Stem Cell therapy-Myths and Facts
Dr Ng Soo Chin
Consultant Haematologist
(This article appeared in the Star November 4, 2007 and is also reproduced here with the permission of the author)
Preamble:
There is something about Stem cell therapy (SCT)- a google search on the subject yielded 3.35 million hits! It is of interest to a diverse groups of people including doctors (haematologists, cardiologists, neurologists, paediatricans, geriatricians endocrinologists ….), basic research scientists, politicians, religious leaders, businessman in pharmaceutical industry, and last but not least the lay public including patients. Recently our honorable Health Minister rightly pointed out that they are many claims of stem cell therapy that are misleading and advised patients to exercise caution to avoid being taken for a ride. There are some ‘stem cell therapists’ touting promising treatment results in Malaysia and worldwide. This is an immediate and present danger to our innocent patients (refer to ATC saga).
1) What are stem cells?
Stem cells are fascinating. They are undifferentiated, master cells capable of self renewal (immortal!) and have the ability to differentiate into various specialized tissues. It is important to distinguish the type of stem cells we are talking about-the embryonic stem cells (ESC) present in the inner cell mass of pre-implanted embryo or the ‘adult’ stem cells (ASC) present in umbilical cord blood, amniotic fluid or in blood/marrow. There are significant differences between ESC and ASC. ESC is pluripotent i.e. capable of developing into any of the cell types found in the human body. ASC are able to make a few cell types and are considered as multipotent. To date no formal trials using ESC have been conducted because of safety issue related to uncontrolled growth which results in tumor formation which has been seen in laboratory animals. ASC are attractive as research tools and for treating disease as they do not involve the destruction of embryos. They are also attractive as it may be possible to use a patient’s own stem cells to generate tissue for transplant, thus avoiding problems with immune rejection common to other types of transplantation. However the limited ability to form other tissues may limit its application. Though the phenomenon of plasticity has been described in ASC i.e. Ability of ASC to form cells of different lineage under suitable environment but scientists are not sure how this can be exploited adequately in clinical settings.
2) What are the potential uses of stem cells?
Stem cells have potential uses in many different areas of research and medicine. It has the potential to revolutionize our approach to study of human biology and treatment of diseases. Some of the important potential applications are as below:
a) In regenerative Medicine:
Due to their ability to replace damaged cells in the body, stem cells could be used to treat a range of conditions including heart failure, spinal injuries, diabetes and Parkinson disease. It is hoped that transplantation and growth of appropriate stem cells in damaged tissue will regenerate the various cell types of that tissue. For example, haematopoietic stem cells (stem cells found in bone marrow) could be transplanted into leukaemia patients to generate new blood cells, or neural stem cells may be able to regenerate nerve tissue damaged by spinal injury.
b) For human developmental studies which will shed light on why some cells become cancerous and how some genetic diseases develop, which may lead to clues as to how they may be prevented.
c) New drug testing and screening of toxins. These can be done on stem cells grown in the laboratory which would provide a better testing model than current animal model.
3) Is stem cell therapy an established form of therapy?
Depending what type of stem cell therapy we are talking about. Haematopoietic stem cell transplant (HSCT) or better known as bone marrow transplant is an established and curative form of treatment for blood cancers such as leukemia ,lymphoma, myeloma , bone marrow failure syndromes such as aplastic anemia and certain genetic diseases such as thalassemia or severe combined immunodeficiency state. It has taken haematologists (experimental and clinical) a good 35 years to reach the current state of practice whereby annually up to 40000 or more HSCT are done yearly. In Malaysia more than a thousand patients had HSCT and around 70% of these patients are long term survivals. Transplant medicine is now rather refined with various form of HSCT being performed ranging form autologous transplant (stem cells from patient) to allogeneic transplant (stem cells from donors). Innovative changes to the conditioning regimen enable older patients to undergo HSCT in reduced intensity HSCT. Stem cell therapy other than HSCT remain experimental treatment and should only conducted in the setting of clinical trials under close supervision and also need clearance from appropriate ethic committee.
4) What are clinical trials all about? Should not we just trust the opinions of our ‘prominent doctors’?
