Medical Megatrends Stem Cells – Part III

A cure for spinal cord injury? Diabetes? Macular degeneration?  Hope or just hype?

There are now some clinical trials using embryonic stem cells to treat serious diseases for which no other good therapy is currently available. But this is just the beginning of a major medical megatrend that will blossom forth in the coming years.

Embryonic stem cells are present after a fertilized egg divides for two or three days. They have the seemingly miraculous ability to turn into any of the tissue types in the body—whether brain neurons, beating heart cells, bone, or pancreatic islet cells. It is important to understand just where these cells come from. Those used in science are the byproduct of in vitro fertilization (IVF), cells taken from the often “left over” embryos that are otherwise discarded.

In 1998, scientists under the leadership of Dr James Thomson at the University of Wisconsin, learned how to take some of the cells from these about to be discarded embryos and put them into a cell culture – basically a fluid in which the cells can grow to produce more cells. These cells in turn can then be directed to grow into heart or lung or pancreas or other types of cells by the addition of various additives to the fluid in which they are growing. So it is from these discards that embryonic stem cells are available to us. Just to be clear. The blastocyst or embryo with its 32 or so cells is not grown in the culture dish. Rather, individual cells are removed and allowed to divide and grow. These are the so called embryonic stem cells. But no embryo is growing, just individual cells.

It is true that much can be done with adult stem cells as discussed last time but science so far suggests that embryonic stem cells hold promise for much more benefit. It will probably be embryonic stem cells (or perhaps induced pluipotent stem cells – see the first in this series) that pave the way for replacing the islet cells of the pancreas with new insulin producing cells to cure diabetes or replace the damaged cells in the brain that are key to Parkinson’s disease. Some strongly feel that it is wrong to use cells from embryos. It is important to remember that these are fertilized eggs that were prepared for couples that could not conceive and so had eggs and sperm placed into a dish with special fluids. Experience has shown that success is better if the doctor implants a few embryos into the woman’s uterus rather than just one. But the doctor may have more than enough embryos and the extras will be discarded if the woman becomes pregnant. I look at it this way. Since the embryos will be destroyed anyway, why not use them for creating stem cells that perhaps many people with diverse diseases might benefit from. It is not dissimilar to transplanting the organs of a person who has died in a car accident rather than burying them in the grave. And the embryo, made up of just a few cells, is disrupted so each cell grows independently. Now the cells can be stimulated to become heart cells, liver cells or whatever and might be useful in treating a disease. It will take some years but there will certainly be major advances down the road in how we can repair, restore or replace damaged tissues or organs.

The pace at which we benefit from stem cell therapy will be influenced by factors including cultural attitudes which in turn lead to legislative decisions and legal challanges. The issues revolving around federal funding via the NIH for research on embryonic stem cells reached the federal courts two summers ago and were further addressed by an appellate court in April of 2011. Cohen and Adashi, writing in the New England Journal of Medicine in May, 2011, gave a clear account of the debate in the courts. They concluded with “It is difficult to overestimate the vast potential of stem-cell research. We believe we cannot afford to allow ongoing legal ambiguities to compromise this line of scientific pursuit. Quite the contrary, now is the time to pick up the pace with an eye toward realizing the hoped-for translational benefits. With statutory relief deemed unlikely to be provided before the 2012 elections, it appears all but inevitable that the matter of funding of human ESC research will have to be settled in a court of law.” Of course that never happened and stem cell research is not high on the public’s set of concerns for this year’s elections but the makeup of the coming Congress after the election could be relevant down the road.

Here is an example of how stem cells could be used: islet cells on demand– One day, and I believe it will occur within five to ten years, stem cells will be able to be mass grown into islet cells. They will be ready when the patient needs them. Just give them by vein and they will home into where they need to go.  And if they are created from the process called nuclear transfer or adult cells reprogrammed from the patient by genes (iPSC) or proteins (piPSC) that I described previously, they probably will not be rejected because they will be developed to not provoke the immune system. But still, whatever process destroyed their own islet cells years before will probably still be functional. So these new cells may be destroyed over time as well, unless some new technology or drugs are developed to prevent this cell destruction by the body. But in the meantime, just come back for a new infusion whenever needed. Sort of like going to the gas station to refill the tank!

