the future.”

While CIRM’s favoring of adult stem cell research may be ironic, it is nonetheless understandable.  CIRM knows it needs to show some tangible results to California taxpayers for what will eventually be their $6 billion investment in stem cell research.

Hype -- especially the hype over ESCR that played such a large role in CIRM’s creation – will only get you so far.  And as it noted in handing out the current round of grants, CIRM gives priority to those project which seem the “most promising” to actually result in clinical trials. 

Once again, adult stem research is proving the most promising approach toward achieving both these goals.

And the promise of hESCR still remains “far in the future.”

Scientific Sense and the Sense of Propriety

A student who was doing a project on stem cell research emailed DNH a series of questions, one of which was “Is there any scientific reason to not continue with stem cell research?”

It seems like a reasonable question, given that stem cell research – or, more correctly, human embryonic stem cell research (hESCR) --  is and remains very controversial.  The controversy arises over the ethics of destroying human embryos for research, which is the necessary basis of hESCR.  But, the questioner wanted to know, what about the science? Are there any scientific reasons for ending hESCR?

After some thought though, it becomes clear that the student’s question is based on a misguided assumption, but one that nonetheless has underlined much of the debate over the propriety of pursuing hESCR.  This assumption is that “science” is the ultimate arbiter of what “science” should or should not do.  Throughout the national debate on hESCR we frequently heard the argument that we should be “guided by the science” in determining whether the research should receive federal funding, and that those outside the scientific community had no business telling scientists what they could or could not do.  The ultimate logic of this assumption is that scientists should have the final say on what research projects to pursue, whatever – or in spite of— the ethical objections, however sound, other voices may raise.

Which brings us to a fascinating article in the August issue of Wired: “Seven Creepy Experiments That Could Teach Us So Much (If They Weren’t So Wrong).    

The title pretty much tells the story.  The article highlights seven proposed experiments that --  from a purely scientific perspective --  would benefit us and add to our store of knowledge, but would not (at least at present) be undertaken because of the ethical objections they raise. 

For example, one experiment calls for testing potentially toxic substances in human subjects, rather than in animals.  The benefits from such an experiment should be obvious – as should the ethical objections to it.   Another experiment calls for inserting a “reporter” gene into an embryo in order to directly observe the process of how genes turn on and off and guide the development of the embryo from just a few cells into a fully differentiated human.  “If ethics weren’t an issue” the author notes, the knowledge gained from such an experiment could provide a real boost to the field of regenerative medicine.  Yet another experiment proposes to breed a human-chimpanzee hybrid.  The experiment could help answer many questions surrounding evolution and the origins of humans.  The late biologist Steven Jay Gould called such a proposal “the most potentially interesting and ethically unacceptable experiment I can imagine.”

All of these proposed experiments are as scientifically sound as they are ethically unsound.  All of them, from a purely scientific perspective, make sense, are designed to be carried out as efficiently and effectively as possible, and would add to our store of knowledge and even result in tangible benefits such as preventing and treating disease. 

So, if we were guided first and foremost by science, we would be doing these experiments.  But because of the ethics, we do not.  In other words, while science may be competent to tell us what we are able to do, and the most efficient way to do it, it is not within the competence of science to tell us what we should or should not do.  That judgment must come from outside of science. 

The same is true for human embryonic stem cell research.  Which is why the argument that we should let the “science” determine whether or not to pursue hESCR is so misleading and disingenuous.  As the examples from Wired show, science can make no such determination; it can only come from disciplines outside of science.

During one of the many Congressional hearings on stem cell research, Dr. Stuart Newman, a professor at New York Medical College, laid out the following scenario: in addition to human embryonic stem cells there is another class of pluripotent stem cells called human embryonic germ cells (n.b., Dr. Newman’s testimony [3/5/02] was given before the discovery of induced pluripotent stem cells [iPSCs]).  “On purely scientific grounds,” Newman noted, “embryo germ cells show even greater promise than embryo stem cells.”  However, while embryonic stem cells are typically harvested no later than seven days after conception, embryonic germ cells are derived from eight to nine week embryos.  

