More Embryonic Stem Cell Hype, Less Reality and Ethics

Dr. Prentice is Senior Fellow for Life Sciences at the Family Research Council (FRC) and a founding member of Do No Harm: The Coalition of Americans for Research Ethics.  This blog was originally posted by Dr. Prentice at the FRC website and is reposted here with his permission

More Embryonic Stem Cell Hype, Less Reality and Ethics

Excitement over a newly-released paper on stem cells making insulin is a tribute to the Harvard stem cell Press Office.

The actual report is quite a bit less earth-shaking than you might be led to believe by the Harvard press office.  The science itself, in a paper from the lab of Dr. Doug Melton published in the journal Cell, provides an incremental improvement in the derivation of functional (insulin-secreting) beta cells.  Melton’s lab developed an improved method to generate millions of insulin-secreting cells from human embryonic stem cells (hESC, which require the destruction of a young human being) and from human induced pluripotent stem cells (hiPSC, the stem cells created from normal skin cells, without using embryos.)  The multistep protocol, which took 4-5 weeks and treatment with eleven different factors, produced insulin-secreting cells which the paper termed “SC-β” cells, that secreted about half the amount of insulin as normal adult beta cells from the pancreas.  Previous attempts resulted in insulin-secreting cells that were immature and more like fetal than adult cells.  In this new report, the authors note that global gene expression analysis showed “SC-β cells made ex vivo are most similar, but not completely identical, to cadaveric beta cells.”  The SC-β cells secreted insulin in response to different glucose levels in the lab dish and when injected into immunocompromised mice.  When the new SC-β cells were tested in a diabetic mouse model, 5 out of 6 mice survived up to 4 months, compared to 1 out of 6 control mice.

Embryonic Stem Cells Unnecessary

The paper itself makes the case that embryonic stem cells are not needed for even this incremental advance or any subsequent work.  The authors tested batches of SC-β cells made from hESC as well as from hiPSC.  The results were equivalent no matter the starting cell type.  So for any future production of SC-β cells, the authors have shown that no embryonic stem cells are necessary.

Unanswered Questions—Transplant Rejection and Safety

The paper and its results do not address some significant questions related to these new SC-β cells—immune rejection and safety (tumor formation).  The cells were tested in immunocompromised mice, so they were free from immune attack.  This will be an issue in any potential treatment if the SC-β cells are derived from hESC.  Use of hiPSC made from a diabetic patient might provide a way around immune attack on the SC-β.

Safety, especially from aberrant cell growth including tumor formation, is always an issue with pluripotent stem cells, especially hESC.  In the mouse experiment, the authors note that large masses of tumors were not seen, but also point out: “A much larger number of transplants and more extensive histological examination will be needed to assess the possibility of undesired cell growth in the grafts.” 

While the Harvard press release discusses testing of an implantation device to protect SC-β cells implanted into mice, this simply makes the point that the issues of immune rejection, as well as keeping the implanted cells from running free in the patient, have not been tackled.  In the end, this combination device is simply a potential cell-based insulin pump, not a cure for diabetes.

Embryonic Stem Cells Questionable

In the past, the obsession with ESC has led to some questionable claims about their abilities to treat diabetes.  Their ability to make authentic insulin, in quantities that would be useful, were first trumpeted and then shown to be incorrect and even artifactual (see, e.g., here and here).  In fact, teratoma formation was often the result or even the inducer of insulin secretion from ESC.

In fact, the high-efficiency production of insulin-secreting cells from hESC and hiPSC has been done before today’s announcement—similar results were published in September 2014 by Rezania et al.  That report also failed to address the questions that the current paper did not address, such as transplant rejection.

Other Ways to Make Insulin-Secreting Cells—No Embryonic Stem Cells Needed

The obsession with ESC continues to make headlines, but not help patients.  Even Melton’s lab has shown various other ways to make insulin-secreting cells, including: stimulating growth of pancreatic beta cells (which improves glucose tolerance) by expression of betatrophin growth factor; direct reprogramming to turn other pancreatic cells into new insulin-secreting cells within the body; and regeneration of insulin-secreting beta cells by the normal pancreas, achieved by stopping the autoimmune attack typical of Type 1 diabetes.

This latter result is important, because it addresses the underlying cause of Type 1 diabetes:  the autoimmune attack on the insulin-secreting cells.  Stopping the autoimmune destruction of beta cells allows the body to regenerate normal, insulin-secreting cells from the body’s own adult stem cells and progenitors.

