[Please Note: I am not opposed whatsoever to embryonic stem cell research which continues to lead to valuable understandings about cell-cell interactions. However, these synthetic laboratory models are not likely to lead to any patient therapies, which for many people, particularly patients with debilitating diseases, is the most important goal of stem cell research.]
It has been almost 16 years since the first embryonic stem cells were identified by Dr. James A. Thomson. [Thomson, J.A., Itskovitz-Eldor, J., Shapiro, S.S., Waknitz, M.A., Swiergiel, J.J., Marshall, V.S., and Jones, J.M. (1998). Embryonic stem cell lines derived from human blastocysts. Science. 282, 1145-1147]
So what do we have and where are we going with this new science.
Embryonic Stem Cells have proven to be worthless for patient therapy
If one is looking toward patient therapy and not just unending biomedical research, we can certainly say that the dream of miracle therapies derived from embryonic stem cell research is over for the most part. Embryonic stem cells (ESC’s) as far as patient therapy is concerned have been a dismal failure and are likely never to result in any useful therapy. As we say in one of our stem cell courses at the Panama College of Cell Science, if any student can point to any therapy using ESC’s anywhere in the world, please share with us and collect your “A” for the course.
As I have said before, ESC’s are artificially created cells that are fun to play with in the lab, but will never yield any results leading to patient therapy. Never say never they say…..But the role of ESC’s in therapy can best be summarized by the “secret clinical trials” performed by Geron Inc. The Embryonic Stem Cell Camp, which controls what is done in the USA, is so protective of their pet ESC’s (please give us billions more money and we will find some cure for something), that they convinced the US Government to permit a secret clinical trial so that in the event a bad result was obtained, no bad publicity would ensue. Details of the test are unavailable. But the results of the secret clinical trial are not. In 2011, Geron immediately closed down its entire ESC research program and withdrew from all further development of ESC’s as a future therapeutic modality.
The use of this artificial “model”, namely using various laboratory derived stem cell lines that last in culture for years has done little more than clog up all the medical journals with worthless “observations” and “findings” that relate to the artificial models the ESC scientists created but have no real relevance whatsoever to stem cell therapy for patients.
Why are ESC’s worthless for therapy?
(1) They are foreign cells when injected into a patient, and are thus eliminated by the immune system unless powerful immunosuppressive drugs are used (like in a kidney transplant).
(2) They always form tumors and teratomas because their differentiation is uncontrollable
(3) Because ESC’s can form any cell of the body, their differentiation into the desired type of cell and tissue is essentially impossible to control, define or regulate.
But enough of these silly cells…let’s be serious and talk patient therapy.
There are 5 broad categories of conditions for which adult stem cells might be helpful:
(1) Treatment of Injury: An example of this is the treatment of burn victims with stem cell skin precursors. Another example is the treatment of severe spinal injury by use of neural stem cells applied in the area of the injury to regrow the spinal cord. Trauma due to heart attack or stroke also fit into this category. As an aside, I would like to note the incredible successes of Dr. Carlos Lima (now deceased) in treating spinal cord injury using neural stem cells harvested from the patient’s nose. Some paralyzed patients were able to walk following treatment. Yet for many, the treatment did not work. My feeling about this is that if one is a paraplegic or quadriplegic of long duration, fixing the spinal column alone may not successfully lead to full bodily function because the nerve-muscle feedback mechanism may be permanently damaged. The nerves are restored, but muscle is not working to the point where both systems are functioning. This is why Dr. Lima prescribed extensive physical therapy in connection with his treatment. The bottom line is that if one has a spinal injury, early adult stem cell therapy is essential to a successful result, the earlier the better, but certainly within 1 year or so if possible.
(2) Treatment of Disease: For this category we are generally referring to a disease which occurs other than from genetic defect. An example might be damage to the liver from viral hepatitis, which is reversed by the use of stem cells. Another similar example might be the regeneration of a liver following cirrhosis caused by alcohol abuse or other causes. What we are referring to is treatment of tissue or organ that was once normal but which has become non-functional due to viral disease or abuse. Cardiac disease would be in this category.
