Myth of Perfect Stem Cell: meaning for ACT, Geron and field

 

There are a lot of myths in the stem cell field, some even embraced by some stem cell scientists such as the notion that teratoma are always benign.

But when we start talking about translating stem cell technology into the clinic, to the bedside, it is especially important to cast aside our myths, no matter how comforting they might be.

One such myth is the idea that there can be a perfect or entirely “normal” stem cell, one that is definitely 100% safe. Another myth is that we must reach that milestone to move forward with stem cell based-regenerative medicine therapies.

Sometimes this Perfect, Safe Stem Cell Myth takes the form of scientists arguing that actual specific types of stem cells are already proven 100% safe.

Another form of this myth is the more idealized notion that if only we could do X, Y, and Z, then we could make completely safe stem cells.

The reality is that, at least from a transplant perspective, there is no such thing as a normal or safe stem cell. We have learned over the years that even drugs that we thought were relatively benign such as aspirin are extremely powerful and can have negative side effects in a surprising number of patients.  The FDA views stem cells as drugs and like other drugs, stem cells are never going to be risk free. However, the importance of any given risk is all relative to the potential reward as well as the seriousness of the condition that a patient faces. What this means is that even mildly “abnormal” stem cells, even ones that might have some mutations, and might cause side effects in a certain percentage of patients, may still be meritorious drugs because the patients that might be treated with these cells would otherwise face death or lifelong disability.

What does this mean for human iPS and embryonic stem cells?

We have learned a great deal about how iPS cells contain mutations in their genomes as well as many other potential issues such as epigenetic changes.

It is crucial that these imperfections in iPS cells be addressed and they will be. In fact, I predict scientists can make iPS cells that are, at least relatively speaking, far more “normal” than any that now exist, but we also need to come to grips with the reality that there is never going to be a perfect iPS cell line.

The same is true for ES cells. I think it is safe to say that no ES cells are entirely 100% normal. ES cells are not the same as the inner cell mass cells (or individual blastomeres in the case of ACT) from which they were derived and any period of in vitro culture can readily cause some degree of mutations, even if we can’t easily detect them.

What’s important from a clinical standpoint is not whether we can call a certain iPS cell line entirely perfect or 100% “safe”, but how it might be used to help patients and whether the potential reward is worth the risk.

The bottom line is that there are millions of patients who might benefit from iPS and embryonic stem cell technology, many of them in dire need of help. It is exciting that both Advanced Cell Technology and Geron have started FDA approved Phase I or Phase I/II clinical trials, and these trials give hope to millions of people with blindness or spinal cord injury as well as their families.

The first rule of medicine is “do no harm” but that does not equate to a mantra “medicines must have zero risk”.

If that were true, there would be no medicines at all.

So as we push to improve iPS cell technology, to enhance relative iPS cell safety by reducing the amount of mutations they have, to better understand the functional meaning of these mutations, and finally to really clarify just how tumorigenic different iPS cell lines are in a clinically relevant setting…we have to keep in mind that perfection is an illusion and should not be the only milestone for moving iPS cells to the clinic. The same is true for embryonic stem cell technology. If enough clinical trials get going, and stem cell-based drugs are approved to treat patients as I think they will be, at some point someone is going to get a tumor from stem cells. It may be one person out of a 100 or  a 1000 who were otherwise treated safely. Even the best, “safest” drugs, will cause fatal side effects in some rare people. If you give 1000 people aspirin every day for a month, some are going to get sick from the aspirin and a couple might even die. The problem is that in the stem cell field there is so much politics and rhetoric that even if stem cell-based drugs are very safe overall, opponents of stem cell research will pounce on one negative outcome.

Any treatment whether it is an aspirin, open-heart surgery, or a stem cell-based transplant, has risk, but it is critically important to recognize that NOT treating patients because we have no FDA approved stem cell drugs has tremendous known risk. Not treating a patient means the patient will fail to get better and often will get worse.

I am arguably more obsessive about stem cell safety than almost anyone else especially when it comes to tumorigenicity, but I’m also a realist. I have not only studied cancer, but I have faced cancer myself and I have met cancer patients as well as other patients. When you are a patient, risk becomes very real, but so does illness.  We need new treatments, even if they aren’t 100% perfect.