Other scientists have shown the real promise of this approach. 

Faustman et al. used a simple treatment with BCG to achieve a transient improvement in patients, providing proof of principle for the concept.

Zhao et al. used cord blood-derived adult stem cells to “re-educate” the immune cells of diabetic patients, providing lasting improvement in metabolic control.

The best results thus far for Type 1 diabetic patients has resulted from the collaboration of Voltarelli and Burt, using immunosuppression to remove rogue immune cells followed by transplantation of the patient’s own adult stem cells.  Their success was reported in 2007 and in 2009 in JAMA.  This was able to induce complete remission (insulin independence) in most patients with early onset type 1 diabetes mellitus.  As they noted after publication of their second paper in 2009: “It's the first therapy for patients that leaves them treatment-free — no insulin, no immune suppression for almost five years.”  Sadly, Dr. Voltarelli died in 2012, but his team continues to work on effective patient treatments.

Adult stem cells remain the gold standard for real patient treatments.

Non-Embryonic Stem Cell “Alternatives” Again Taking the Lead

The New York Times has long been – and continues to be – a vocal advocate for human embryonic stem cell research (e.g., here).  From the time hESCs were first isolated in 1998, the Times has published numerous editorials endorsing the research and calling for federal funding of it.

So a recent Times story providing a look at where stem cell research stands today was – no doubt unintentionally – revealing.

In marked contrast to the delirious enthusiasm with which advocates promoted hESCR,  promising it would lead to cures for virtually all diseases and conditions (one prominent politician at the time said human embryonic stem cells could become a “veritable fountain of youth”), the tone of the article is far more cautious and restrained in assessing what advances have actually been made to date in the field of  stem cell research.

The article’s title sets the newly sober tone: “The Trials of Stem Cell Therapy;” “trial” here can mean “to test,” as in a clinical trial, but also “difficult” as in the difficulties researchers face in bringing stem cells to therapy.  The article calls the process “halting” and notes that “progress has been slow.” 

But while progress may be “slow” and “halting” the article does note some promising developments.

And they are all being accomplished with adult and other non-embryonic sources of stem cells.

The article opens anecdotally, with the story of a heart disease patient who lost one-third of his heart’s functioning ability.  The patient volunteered for a medical trial in which researchers injected adult stem cells, derived from the patient’s own bone-marrow, directly into his heart.  While the article notes that “It’s impossible to know for sure whether the bone marrow cells’ descendants became heart muscle cells or if repairs were spurred some other way,” doctors nonetheless were able to tell the patient that his heart “is one-third of the way back to normal.”  The patient himself is quoted saying, “My quality of life is like night and day to before the treatment.”

The article further notes there are “as many as 4,500 clinical trials involving stem cells” currently underway in the U.S. for a whole host of diseases and conditions, but it does not clarify that virtually all of these trials are using non-embryonic stem cells.  That’s because only three trials using embryonic stem cells have been approved here: two are testing hESCs in two types of macular degeneration; they are ongoing and valid results have not yet been reported.  The third approved trial was for spinal cord injury; however, it was halted in 2011, a little over a year after it began. The California-based Asterias Biotherapeutics Inc. recently announced that it would resume the trial.

Another sign of progress mentioned in the article is that the California Institute of Regenerative Medicine (CIRM) has awarded over $2 billion since 2006 to stem cell researchers, and that it is enrolling patients for 10 clinical trials.

Unmentioned again, is the fact that the clear majority of these trials all involve non-embryonic stem cells.

A look at CIRM’s website shows a list of eight clinical trials “directly funded by grants from CIRM.”  Of these eight, just one employed embryonic stem cells, and it was the one mentioned above for spinal cord injury that was eventually shut down.

As for CIRM’s $2 billion in research grants awarded, this blog has noted several times that, over the years, more and more of the money awarded by CIRM has gone to fund adult and other non-embryonic stem cell research projects (here, here, and here).

The article also references the work being done using non-embryonic, induced pluripotent stem cells (iPSCs) for disease modeling and drug testing.  Dr.  Kevin Eggan of Harvard, the article notes, has used the iPSC process to create patient-specific stem cells from two patients with ALS (i.e., Lou Gehrig’s disease) and then coaxed those cells into becoming neurons.  Dr. Eggan noticed a signaling defect between those neurons that appeared to cause the neural degeneration typical of ALS. After extensive testing on the iPSC-derived neurons, Dr. Eggan has singled out a drug currently used to treat epilepsy that may correct the defect in the ALS neurons, which he expects to test on patients by the end of this year.