(3) Genetic Defects: These are defects in the genes which cause disease. For example, diabetes is in this category. There are quite a few genetically caused diseases that result from the defective production or lack of production of some necessary protein, enzyme or other substance. Stem cell treatments will not be able to “cure” diseases caused by genetic defects. Why is this? Because cellular environment is the #1 and most important criteria for how a stem cell will differentiate and into what form it will differentiate. Normal stem cells, say derived from adipose tissue of a patient, and then placed into a cellular environment (tissue or organ) containing genetically defective cells, will be likely signaled to become like the defective cells, and exhibit a genetic defect. Stem cell treatments may in fact still likely be effective in assisting in the control of the disease, but the effect will be short lived. By this I mean that a patient may need stem cell treatments for life, possibly four times per year, or at worst, maybe one time per month. Genetic defects will require repetitive stem cell treatments. This problem makes it even more crucial that we are able to generate stem cells from a patient for injection cheaply and efficiently. And we do not have this capability at this time.
(4) Pathology: In this category I place Aging in general. Recall the terrific little video of Aubrey de Grey and his novel formula of aging that you saw in the Hormonal Rejuvenation course: “Metabolism causes Damage, Damage causes Pathology”:
Parkinsons Disease may be in this category, as it results from death of dopamine generating cells and the accumulation of protein inclusions. Alzheimers disease, which is associated with plaque formation in the brain may be another pathology induced condition. Stem cell treatments should be helpful in these kinds of situations wherein normal bodily functions are restored by the transplanted cells. And indeed, these two conditions have already proven to be treatable with stem cells. Again, we are talking about the treatment of tissue or organs that once functioned normally.
(5) Developmental Defects: The final category of conditions are those that arise through non-normal development. The DNA (genes) are OK, but something occurred during development that resulted in a defect, such as certain forms of blindness.
Some current International Examples of Stem Cell Therapy Centers
The international medical community is using adult stem cells (ASC’s) with excellent success
Those in control of stem cells in the USA continue to label all international treatments as “unproven” and “fraudulent” and continue to warn patients against traveling to a foreign country for stem cell treatment.
But many international centers are government sponsored. Thailand, China, and India are just three countries that are promoting adult stem cell treatment. Adult stem cell treatment many times involves the use of a patient’s own stem cells, and consequently, such therapy is sometimes referred to as “autologous” stem cell treatment. In other cases, umbilical cord blood containing adult stem cells from normal deliveries is used, due to the observation that such cells do not cause any immunogentic event when transplanted into an adult for treatment. Lastly, in the adult stem cell arsenal are stem cells derived from fetal tissue harvested from legal abortions, due to the observation again that fetal tissue from the first trimester of pregnancy can be transplanted into an adult with no immunogenic effect because the Hla and other antigens have not developed on the cell membranes at that point. If these new therapies are so “unproven” as the USA embryonic stem cell lobby contends, then it appears that the governments of whole countries must be engaged in medical quackery!!! Well, like they said, if you believe that, I have a bridge I can sell you…
Rules for Success
In order to have a successful therapeutic result with adult stem cells, I believe that the following are required:
(1) You must have a sufficient number of adult stem cells in order to achieve a therapeutic result. While every kind of therapy and patient may require a different amount, as a starting point for discussion, we need a billion stem cells. And you are not going to have that number from just a tube of the patient’s blood or from aspirated fatty tissue. The adult stem cells have to be expanded, that is multiplied, before re-implantation to the patient. Which is why I proposed the need for a Stem Cell Expresso machine. Different therapeutic numbers (lower or higher) may eventually be determined for different diseases, or for different methods of transplantation, and likely even related to the age of the patient. But two things we can say for sure. First, if we are talking about a tube of the patient’s blood or a few cc’s of adipose tissue, there is likely to be an insufficient amount of stem cells collected, and ex vivo expansion of the cells will have to be undertaken. Second, if an attempted use of autologous stem cells did not appear to result in a therapeutic benefit, it is highly likely that the cause is an insufficient number of transplanted stem cells.