We are now living in an era whereby the practice of medicine should be evidence –based. Clinical trials are essential to generate unbiased data based on careful studies on variables that we are interested in. For instance if we are interested to find out if treatment A is useful for a particular disease, the answer will be forth-coming after 3 phases of study. In phase1 study we have to ascertain whether treatment A is safe to give to humans follow by phase 2 study which would examine whether treatment A is effective or not. The acid test is in phase 3 trial when treatment A is compared to an established treatment and hopefully it is able to demonstrate superior results with acceptable side effects then treatment A is destined for pay-back time. In the case of a new drug, FDA or EU registration will be sought before marketing is allowed. Before clinical trials are approved, the protocols are subjected to scrutiny by an independent ethical committee comprising of doctors, and at least a lawyer and a lay person. Generally the data after studies are published in established medical journals and also presented in important clinical meetings so that the knowledge gained from study is assessable to every interested party. One would expect the same results be duplicated if similar studies are performed else where.
5) What are the pre requisites for successful stem cell therapy?
For stem cell therapy to work, the prerequisites would include understanding/defining the clinical problem, knowing the right type of cells to give and in adequate number, overcoming the immunological barrier if allogeneic or stem cells from outside source is used, putting the stem cells in the right place and finally getting the transplanted stem cells to work. Referring to table 1, one would appreciate why HSCT is an established science while in the setting of stem cell therapy with aim to replace damaged myocardium after acute myocardial infarction (AMI), there are many unresolved issues. Bortin reported the first 203 cases of BMT done in the 70’s ed only 5 of them survived. The current HSCT results are much better (Transplant related mortality is <5% for autologous HSCT and <15% for allogeneic HSCT respectively). The marked improvement in treatment results is the fruit of intense basic research and clinical work which result in the understanding of HLA system in selecting the right donor and also ability to provide supportive care in terms of blood products, anti-infectives as well as immunosuppressive therapy in appropriate circumstances. Obviously much fine tuning is needed before SCT become a viable treatment in AMI setting.
6) What are the raging ethical debates on stem cell therapy that even President Bush is caught up with?
The ethical issue only arises in ESC as use of ESC results in the destruction or death of the embryo. This is a passionate issue that resulted in strict government regulation in some countries forbidding creation of embryo for research purposes. There are also legitimate fears that some rogue scientists will attempt human cloning which is banned in all countries. ESC when transplanted into experimental animals generally continue to multiply in an untamed fashion, with a tendency to form tumors or various unwanted tissues. It would be difficult to justify use of ESC in human therapy unless the problem of potential tumor formation is fixed.
There are no ethical issues with the use of adult stem cells but one of the potential hurdles for the use of adult stem cells is their limited ability to generate different cell types.
7) There are claims that stem cell therapy could cure diabetes mellitus, spinal injury, and Parkinson's diseases...and the list goes on and how credible are these claims? Apparently such services are available in Malaysia!
These are claims and they will remain as claims unless and until they are backed up by good sciences and data one should view them critically and not let our senses take leave. It is worthwhile checking out some of these claims at good website such as Quackwatch. Quackwatch Inc. is an American non-profit organization that aims to “combat health-related frauds, myths, fads, fallacies, and misconduct” with a primary focus on providing “quackery-related information that is difficult or impossible to get elsewhere.” On the claims by the stem cell companies the Quackwatch comments were: their theories and methods are simplistic; their treatments may have adverse effects; they offer no credible outcome data; and their promises go far beyond what is now possible. No reason to believe that they are providing a legitimate service. As the good old saying goes-when something is too good to be true, it usually is.
8 ) What is the chance of Malaysia becoming the hub of stem cell therapy?
While I do not underestimate the ‘Malaysia boleh’ entrepreneurship, to grow a 250 million RM business from a not tested technology is stretching it too far! It is more than irrational exuberance to believe that this will happen. We should keep our feet on the ground and participate in some good basic research. The local UKM research laboratory headed by Prof SK Cheong performed some interesting studies on the role of mesenchymal cells as cancer delivery agent and continual research in the same direction will enable us to tap on advances that can be translated from laboratory to bedside in time to come.