Islet cells injected into the vein seem to know to go to the liver and live there and do their work. Bone marrow stem cells when injected by vein go to the bone marrow, take up residence and repopulate the marrow of the patient with leukemia who just got very aggressive treatments to eliminate all of his own marrow cells (and hopefully all of the leukemia cells as well.) But would all stem cells know where to go? Or what to do? Would they go to the heart after a heart attack or do they need to be infused directly into the coronary arteries or injected into the heart muscle itself? And stem cells or stem cells prompted to develop into brain cells – will they need to be injected directly into those areas of the brain damaged by Parkinson’s or Alzheimer’s diseases? These are but a few of the issues to be resolved with careful research.

Here are just a few studies in progress, some in animals, some in humans and many in laboratory settings:

                        iPS cells have been created for multiple different diseases by taking cells from affected patients  such as diabetes type I, Lou Gehrig’s disease (amyotrophic lateral sclerosis), Gaucher’s disease  and muscular dystrophy. It is hoped that these cells will help explain the disease processes and their origination. In addition, they might prove useful in growing large numbers of mature cells that could in turn be used for drug screening and drug toxicity evaluations. And in this regard, iPSCs and piPSCs matured into cardiac cells are already being used by pharmaceutical companies to test new drugs for side effects.

We all know that if we have a tooth pulled, that’s it – a tooth won’t grow back. But an intriguing study has taken the cells of the progenitors of the molars from mouse embryos and grown them in culture for a few days. Meanwhile, a molar or two from multiple adult mice were extracted. Then the stem cells were implanted into that space and within two months the mice had new teeth with normal structure and strength, demonstrating that stem cells in the proper setting can lead to the re-growth of an organ or tissue. Think about the potential in humans to get a real new tooth rather than a prosthetic tooth or a bridge when a diseased or damaged tooth must be extracted.

One of the most exciting studies to get underway was a phase 1 trial of stem cells in patients with spinal cord damage. The Geron Company began this FDA-approved trial in late 2010. They took human embryonic stem cells and from them derived oligodendrocyte progenitor cells; in other words, nerve cells. These were injected next to the spinal cord at the level of very recent injury. In extensive animal experiments, these cells were found able to cause the damaged spinal cord cells to remylinate (basically reapply an “insulator” as with the covering of an electric wire) and to create some type of nerve growth stimulation with remarkable restoration of some or all function. The rats began to move much more normally within just a week or so of the injection. Then came the human trial. It was Phase 1 meaning that it was all about studying if the injected cells would cause any toxicity. It is a good guess that they would not but because they were be used initially in low dosage (relative to what was used in the rats to obtain responses) so it is unlikely any functional improvement would occur. That would be the test in later trials (Phase 2 and 3) with higher cell numbers provided this Phase 1 study proceeded successfully. As it turned out, Geron Corporation ended the study after enrolling just four patients citing lack of adequate funding to continue. This left Advanced Cell Technology, Inc. as the only other American company conducting a study of embryonic stem cells – for macular degeneration and for macular dystrophy in the eyes. They use embryonic stem cells to produce retinal epithelial pigment cells to be injected behind the retina in affected patients. Results will be forthcoming.

Another very early Phase I study, this one using adult stem cells, is just beginning in Israel for amyotrophic lateral sclerosis (ALS). The patient’s own bone marrow stem cells will be treated in the laboratory with a proprietary process by BrainStorm Cell Therapeutics and then placed back into patients. So far 12 of 24 patients have been treated with no apparent adverse effects. The final results will be of real interest.

As I said at the beginning, there is still much to be learned before stem cells will become routinely utilized for patient care – but progress is real and the opportunities are exciting for a major transformation of medical care in the coming years. It is becoming more hope than hype. Here, as with genomics, we see the value and the importance of innovation. Scientists with good ideas taking the steps needed to bring new and until recently almost undreamed of possibilities to transform healthcare – clearly a medical megatrend in the making.

Medical Megatrends – Stem Cells – Part II of III

Imagine a man with a recent severe heart attack who has the muscle repaired with stem cells or a child with a severe bladder defect repaired with stem cells grown on a biodegradable scaffold. Sounds like science fiction but these are actual clinical studies in progress today.