(2) Because cellular environment is the most important factor determining how a transplanted stem cell will behave, there should be some basis to believe that the manner of the delivery of the stem cells will result in the stem cells reaching the site of defect or injury. The best result in cardiac disease has been direct injection of cardiac stem cell precursors into cardiac tissue.
(3) The treatment should involve some kind of testing to ensure the quantity and quality of stem cells being transplanted to a patient. This of course can be difficult and expensive.
I like to see a lot of information on a website proposing stem cell treatments that discusses these three elements, and some centers to better than others in this regard.
Some Example Centers
An example of a center using umbilical cord blood:
The Panama Stem Cell Institute has an excellent adult stem cell treatment program. I have heard the criticism…”Oh it is not even run by an MD”… Well that is true, Dr. Riordan, the Director, only holds a lowly PhD degree. But he was perhaps the first one to realize how patient therapy could be based on the use of umbilical cord blood. His terrific review paper appears here: Riordan Cord Blood paper Once Dr. Riordan made that connection that cord blood could be transferred to any patient, the Panama Stem Cell Institute was created….of course, overseas due to constant harassment of anyone that seriously suggest that adult stem cells are a good thing and should be applied to therapy now.
An Example of a center using Autologous Stem Cells:
I think the Thailand stem cell centers are excellent. They are all under a government controlled entity and are set up to provide treatments that are designed to work. Their websites provide excellent information. The Thais were the first to treat cardiac disease using autologous stem cells and smart enough to know that with modern medical test methods, each patient serves as his/her control. The so called “clinical trial” is not necessary in these circumstances. The Thai stem cell treatments for cardiac disease have been ongoing now for maybe 10 years and were initiated by a Thai physician who trained in cardiaology for over 20 yerars at Mt Sinai Hospital in New York, became disgusted when autologous stem cell treatments were not going to be permitted and moved back to Thailand to begin treating patients.
Some of the stem cell centers in Mexico, run by US physicians appear to be pretty good, as an example www.regenexx.com
I think Dr. Roberto Vina’s clinic in Argentina does excellent work at a moderate price for a limited number of diseases: heart disease, lung disease, and diabetes using bone marrow autologous stem cells [fundacionfernandezvina.org/fundacion.php] Although the credentials and experience of Dr. Viña are impeccable, and the cost of treatment very affordable, it may be difficult for a patient to access the treatment center directly unless they speak spanish. However, a patient can go via the Repair Stem Cell Institute [repairstemcells.org] See: http://www.repairstemcells.org/Resources/Featured-Deals/RSCI-Announces-Reduced-Stem-Cell-Treatment-Fees-fo.aspx
Treatment with Fetal Tissue
This is a strange though undoubtedly incredibly useful treatment method, and has a strange history as well. Fetal tissue is derived from legal aborted fetuses. It is ground up and rather than just use the cells in therapy, many times the entire “soup” is injected into a patient. The soup contains theoretically the adult stem cells from the fetal tissue, for example liver, along with cellular proteins, cytokines and other small biological molecules. The treatment makes use of the fact that fetal tissue from fetuses less than 12 weeks into development, contain no cell membrane antigens that cause immunological rejection when implanted into an adult. No immunosuppressive drugs are needed. For over 20 years in Russia and Poland, physicians were regenerating whole livers in adults whose livers were damaged by abuse (alcohol) or disease (hepatitis), or injury. That’s a fact jack, and no liver transplants were required. No immunosuppressive drugs were needed either. I am not sure what occurred in Russia, but this practice seems to have been discouraged recently. The practicioners of this technique are now centered in the Ukraine http://uctclinic.com with a good center in Mexico as well: stemcellofamerica.com
Fetal tissue as a regenerative tool works, there is no doubt about it. But I am not sure whether it is stem cells or the proteins, growth factors, messenger proteins and cytokines in the soup (or both) that is yielding the beneficial result. It is something that defintely works but we don’t know why.
A country to maybe think twice about.