9) Do we need to have some regulations to safeguard the general well being of our patients?
The answer is a resounding yes. Any form of stem cell therapy advertisement should be vetted by the Ministry of Health and stem cell therapy other than HSCT should only be conducted in the setting of a clinical trial so that the practice/ results can be monitored. The chance of a rogue doctors creating havoc with uncontrolled SCT is much higher than a rogue scientist running foul of law. We are duty bound to ‘protect’ our patients.
10) Do I think stem cell therapy will fulfill its great promises and transform the practice of medicine?
It is not a question whether it will happen but rather when this will happen .While haemopoietic stem cell therapy/transplant is an established modality of treatment, other form of stem cell therapy is still at very early stage of development. Prof Peter Braude, a leading stem cell researcher felt that stem cell therapy needs to be nurtured safely and methodically to provide real benefits to patients in the future. Much more basic research work needs to be done. In a positional statement, the International Society for stem cell research proclaimed that no reputable scientists think stem cell therapy (other than haemopietic stem cell therapy) is ready for prime-time yet. The people who are providing such therapies are mavericks!
The saga of ATC
In May 1996 a group of doctors involved in cancer care (including the author) wrote in a letter to Star Editor highlighting the exploits of a Singapore doctor (his clinic was called clinic Sinai!) treating Malaysian patients with advanced cancer using ATC (autologous target cytokines). There were no absolutely firm scientific data on the ATC treatment. The patients were promised fantastic results and charged exorbitant fees. We voiced our distress that patients were misled and wonder whether our health authority can stem such unhealthy practices. There was some interesting follow up development-the Malaysian authority could not take any action against the Singapore doctor since he is not registered here while the Singapore counterpart cannot take action against him because he was not treating patients in Singapore! He was ultimately nabbed by the Singapore authority for internet advertising and deregistered accordingly.
The author is the current President of Malaysian Society of Haematology. Some contents of the article are taken from a lecture entitled ‘Stem Cell therapy-do we know where we are going to? ‘ delivered by the author in the symposium organized by Malaysian Academy of Sciences in July 2007.
Table 1
Consultant Haematologist
(This article appeared in the Star November 4, 2007 and is also reproduced here with the permission of the author)
Preamble:
There is something about Stem cell therapy (SCT)- a google search on the subject yielded 3.35 million hits! It is of interest to a diverse groups of people including doctors (haematologists, cardiologists, neurologists, paediatricans, geriatricians endocrinologists ….), basic research scientists, politicians, religious leaders, businessman in pharmaceutical industry, and last but not least the lay public including patients. Recently our honorable Health Minister rightly pointed out that they are many claims of stem cell therapy that are misleading and advised patients to exercise caution to avoid being taken for a ride. There are some ‘stem cell therapists’ touting promising treatment results in Malaysia and worldwide. This is an immediate and present danger to our innocent patients (refer to ATC saga).
1) What are stem cells?
Stem cells are fascinating. They are undifferentiated, master cells capable of self renewal (immortal!) and have the ability to differentiate into various specialized tissues. It is important to distinguish the type of stem cells we are talking about-the embryonic stem cells (ESC) present in the inner cell mass of pre-implanted embryo or the ‘adult’ stem cells (ASC) present in umbilical cord blood, amniotic fluid or in blood/marrow. There are significant differences between ESC and ASC. ESC is pluripotent i.e. capable of developing into any of the cell types found in the human body. ASC are able to make a few cell types and are considered as multipotent. To date no formal trials using ESC have been conducted because of safety issue related to uncontrolled growth which results in tumor formation which has been seen in laboratory animals. ASC are attractive as research tools and for treating disease as they do not involve the destruction of embryos. They are also attractive as it may be possible to use a patient’s own stem cells to generate tissue for transplant, thus avoiding problems with immune rejection common to other types of transplantation. However the limited ability to form other tissues may limit its application. Though the phenomenon of plasticity has been described in ASC i.e. Ability of ASC to form cells of different lineage under suitable environment but scientists are not sure how this can be exploited adequately in clinical settings.
2) What are the potential uses of stem cells?