Deriving cells from such later term embryos would now be a “hot potato” Newman noted, but not for any scientific reason: “I emphasize that all of this makes perfectly good scientific and medical sense. The only thing that stands in the way is the sense of propriety concerning the uses to which developing human embryos and fetuses may be put. Some of you may draw the line at the tiny clump of cells, others at the two-month embryo, still others somewhat short of full term. Wherever each of you decides to leave this particular train, there will be others who will insert their right to take it to the next station” (please note, Dr. Newman favors abortion rights and noted at the outset of his testimony that his views “do not derive from any notion of the sanctity of the embryo”).

“All of this makes perfectly good scientific and medical sense.” In the context of hESCR, letting science lead the way leads to the commodification of human life.  It turns human life – and the human embryo is human life – into a commodity to be exploited as a means to what someone else deems a worthy end.  And worthy has now come to include something as mundane as desiring smoother skin, as some cosmetic companies now boast the use of fetal cells in their preparations).     

If we used the same standard proponents used to justify hESCR – let “science” have the final say – there would be no reason to judge as “creepy” the experiments described in Wired.   But they are, as is destroying and exploiting human life as a means to someone else’s potential benefit.      

Add hESCR as the eighth experiment on Wired’s list.

New Hope for Treating Kidney Disease

Two recent studies have been published which once again highlight the vast potential of induced pluripotent stems cells (iPSCs) to benefit patients, this time patients with kidney disease.  Both studies were published in the Journal of the American Society of Nephrology

In the first, scientists at Australia’s Monash University, led by Dr. Sharon Ricardo, extracted human kidney cells and reprogrammed them into iPS cells, which could then be transformed into other kidney cells that could potentially be transplanted to repair the damaged organ. 

In the second report, researchers at the Chinese Academy of Sciences in Guangzhou, led by Dr. Miguel Esteban, found they could gather kidney cells from a patient’s urine and reprogram them into iPS cells.  The reprogrammed cells, also, could be transformed into other kidney cells for potential transplant.  An additional benefit is that scientists could freeze the urine cells for future use when needed.

Other researchers into kidney diseases hailed the reports.  Dr. Ivonne Schulman, an assistant professor of clinical medicine and nephrologist at the University of Miami's Interdisciplinary Stem Cell Institute in Florida, said that "Two papers back-to-back show that two different kidney cell types are able to be reprogrammed…This is very significant."  She added: "It could theoretically help all types of kidney disease…it just depends on the ability of these cells to differentiate back into the cell types needed for that disease."

Dr. Jeffrey I. Silberzweig, co-medical director of the Rogosin Institute Manhattan Dialysis Center in New York City, also welcomed the reports: "The idea that you can have the ability to do stem cell transplants during the early stage of kidney disease and regenerate the damaged part of the kidney would be a tremendous benefit for patients and the country as a whole."

In addition to their potential use in transplants, the reprogrammed kidney cells could also be beneficial for disease modeling, to study the origins and development of kidney disease and for drug screening of new medications to treat kidney disease.

Both these studies come soon after a report that scientists working with insulin producing beta cells successfully reprogrammed such cells to become iPSCs, and that these reprogrammed cells were very efficient in producing more beta cells for potential transplant.  The researchers believe the reason for such efficiency is because the reprogrammed cells retain a “memory” of their origin as beta cells so they already have an “understanding,” as it were, of their purpose to generate additional beta cells.  It may well be that scientists working with the reprogrammed kidney cells will find the same phenomenon at work here as well (see previous blog “Advances in Diabetes Research –Without hESCs”).

Meanwhile, research using human embryonic stem cells (hESCs) to treat kidney disease shows that it has the potential to generate, well, a lot of talk about the potential of hESCs to treat kidney disease…

Advances in Diabetes Research -- without hESCs

Prominent foundations for diabetes research, led by the Juvenile Diabetes Research Foundation, have long been leading advocates for human embryonic stem cell research (hESCR), giving scant attention to the promise of adult stem cells and other alternatives to embryonic stem cells to treat this disease.