From the standpoint of volume, the Chinese have turned out more therapies than anyone. At first, say 10 years ago, their programs seems to be avant garde and they led the world in some aspects. This is due to the fact that their initial medical practicioners were trained atthe prestigious USA National Institutes of Health, and then a bunch of them left en masse to return to China to establish the first Chinese adult stem cell treatment center. Now, as with all things Chinese, there are a lot of copycats, and it is difficult to figure out which are the genuine centers and which are not. After all, this is a country that has yet ot produce its own automobile or truck. Why is it that Thailand produces all the trucks for the USA and Japan, yet no one trusts China to produce any?? Even tiny Malaysia manufactures their own vehicle for export (Proton), and India as well produces thier vehicles for the domestic and export market. The second thing is I wish the Chinese websites would improve their infomration on their website as to sources of stem cells used, numbers for therapeutic result and whether any expansion of cells is undertakien. I am also wary of “secret ingredients” that result in success. Hey, if you have something that works, why not share it with the world. If you need a kidney transplant, you don’t have to wait, you can go to China right now, stay at a hospital for two weeks and fly home with a new kidney. But, their failure rate has been reported to be 50%. Now why is that?? Are they cutting corners in some way, is the source of the kidneys suspect?
Fat cells and cosmetics
Yes, to be sure, there are mesenchymal stem cells located within adipose tissue (fatty tissue in the abdomen for example). And some practitioners are harvesting fatty tissue from a patient and reimplanting the tissue into the face, alleging that the stem cells will cause a rejuvenating effect. The problem with this idea, at least at this time, is that the identification of what cells are being injected, and How Many are being injected, is usually sadly lacking. It is never clear what is causing a supposed beneficial cosmetic effect. Possibly just the injection of fatty tissue is leading to a healthier looking face…or possibly just the manipulation itself resulting in a general inflammatory response is causing a resultant “youthful glow”. Unless you are being treated at a center that can define what cells are being injected, and how many, you are probably wasting your money. And whatever effect is being achieved or sought to be achieved will not last more than a couple of months.
Aging and Stem Cell Therapy
It is now quite clear that autologous stem cell therapy in the aged adult is not as successful as in a more youthful patient. It can be successful, just not as much so. This fascinating Howard Hughes Medical Institute video presents the “paired mouse experiments” (Video Chapters 14-19, Time Sections 16:14 to 24:20 minutes):
This is the section of the video that presents the experiment on muscle regeneration in old mice who are conjoined by surgery to create a shared blood stream with a young mouse. The experiment demonstrates that when an old animal is paired with a young animal, the capacity of the old animal’s stem cells to regenerate injured muscle is increased. There were two follow-up experiments: (1) Serum (not cells) from a young mouse activated stem cells from an old mouse in vitro; (2) Cells from a mouse containing a green fluorescent tag in every cell were NOT transferred to an old paired mouse, thereby clearly showing that it is serum factors, cytokines and the like from the younger animal that is restoring high activity in the stem cells of the older animal rather than any stem cells being transferred to the older animal.
As mentioned in the video, the three factors affecting stem cells in the older animal (human as well) are:
1. The decreased number of stem cells which occurs as we age;
2. The reduction in the capacity of remaining stem cells to regenerate injured tissue;
3. The altered cellular environment in the aged animal contributes to decreased stem cell activity (as shown in the above experiments).
So, when we treat the older patient with autologous stem cells, we are creating a therapeutic effect, but we are only successfully fixing one of the three items: namely decreased number of stem cells.
An excellent summary of aging issues relating to stem cell therapy can be found at: Aging and Stem Cells
Summary
So, as we move forward with learning some of the therapeutic approaches involving adult stem cells, keep these things I have just covered in mind:
A. Genetic defects play a role in how successful a therapy is likely to be (because of cellular environmental factors). Stem cell therapy may very likely be successful for a short term but will likely have to be repeated from time to time in order to obtain a sustained beneficial result.
B. Age is an important factor in how successful therapy is likely to be, again because of the contribution of as yet unknown cellular factors (or absence of such) which tend to reduce effective stem cell activity.