Commenting on the use of iPSCs for such disease modeling and drug testing, Dr. Eggan said that “the whole process is something that’s never been remotely possible before.”

Other researchers agree.  Earlier this year, in July, scientists used this same method to study Down syndrome, allowing them to discover a possible cause of the condition and a possible drug to treat it. “The advent of induced pluripotent stem cell technology has created exciting new approaches to model neurodevelopmental and neurodegenerative diseases for the study of pathogenesis and for drug screening,” said David Pleasure, a coauthor of the study.

The more sober approach to reporting on the therapeutic progress of stem cell research, as reflected in this New York Times article is, no doubt, a welcome development.

But however “halting” such progress may be, it is important to note, as the examples cited by the Times article – however unwittingly – show, that virtually all of it is being made on the non-embryonic stem cell front.

Adult Taking Charge

The California Institute for Regenerative Medicine’s (CIRM) choice for its new head would have been unthinkable when the institute was first established almost 10 years ago.   Yet today, it seems fitting, given the direction stem cell research has taken over the same decade.

C. Randal Mills recently took over as CIRM’s new president.  Before taking his new post, Mills had been president and CEO of Osiris Therapeutics.  Osiris pursues therapies based on stem cell research, so in that regard, Mill’s appointment to head up CIRM would seem highly appropriate.

However, Osiris pursues non-embryonic, adult stem cell research, particularly with mesenchymal stem cells.  That why his appointment would have been so unthinkable at CIRM’s founding.

Apart from the federal government, CIRM is the nation’s largest funder of stem cell research.  As noted before in this blogspot, CIRM was established for the express purpose of giving priority funding for embryonic stem cell research and SCNT (i.e., cloning) over all other avenues of stem cell research.  And in its early years, CIRM did just that.  But over the years, more and more of CIRM’s grants have gone to support adult and other avenues of non-embryonic stem cell research such as induced pluripotent stem cell (iPSC) research.  So in this regard, Mill’s appointment to head CIRM today makes perfect sense.

Mills succeeds Alan Trounson as president of CIRM.  Trounson was an enthusiastic supporter of human embryonic stem cell research (hESCR), being one of the first Australian researchers to have isolated hESCs.  

In contrast, Mills has said he is “agnostic” when it comes to stem cell research, explaining that “for me, it is all about getting stem cell solutions to patients.”  In other words, Mills will not show any favoritism towards funding hESCR projects over non-embryonic stem cell research projects simply because they use embryonic stem cells; instead, funding will go to projects that have the greatest chance of “bringing treatments to patients, fast.”

In the context of CIRM’s founding mission to prioritize funding for hESCR, Mills’ apparent refusal to do so is remarkable.

It is, however an accurate reflection of how CIRM’s funding has been shifting over the years towards funding non-embryonic stem cell research projects.  In fact, it is an accurate reflection of how the whole field of regenerative medicine has shifted over the years.  Human embryonic stem cell research has completely failed to live up to the hype it generated after embryonic stem cells were first isolated in 1998. 

And no longer can proponents of hESCR fairly claim that it is the front-runner in the race to develop therapies for patients.  

Obsolete from the Start

The Washington Post gave a ringing endorsement to the recent news that scientists had  succeeded once again in creating cloned human embryos and then destroying them for their stem cells (about one year ago, another team of researchers became the world’s first to successfully create cloned embryos for their stem cells, but the original somatic cells used to create those cloned embryos came from newborns and aborted fetus; this time, the somatic cells came from a 35-year old and a 75-year old).

While noting that “some ethical worries are reasonable,” the Post nonetheless concludes such worries are “not enough reason to hold back this research.”

But in endorsing human cloning to obtain stem cells, the Post conveniently – and disingenuously – ignored certain facts about the cloning process of somatic cell nuclear transfer (SCNT).  This process does not create stem cells as the Post editorial misleadingly suggests; it creates a human embryo that is then destroyed to obtain its stem cells (the Post is hardly alone in this – numerous media outlets routinely use this journalistic sleight of hand when reporting on this subject to mislead readers into believing that SCNT directly produces stem cells).

Interestingly, the Post was not always so evasive. In an editorial from 10/2/94, the Post acknowledged cloning creates a human embryo and then opposed doing this for any reason, including research and despite any theoretical therapeutic benefits. “Do we want official support of human-cloning research in this country? Do we want it anywhere?” the Post’s editors asked, and they then answered “Potential medical benefits make this a close call, but on balance the answer must be no.