How ironic, then, that two of the most promising advances in treating diabetes have nothing at all to do with embryonic stem cells.

First, a little background. With regard to diabetes, it has long been medical orthodoxy that once the body’s insulin producing beta cells, found in the pancreas, are destroyed they are gone forever – they do not regenerate. Thus, the promise of stem cells to treat diabetes was that they could be coaxed into becoming insulin producing cells suitable for transplantation for those suffering with diabetes. Proponents of hESCR claimed that embryonic stem cells would prove ideal for this task.

It seems things are turning out differently from what they so confidently predicted.

Scientists have actually had very disappointing results in their efforts to transform hESCs into pure colonies of beta cells suitable for transplant.

However, in a recent issue of Cell Stem Cell, scientists report that induced pluripotent stem cells (iPSCs) derived from beta cells are very efficient at generating insulin producing cells that could be used for transplant.

The scientists involved in the study believe that because the iPSCs are derived from beta cells, they retain a “memory of what they once were,” thus making them actually more efficient than embryonic stem cells for generating insulin producing cells.

Lead researcher Professor Shimon Efrat of the Tel Aviv University stated, “This discovery promises to advance the development of cell replacement therapy for diabetics, possibly leading to an effective alternative to organ transplants.” He added, “When generated from human beta cells, pluripotent stem cells, these memory cells act as though they are receiving a prompt from their past life; the cells already have some understanding of their purpose, making them more efficient in generating beta cells.”

As promising as this development is, others involved in research on diabetes point out that as long as the body continues its auto-immune attack on the pancreas, where the insulin producing beta cells are found, transplanting new beta cells will not provide a permanent cure – the body will just attack these newly transplanted cells as well. So these researchers have turned their attention on finding ways to stop the auto-immune reaction against the beta cells.

In June, before a meeting of the American Diabetes Association in San Diego, Dr. Denise Faustman presented very positive findings in her research to stop the underlying auto-immune attack responsible for diabetes.

In her research with mice (which Do No Harm has closely followed and reported on over the years) Dr. Faustman found that BCG, a relatively inexpensive vaccine typically used to treat tuberculosis, also stops the auto-immune attack that destroys the insulin producing cells in the pancreas. At first, she thought this was just the first step in treatment, the second being to transplant donated islet cells now that the threat of attack had been ended.

But to her amazement, it seemed that the pancreas began to regenerate islet cells on its own, without the need for any newly-transplanted cells. This directly contradicted the prevailing orthodoxy that once an insulin producing cell is gone, it is gone (scientific consensus, anyone?). When she first published her results in 2001, they were so controversial that she was not allowed to use the term “regenerate” because the scientific community “knew” an organ could not regenerate itself.

In a 2003 paper published in Science, Faustman confirmed her finding and speculated the adult stem cells found in the spleen were responsible for aiding the pancreas to regenerate the islet cells.

This was met with even greater skepticism. Nonetheless, by 2007 her findings had been replicated in six other labs, both here and overseas.

At the June meeting in San Diego of the ADA, Faustman reported positive findings for the first use of her protocol in humans. Six patients who were diagnosed with diabetes for an average of 15 years were divided into one group that received low-level doses of the BCG vaccine and one group that received a placebo. All those receiving the vaccine showed reduced levels of the cell responsible for attacking the pancreas, as well as indications that new production of insulin had begun.

Faustman now hopes to expand her trial with a larger number of patients and to win FDA approval to increase the amount of BCG used to treat them.

So within a month of each other, we hear of two very promising findings in the treatment of diabetes. One showed that iPSCs should prove very useful in producing insulin producing cells for transplant should they be needed. And the other showed that transplants may not be needed at all if the auto-immune attack on the pancreas can be stopped, allowing the cells to regenerate on their own.

And the thundering silence you hear are the reports about all the advances using hESCs to treat diabetes.

The Spinning Never Stops

please note: this blog was originally posted on 6/21/11

The National Science Foundation (NSF) on June 10 issued a press release calling attention to a study the NSF funded on stem cell research and published in the June 9 issue of the scientific journal Cell.