C. Do we have enough stem cells for a therapeutic result?
Clinical trial not necessary for adult stem cell therapy
I would argue that clinical trials (of the kind applied to new drugs) are not necessary for adult stem cell therapy because modern medical instrumentation can monitor the patient before and after therapy to yield objective findings.
From the book “Design and Analysis of Clinical Trials” we have the following account of the first “clinical trial” as described by James Lind carried out in 1747 while at sea on board the Salisbury:
“On the 20th May, 1747, I took twelve patients in the scurvy on board the Salisbury at sea. Their cases were as similar as I could have them. They all in general had putrid gums, the spots and lassitude, with weakness of their knees. They lay together in one place, being a proper apartment for the sick in the fore-hold; and had one diet in common to all, viz., water gruel sweetened with sugar in the morning; fresh mutton broth often times for dinner; at other times puddings, boiled biscuit with sugar etc.; and for supper barley, raisins, rice and currants, sago and wine, or the like. Two of these were ordered each a quart of cyder a day. Two others took twenty five gutts of elixir vitriol three times a day upon an empty stomach, using a gargle strongly acidulated with it for their mouths. Two others took two spoonfuls of vinegar three times a day upon an empty stomach, having their gruels and their other food well acidulated with it, as also the gargle for the mouth. Two of the worst patients, with the tendons in the ham rigid (a symptom none the rest had) were put under a course of sea water. Of this they drank half a pint every day and sometimes more or less as it operated by way of gentle physic. Two others had each two oranges and one lemon given them every day. These they eat with greediness at different times upon an empty stomach. They continued but six days under this course, having consumed the quantity that could be spared. The two remaining patients took the bigness of a nutmeg three times a day of an electuray recommended by an hospital surgeon made of garlic, mustard seed, rad. raphan., balsam of Peru and gum myrrh, using for common drink narley water well acidulated with tamarinds, by a decoction of wich, with the addition of cremor tartar, they were gently purged three or four times during the course.
The consequence was that the most sudden and visible good effects were perceived from the use of the oranges and lemons; one of those who had taken them being at the end of six days fit four duty. The spots were not indeed at that time quite off his body, nor his gums sound; but without any other medicine than a gargarism or elixir of vitriol he became quite healthy before we came into Plymouth, which was on the 16th June. The other was the best recovered of any in his condition, and being now deemed pretty well was appointed nurse to the rest of the sick “
“In spite of the relative clear-cut nature of his findings, Lind still advised that the best treatment for scurvy involved placing stricken patients in “pure dry air”. No doubt the reluctance to accept oranges and lemons as treatment for the disease had something to do with their expense compared to the ‘dry air’ treatment. In fact it was a further 40 years before the British Navy supported lemon juice for crews of its ships at sea; once again the question of cost quickly became an issue with lemons being substituted by limes, condemning the British sailor to be referred to for the next two hundred years as ‘limeys’. “
*******************************************
Clinical trials for humans relating to autologous adult stem cell therapy should be abolished, strongly curtailed, or modified. Clinical trials have no place in stem cell studies because each patient can serve as his or her own control. The supposed yet outdated requirement for clinical studies involving a patient control group is being used by the FDA and medical establishment to bar stem cell therapies in the US, and is one of many reasons why the US lags behind other countries in advancing stem cell therapies.
Stem Cell therapy with autologous adult stem cells constitutes the “New Medicine”. With all the modern technology for objective scientific assessment of a patient’s medical condition, there is no need for a randomized study. Each patient can be carefully evaluated, before and after treatment, by objective medical testing using various equipment, and their condition after therapy compared to that before. Consequently, the treatment of each individual patient constitutes a “single patient clinical trial”. Moreover, the outdated clinical trial format is not relevant nor applicable to “patient specific” therapy involving adult stem cells or even adult fetal stem cells.
Moreover, the fact of the matter is that the so called “clinical trials”, the gauntlet that new medical applications and drugs must run in order to become approved, are immoral. A clinical trial is a study in which 1/2 of the patients are given no treatment. They are the “control group”. Would you ever want to be in the “control group”, needing treatment and getting none??
One questions what kind of informed consent is obtained from patients who will receive no treatment. Are they invited “to be part of a study” and therefore believe they will all be receiving some new experimental treatment?? This appears to some to be a medical fraud.