The Post even used a “slippery slope” argument to oppose cloning to create human embryos for research:

“Though therapeutic cloning for parts is not the same as nurturing a human clone to birth, research that perfected the techniques needed for the first purpose would bring the second closer. It is frequently said that, whatever governments do, a human being sooner or later will be cloned. That does not relieve governments of their obligation to do what they can to block that creepy outcome.”

Moreover, on 4/10/00, the Post's editors reaffirmed this stance, and specifically opposed cloning to create human embryos for stem cell research, saying it was “flat wrong,” “unconscionable,” “alarming,” “a step too far” and that “the government has no business funding it.”  The editorial also, like the earlier one, acknowledged cloning’s “slippery-slope potential.”

In addition to the ethical problems with human cloning that the Post once so clearly acknowledged, there are practical problems with it as well. 

Cloning remains notably inefficient, requiring a large number of eggs to produce very few stem cell lines, and the process of obtaining the eggs is not without risks, some serious, to women.

The South Korean team that in April became the second to successfully clone human embryos used 77 eggs to produce 2 stem cell lines from the cloned embryos they created and destroyed.  That’s a 3 percent success rate. 

Following this development, a New York team showed a slight increase in efficiency, using 71 eggs to produce 4 stem cell lines from the embryos they created and destroyed.  That’s a 5.6% success rate.

According to the National Academy of Sciences (NAS), the potential U.S. patient populations for stem cell-based therapies are as follows:

Condition                                Number of patients

Cardiovascular disease            58 million

Autoimmune diseases             30 million

Diabetes                                  16 million

Osteoporosis                           10 million

Cancers                                   8.2 million

Alzheimer’s disease                5.5 million

Parkinson’s disease                 5.5 million

Burns (severe)                         0.3 million

Spinal-cord injuries                 0.25 million

Birth defects                           0.15 million/year

These numbers give a total patient population of 133.9 million. But as the NAS notes, these conditions “occur in many forms and thus not every person with these diseases could potentially benefit from stem cell therapies.”  Conservatively, let us say that perhaps 10% of the total will be eligible for such therapies, or 13.4 million.

At a success rate of 3%, treating this patient population with stem cells derived from cloned embryos would require an astounding 446.6 million eggs.  This in turn would require 29.7 million women to donate the average of 15 eggs per donor.

At the more efficient rate of 5.6 percent, 239.3 million eggs would be required to treat the potential patients for stem cell therapies. 

But now let’s assume scientist refine their skill at cloning to achieve a 20 percent efficiency rate; some 67 million eggs would still be required.

Let’s go even further:  assume scientists achieve an astounding 90 percent efficiency rate; some 15 million eggs would still be required.

Now let’s say scientists became so skilled, they could produce genetically matched stem cells from donors without using any eggs at all!

Oh wait….they’ve already done that.

In 2007, Shinya Yamanaka became the first scientist to reprogram a donor’s somatic cell (such as a skin cell) to generate fully pluripotent, embryonic-like, genetically matched stem cells – no eggs or embryos involved.  “I’ve never used either,” Yamanaka said.  Yamanaka dubbed these stem cells “induced pluripotent stem cells” (iPSCs) because they are generated by inducing somatic cells into a pluripotent state.  So important was Yamanaka’s work to the field of regenerative medicine that within just 5 years of his discovery he was awarded a Nobel Prize.

  

Numerous scientists have hailed these cloning developments for the technical prowess involved in achieving them.  “I think part of the significance is technical and part of the significance is historical,” said John Gearhart, one of the first scientists to isolate, in 1998, human embryonic stem cells.

But they also noted that the therapeutic value for cloning is probably not much.  According to Gearhart,”the more we learn about reprogramming, the more I think IPS will be the one of choice."  Similarly, commenting on the work of the Oregon team that first succeeded in creating cloned human embryos in 2013, MIT professor Rudolf Jaenish, a vocal proponent of cloning for research, called that development “an outstanding issue of whether it would work in humans has been resolved,” but one, he added, that “has no clinical relevance.”

Non-embryonic stem cells are already achieving many of the therapeutic benefits the Post now posits as merely potential for stem cells derived from cloning. For example, scientists are producing whole organs from patients’ own adult stem cells, such as tracheas that have already saved people’s lives.

One wonders what has changed in the scientific and ethical calculus to make the Post now embrace what it once abhorred – especially since the argument for a need to go down this path is weaker than ever.