“Social scientists study impact of human adult stem cell research” the headline reads, followed by: “Researchers say human adult and embryonic stem cell research is complementary.”

The release then sums up the study’s main finding: “New research says studying both adult and embryonic stem cells can benefit medical science, but banning the study of either type could harm studies of the other.” The remainder of the release elaborates on this point to the effect that any effort to cut back or eliminate federal funding for human embryonic stem cell research (hESCR) would have negative effects for adult stem cell research as well.

Now Cell is a very specialized scientific journal with a subscription rate of $212 annually, meaning most outside the scientific/research community will not have access to the full study described in the press release; for interested lay people, any information on the study will in all likelihood come from this press release.

But if you do read the original study in full, you will be struck by a rather amazing fact: what the press release reports actually has nothing to do with the study itself.

The study reports on the intersection of research using induced pluripotent stem cells iPSCs) and human embryonic stem cells (hESCs). It has nothing at all to do with adult stem cell research, adult stem cell research is never addressed or discussed and in fact the word “adult” only occurs twice in the whole study and on the last page at that (one is a reference to “two adult stem cell researchers” who brought a lawsuit challenging federal funding of hESCR and the other is at the very end of the study reflecting an opinion of the authors).

So outrageous was the deceptiveness of the press release vis-a-vis the actual study itself that David Prentice, PhD, a Do No Harm founding member and Senior Fellow for Life Sciences at the Family Research Council, said he was “appalled that the National Science Foundation would publish an ideological paper that promotes embryo-destructive research by attempting to link such research to advances in iPS cell research. While even this possible linkage is questionable based on the limits of the data presented, NSF in its headlong rush to promote ES cell research goes over the edge in confusing and prejudicing the public.”

So where’s the confusion and why does it matter?

By equating iPSCs with adult stem cells, the press release deliberately confuses what are two separate and very distinct types of stem cells. As Dr. Prentice noted in his statement on the study and release: “While iPS cells provide an ethical method to form pluripotent stem cells almost identical to ES cells, from any person, but without embryo destruction, iPS cells are not adult stem cells” (emphasis added).

Why does this matter?

Because the release (which, as already noted, is where most interested lay people would find out about this study) would have you believe that the proven and ongoing success of adult stem cells to actually provide real therapeutic benefits to patients depends on continued federal funding for embryo destructive stem cell research. And this is simply not true, nor has it ever been true.

Adult stem cells have provided therapeutic benefits for human patients for 73 diseases and conditions, including spinal cord injury; heart disease; multiple sclerosis; lupus; sickle cell anemia and Parkinson’s, among others. In contrast, only two patients have been treated with hESCs, both in a clinical trial for spinal cord injury (no results have been reported yet) and two more are slated to receive injections of hESCs for two different types of vision loss.

The success that adult stem cell research has had in treating patients did not come from the use of hESCs and does not in any way depend on continued federal funding for embryo-destructive research. In fact, the case could be made that the exact opposite is true: continued federal funding for hESCR may actually be hurting adult stem cell research by drawing limited funds away from it -- the very research that is actually helping patients now. As evidence of this, consider that a federal appeals court agreed with two adult stem cell researchers that by funding ESC research, the Administration is depriving adult stem cell researchers of the opportunity they would otherwise have to access these funds and advance stem cell research that is ethically non-controversial and which everyone accepts. This “competitive disadvantage” is what gave the two adult stem cell researchers standing to sue the Department of Health and Human Services.

The NSF press release is just another misdirection, the latest in a long string of deceptions and falsehoods proponents of embryo-destructive research have used to advance their agenda.

New Advances

An article in the current issue of the New Scientist focuses on some recent – and major – developments in the both real and potential therapeutic benefits from stem cells.

“Stem cell therapies ready for the real world” the article states.

Ready for the real world. For all the hype over embryonic stem cells for at least 10 years now, you might think the article would be about them, right?

Wrong. The article instead celebrates ongoing therapeutic advances utilizing adult stem cells.