Professor Georges Mathé, a well respected pioneer in stem cell transplantation and winner of the Grand Medal of the National Academy of Medicine (France’s highest medical honor) gave a lecture in 1998 entitled: “From Moral via Ethics to the Politically Correct”. He discussed how ethics boards determine what is ethical, and thereby change the publics’ perception of what is moral. He stated: ”One of the most immoral such acts concerns medical experimentation. Most people are unaware that 500 patients are chosen at random to receive a “placebo”, while 500 others are given an experimental drug.” [Excerpted from the lecture given at the World Philosophers Meeting , Geneva, Switzerland 1998].
One might also find it strange that, although scarcely reported, more and more so called “clinical trials” are being performed overseas outside of the USA. A whole new industry has formed over the last 5-10 years to perform clinical trials overseas. If these “studies” are so great for a patient to be involved in, why are they being sent overseas? One would suspect it is because the level of informed consent, if any, is probably a lot more lax overseas. Almost 3/4 of US clinical trials are being conducted overseas, with India’s share growing each year.
A better approach is that used in Thailand, in which ALL patients receive the proposed treatment regimen. There is no “control group” receiving nothing. Each patient serves as his/her own control. Particularly in the case where patients receive products of their own blood and tissues, such as autologous stem stem cells, there is no need for controlled studies. See for example: Thai Cardiac Paper [ Chaithiraphan,S et al.: Transcoronary Injection of Angiogenic Cells Precursors and Autologous Stem Cells in Ischemicc Cardiomyopathy: A Clinical Study of 106 Cases in Thailand. Asean Heart Journal, 17(No.1): 13-22, 2009] Outcomes are compared to the patients’ condition prior to the treatment to determine its efficacy.
Clinical trials, which are one of the foundations of modern medicine, should be abandoned or modified for stem cell studies. This type of experimentation is certainly appropriate for animal studies but not for humans. First, stem cell therapy does not involve any drug. Particularly with respect to the injection of autologous stem cells (that are found naturally in the patient), the patient is receiving what one already has, just more of it.
Second, with all the modern technology for objective scientific assessment of a patient’s medical condition, there is no need for a randomized study. Each patient can be carefully evaluated, before and after treatment, by objective medical testing using various equipment, and their condition after therapy compared to that before. Why is such a collection of testing evidence using modern scientific equipment not sufficient to ensure that a positive beneficial effect of a stem cell treatment with autologous adult stem cells is well documented, and hence, “proven”???
“Clinical Trial” requirements, for treatments involving autologous adult stem cells, should be modified so as to focus not on who is included in the study and their treatment protocol, but rather to focus on the identity of the appropriate medical tests to define the patient’s condition before and after treatment.
If just this one small change were to be made, stem cell treatment with autologous adult stem cells could proceed in the US at am amazing pace!!
Randomized Clinical Trials Are Not Always Necessary
We find great solace and support for the position that the need for clinical trials in the case of autologous stem cell transplants should be eliminated or modified in this amazing report from the prestigious British Medical Journal (BMJ 334:349-351 (2007) [randomizedtrialsnotnecessary.pdf] to the effect that when treatments have dramatic results, biases can be ruled out without the necessity of randomized clinical trials!!! When the relation between treatment and its effect is so dramatic, randomized trials are unnecessary.
When will the new bell ring????
When an important member of Congress or even a President, has to go overseas for a stem cell treatment, only then will a new tune ring in the halls of Congress……
*****************************
The Panama College of Cell Science, located in the Commonwealth of Dominica, offers the only 3 year online doctoral program in stem cell biology leading to a PhD degree. Sponsored in part by the Drake Biomedical Institute, the program can be completed entirely online and features a USA style curriculum that meets the equivalency standards for foreign education. Containing 72 trimester credits, graduates may for a nominal fee obtain a certificate from a foreign credential evaluation service approved by the US Department of Education to the effect that the program is equivalent to a doctoral degree from a regionally accredited USA college or university.
Panama College of Cell Science 