Stem cells have potential uses in many different areas of research and medicine. It has the potential to revolutionize our approach to study of human biology and treatment of diseases. Some of the important potential applications are as below:
a) In regenerative Medicine:
Due to their ability to replace damaged cells in the body, stem cells could be used to treat a range of conditions including heart failure, spinal injuries, diabetes and Parkinson disease. It is hoped that transplantation and growth of appropriate stem cells in damaged tissue will regenerate the various cell types of that tissue. For example, haematopoietic stem cells (stem cells found in bone marrow) could be transplanted into leukaemia patients to generate new blood cells, or neural stem cells may be able to regenerate nerve tissue damaged by spinal injury.
b) For human developmental studies which will shed light on why some cells become cancerous and how some genetic diseases develop, which may lead to clues as to how they may be prevented.
c) New drug testing and screening of toxins. These can be done on stem cells grown in the laboratory which would provide a better testing model than current animal model.
3) Is stem cell therapy an established form of therapy?
Depending what type of stem cell therapy we are talking about. Haematopoietic stem cell transplant (HSCT) or better known as bone marrow transplant is an established and curative form of treatment for blood cancers such as leukemia ,lymphoma, myeloma , bone marrow failure syndromes such as aplastic anemia and certain genetic diseases such as thalassemia or severe combined immunodeficiency state. It has taken haematologists (experimental and clinical) a good 35 years to reach the current state of practice whereby annually up to 40000 or more HSCT are done yearly. In Malaysia more than a thousand patients had HSCT and around 70% of these patients are long term survivals. Transplant medicine is now rather refined with various form of HSCT being performed ranging form autologous transplant (stem cells from patient) to allogeneic transplant (stem cells from donors). Innovative changes to the conditioning regimen enable older patients to undergo HSCT in reduced intensity HSCT. Stem cell therapy other than HSCT remain experimental treatment and should only conducted in the setting of clinical trials under close supervision and also need clearance from appropriate ethic committee.
4) What are clinical trials all about? Should not we just trust the opinions of our ‘prominent doctors’?
We are now living in an era whereby the practice of medicine should be evidence –based. Clinical trials are essential to generate unbiased data based on careful studies on variables that we are interested in. For instance if we are interested to find out if treatment A is useful for a particular disease, the answer will be forth-coming after 3 phases of study. In phase1 study we have to ascertain whether treatment A is safe to give to humans follow by phase 2 study which would examine whether treatment A is effective or not. The acid test is in phase 3 trial when treatment A is compared to an established treatment and hopefully it is able to demonstrate superior results with acceptable side effects then treatment A is destined for pay-back time. In the case of a new drug, FDA or EU registration will be sought before marketing is allowed. Before clinical trials are approved, the protocols are subjected to scrutiny by an independent ethical committee comprising of doctors, and at least a lawyer and a lay person. Generally the data after studies are published in established medical journals and also presented in important clinical meetings so that the knowledge gained from study is assessable to every interested party. One would expect the same results be duplicated if similar studies are performed else where.
5) What are the pre requisites for successful stem cell therapy?
For stem cell therapy to work, the prerequisites would include understanding/defining the clinical problem, knowing the right type of cells to give and in adequate number, overcoming the immunological barrier if allogeneic or stem cells from outside source is used, putting the stem cells in the right place and finally getting the transplanted stem cells to work. Referring to table 1, one would appreciate why HSCT is an established science while in the setting of stem cell therapy with aim to replace damaged myocardium after acute myocardial infarction (AMI), there are many unresolved issues. Bortin reported the first 203 cases of BMT done in the 70’s ed only 5 of them survived. The current HSCT results are much better (Transplant related mortality is <5% for autologous HSCT and <15% for allogeneic HSCT respectively). The marked improvement in treatment results is the fruit of intense basic research and clinical work which result in the understanding of HLA system in selecting the right donor and also ability to provide supportive care in terms of blood products, anti-infectives as well as immunosuppressive therapy in appropriate circumstances. Obviously much fine tuning is needed before SCT become a viable treatment in AMI setting.
6) What are the raging ethical debates on stem cell therapy that even President Bush is caught up with?