The first involves the successful transplant of an artificial trachea (windpipe) into a patient whose own, cancerous trachea had been removed. Modeled on the diseased trachea, a new one was constructed of a “novel polymeric material.” This was then coated, inside and out, with the patient’s own cells that had been derived from stem cells in the patient’s bone marrow. The Karolinska University Hospital in Stockholm, Sweden, where the transplant took place, issued a statement noting that "because the cells used to regenerate the trachea were the patient's own, there has been no rejection of the transplant and the patient is not taking (anti-rejection) drugs." The patient has recovered and been sent home.

The next advance noted in the New Scientist involves a South Korean company which became the first in the world to receive official approval for the sale and use of a stem cell treatment for heart disease. Called “Hearticellgram-AMI” the treatment takes the patient’s own bone marrow derived adult stem cells, multiplies and then injects them directly into the coronary arteries to regenerate cells damaged or lost due to acute myocardial infarction.

The article also refers to a recent development that saw Japanese scientists successfully grow teeth using tissue stem cells derived from fetal mice (the New Scientist mistakenly refers to them as “embryonic” stem cells). The treated stem cells were grown in a box placed within a mouse’s kidney; they then developed into fully formed teeth with ligament and bone; when transplanted into the mouse, the teeth connected with the animal’s blood and nerve supply to function as naturally formed teeth. According to one news report, Professor David Leavesley, from the Institute of Health and Biomedical Innovation at Queensland (Australia) University of Technology, said this development suggested adult stem cell could be used to create other complex organs such a liver, pancreas and even eyes.

Finally, the article notes that scientists had isolated the “mother” stem cell for blood, from which both red and white blood cells are derived. “This raises the possibility of being able to completely reconstitute a patient's blood - perhaps after chemotherapy for leukaemia - from a single cell extracted from bone marrow before treatment began,” the New Scientist notes. The study was published in Science.

Embryonic stem cells are nowhere even close to duplicating these advances. Yet more reason to direct limited resources away from embryonic stem cell research and into research that is actually helping patients…adult stem cell research.

Ethical Problems with Adult Stem Cell Research?

Using a rather unusual approach to address the inherent ethical issues surrounding destructive human embryonic stem cell research (hESCR), Dr. Insoo Hyun, director of the Case Western Reserve Stem Cell Ethics Center, seeks to divert attention from those ethical difficulties by pointing to what he supposes is the ethical baggage carried by adult and induced pluripotent stem cell research.

First, the background: hESCR is controversial because of the inherent ethical problem that it requires the destruction of human life – at its embryonic stage – to provide a possible benefit to others. Inherent to hESCR is the fact that it commodifies and then destroys human life, making such destruction the means to another’s potentially beneficial ends.

So, according to Prof. Hyun, what are the ethical controversies associated with research using induced pluripotent stem cells (iPSCs) and adult stem cells?

Well, one day in the future someone may discover a way to direct iPSCs to become functioning egg and sperm cells. These could, for example, be used to help someone who has lost their fertility because of chemotherapy treatment for cancer, Hyun posits. But he further posits that “It may also offer hope for homosexual couples who may want to produce biologically related children together (men would be able to produce both sperm and eggs; women could not produce sperm cells because they lack the Y chromosome)”.

He comments: “Undoubtedly there will be individuals who would support the former but strongly oppose the latter”.

That is undoubtedly true.  The adoption of children by homosexual couples is already a contentious issue. Undoubtedly it would be more so if a homosexual male used induced pluripotent stem cells to become both the genetic mother and father of a child. And no doubt this would also be ethically contentious if a heterosexual male attempted to do the same. But none of the ethical issues that would arise from such a circumstance has anything inherent to do with the ethics of research using iPSCs.

Remember, one of the two researchers credited with discovering iPSCs, Shinya Yamanaka, did so precisely because he was motivated to overcome the ethical problems inherent in hESCR. Recalling looking at a human embryo through a microscope several years earlier, Yamanaka said: ''When I saw the embryo, I suddenly realized there was such a small difference between it and my daughters…I thought, we can't keep destroying embryos for our research. There must be another way'' (“Risk Taking in His Genes;” The New York Times, 12/11/07).