The ethical issue only arises in ESC as use of ESC results in the destruction or death of the embryo. This is a passionate issue that resulted in strict government regulation in some countries forbidding creation of embryo for research purposes. There are also legitimate fears that some rogue scientists will attempt human cloning which is banned in all countries. ESC when transplanted into experimental animals generally continue to multiply in an untamed fashion, with a tendency to form tumors or various unwanted tissues. It would be difficult to justify use of ESC in human therapy unless the problem of potential tumor formation is fixed.
There are no ethical issues with the use of adult stem cells but one of the potential hurdles for the use of adult stem cells is their limited ability to generate different cell types.
7) There are claims that stem cell therapy could cure diabetes mellitus, spinal injury, and Parkinson's diseases...and the list goes on and how credible are these claims? Apparently such services are available in Malaysia!
These are claims and they will remain as claims unless and until they are backed up by good sciences and data one should view them critically and not let our senses take leave. It is worthwhile checking out some of these claims at good website such as Quackwatch. Quackwatch Inc. is an American non-profit organization that aims to “combat health-related frauds, myths, fads, fallacies, and misconduct” with a primary focus on providing “quackery-related information that is difficult or impossible to get elsewhere.” On the claims by the stem cell companies the Quackwatch comments were: their theories and methods are simplistic; their treatments may have adverse effects; they offer no credible outcome data; and their promises go far beyond what is now possible. No reason to believe that they are providing a legitimate service. As the good old saying goes-when something is too good to be true, it usually is.
8 ) What is the chance of Malaysia becoming the hub of stem cell therapy?
While I do not underestimate the ‘Malaysia boleh’ entrepreneurship, to grow a 250 million RM business from a not tested technology is stretching it too far! It is more than irrational exuberance to believe that this will happen. We should keep our feet on the ground and participate in some good basic research. The local UKM research laboratory headed by Prof SK Cheong performed some interesting studies on the role of mesenchymal cells as cancer delivery agent and continual research in the same direction will enable us to tap on advances that can be translated from laboratory to bedside in time to come.
9) Do we need to have some regulations to safeguard the general well being of our patients?
The answer is a resounding yes. Any form of stem cell therapy advertisement should be vetted by the Ministry of Health and stem cell therapy other than HSCT should only be conducted in the setting of a clinical trial so that the practice/ results can be monitored. The chance of a rogue doctors creating havoc with uncontrolled SCT is much higher than a rogue scientist running foul of law. We are duty bound to ‘protect’ our patients.
10) Do I think stem cell therapy will fulfill its great promises and transform the practice of medicine?
It is not a question whether it will happen but rather when this will happen .While haemopoietic stem cell therapy/transplant is an established modality of treatment, other form of stem cell therapy is still at very early stage of development. Prof Peter Braude, a leading stem cell researcher felt that stem cell therapy needs to be nurtured safely and methodically to provide real benefits to patients in the future. Much more basic research work needs to be done. In a positional statement, the International Society for stem cell research proclaimed that no reputable scientists think stem cell therapy (other than haemopietic stem cell therapy) is ready for prime-time yet. The people who are providing such therapies are mavericks!
The saga of ATC
In May 1996 a group of doctors involved in cancer care (including the author) wrote in a letter to Star Editor highlighting the exploits of a Singapore doctor (his clinic was called clinic Sinai!) treating Malaysian patients with advanced cancer using ATC (autologous target cytokines). There were no absolutely firm scientific data on the ATC treatment. The patients were promised fantastic results and charged exorbitant fees. We voiced our distress that patients were misled and wonder whether our health authority can stem such unhealthy practices. There was some interesting follow up development-the Malaysian authority could not take any action against the Singapore doctor since he is not registered here while the Singapore counterpart cannot take action against him because he was not treating patients in Singapore! He was ultimately nabbed by the Singapore authority for internet advertising and deregistered accordingly.
The author is the current President of Malaysian Society of Haematology. Some contents of the article are taken from a lecture entitled ‘Stem Cell therapy-do we know where we are going to? ‘ delivered by the author in the symposium organized by Malaysian Academy of Sciences in July 2007.
Table 1
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