There was and Yamanaka succeeded in discovering it. There are no inherent ethical problems associated with research using iPSCs. That someone, someday, may use them for ethically dubious purposes, such as the one Prof. Hyun posits, does not change this fact. Is the use of morphine and other powerful pain-killers in providing hospice care inherently unethical because some want to push it into the ethically questionable area of assisted suicide and euthanasia?

And what are the ethical problems associated with adult stem cells? Prof. Hyun asserts that adult stem cells have in effect become enablers of “stem cell tourism - i.e. desperate patients traveling across borders for fraudulent therapies.”

Well, the same holds true for hESCs. India’s Geeta Shroff has lured hundreds of patients from around the world to her clinic claiming—without a shred of evidence – to use hESCs to help them.

More to the point, the peddling of snake oil is as old as the practice of medicine itself. Just because quacks peddle fake treatments and medicines to make a buck does not make the fields of medicine and pharmacology, and those who honorably serve in those fields, inherently unethical.

Another ethical problem Prof. Hyun asserts regarding adult stem cell research is that part of it involves using stem cells obtained from abortive fetuses, which many consider unethical.

This statement is at best misleading. It’s no doubt true that many find using research tissue from abortive fetuses to be unethical. But in terms of the embryonic stem cell debate, Prof. Hyun seems to be the only one raising the issue of stem cells derived from abortive fetuses (that public policy debate took place over two decades ago).

While true that both fetal stem cells and adult stem cells are partly differentiated and tissue specific cells, in terms of the public policy debate “adult stem cell research” has always referred to research using cells obtained after birth, whether it be from the patient him/herself or other sources such as umbilical cord blood, solid cord, placenta, amniotic fluid or adipose (fat) tissue. All sides in the public policy debate over hESCR agree that research using cells from these sources is ethically non-contentious. That some are doing research on tissue specific stem cells derived from abortive fetuses does not change this fact.

Furthermore, in terms of actually providing therapeutic benefits to patients, not one of the 73 diseases or conditions that the Do No Harm coalition lists on its website, using peer-reviewed literature, were treated with fetal stem cells. All of the benefits came from using adult stem cells from the patient him/herself or from the other sources listed above, or from donors. As far as Do No Harm knows, no therapeutic benefits to patients have been shown using stem cells from abortive fetuses. For Prof. Hyun to introduce stem cells derived from abortive fetuses into the public policy debate on hESCR is a non sequitor at best and a rather transparent, clumsy attempt to discredit adult stem cell research on ethical grounds at worst.

Especially because fetal tissue has shown the opposite of therapeutic benefits to patients. A May, 1996, Neurology article disclosed a patient's death caused by an experiment in China in which fetal nerve cells and embryo cells were transplanted into a human Parkinson's patient. After briefly improving, the patient died unexpectedly. His autopsy showed not only that the tissue graft had failed to generate new nerve cells to treat his disease as had been hoped; even worse the man's death was caused by the unexpected growth of bone, skin, and hair in his brain, material authors theorized resulted from the transformation of undifferentiated stem cells into non-neural, and therefore deadly, tissues.

In a clinical trial reported in March, 2001 in The New England Journal of Medicine, researchers using fetal tissue to treat Parkinson’s patients reported that 15% of those treated saw their condition worsen, as they developed uncontrollable, disabling movements. Dr. Paul Greene, a member of the team conducting the trial called this development “absolutely devastating” to the patients and called for an end to fetal tissue transplants.

In 2009, scientists published evidence showing that a young Israeli boy’s brain and spinal tumors were derived from injections of fetal stem cells. No one confused them with adult stem cells, when they identified the source of the cells, when fetal stem cell researchers took pains to claim their fetal stem cells were purified, unlike those injected into the Israeli boy, or when the FDA put a fetal stem cell company’s clinical trial on hold.

Prof. Hyun’s whole effort to divert attention from the very real, inherent ethical problems with hESC by trying to cast contrived ethical shadows over adult and induced pluripotent stem cell research is misinforming and misleading.