Stem cell therapies promise to be one of those scientific breakthroughs that will have an enormous impact on health care in the future. Stem cells will bring us closer to the goal of personalized medicine, just as genomics is doing. The course of a disease will change once we have the technology to develop and then insert stem cells into the human body to actually create a tissue. For example, a person with a heart attack will not go on to live the rest of his or her life with damaged heart muscle and resultant heart failure. Instead, stem cells will repopulate the heart muscle and make it whole again. Similarly, a person with Parkinson’s disease will recover full faculties thanks to the ability of stem cells to regenerate the damaged area of the brain. The person with type I diabetes will be free of the disease because of the formation of new pancreatic islet cells. The athlete will play again because new cartilage will be created for the worn knee. This is the promise of “regenerative medicine.” I have written the above as though each will definitely happen, a promise that will be kept. They probably will, but it may be a long time before the science of stem cells is sufficiently developed that these types of incredible results will be commonplace.

            Adult stem cells are being used today for treatment of a few diseases and there are studies ongoing and planned for many additional possibilities. Let’s consider a few of them. Each of our tissues has a population of cells that can divide as needed to keep the organ or tissue functional as cells die or are injured. We see this with our skin as it constantly lays down new cells which make their way to the surface as the dead cells on the surface are rubbed off in the shower. We also see it when we cut ourselves and yet in a few days the wound is completely healed – that was stem cells at work. It appears that essentially every organ has its own pool of such cells. There are cells in the bone marrow that can become stem cells for many different tissues. These cells circulate in the blood and can be called to assist a tissue or organ to rebuild itself after injury or damage. So for example, if a surgeon takes one half of a father’s liver for transplantation into his son, we know that the father’s liver will grow back to normal size within about 6 to 8 weeks. Some of the stem cells will have been those already in the liver but some will have come from the blood stream to assist. Of course, the liver is the exception to the rule that if a portion of an organ is removed by trauma or surgery, it will not grow back. Cut off your finger and stem cells will help it to heal but not to grow back to its original state. 

            Adult stem cells are the ones used for treating leukemia, myeloma and other cancers and for correcting certain childhood immune deficiencies. Most often is the use of allogeneic hematopoietic stem cell transplantation, meaning the use of stem cells obtained from a closely matched individual. An identical twin is ideal but few have such a potential donor. Only 25% of siblings will likely match completely. This leaves the use of the National Marrow Donor Registry to find as close a match as possible from unrelated individuals. The Registry has markedly improved the chances for a close match and thus for successful transplantation outcomes. Many parents are now having umbilical cord blood saved and frozen to have available in the unlikely event that their child requires a transplant many years later. Although these cells are identical they usually are not sufficient in numbers to lead to engraftment and often the white blood cells (neutrophils) recover only very slowly leaving a prolonged period of infection risk. Perhaps a technique will be found to get the umbilical stem cells to multiply in the laboratory so that a larger number would be available.

                        Adult stem cells are being used in studies of myocardial infarction and heart failure. Current guidelines of immediate angioplasty and stent insertion as appropriate help protect the heart from permanent damage after an infarct. Still, about 400,000 new cases of heart failure are developing in the USA each year. Long term survival is limited once overt failure develops. Could the damaged heart muscle be fixed? The concept is to use stem cells to repopulate the muscle fibers and to have those cells divide over and over and differentiate into new muscle fibers or perhaps also the small vessels that carry blood to the muscle cells.  So far there are some exciting animal studies and even some trials in patients that are encouraging enough to warrant further evaluations. For example, one study uses adult mesenchymal stem cells derived from the bone marrow and infused intravenously within 7 days after a heart attack. 42 centers are collaborating in this double blind, randomized trail in conjunction with Osiris Therapeutics. 220 patients will receive either the stem cells or a placebo and then be monitored with various imaging and functional studies.  So, stay tuned.

            Another common albeit less lethal problem is loss of bladder control leading to incontinence. There are studies in progress to determine if stem cells placed into the bladder’s sphincter muscle will help it regain control. The adult stem cells are obtained from a leg muscle biopsy. Stem cells are isolated and allowed to grow in tissue culture. These are then injected into the weakened bladder sphincter muscle. Once again, these are studies just beginning but with intriguing early results.

            Here is another bladder repair concept. When the bladder muscle is weak or largely missing in children it may be possible to literally rebuild the bladder by tissue engineering. A biopsy of the bladder yields cells that can be grown in the laboratory to large numbers. They can then be placed on a biodegradable scaffold and grown further. In time they seem to create a new bladder muscle wall complete with blood vessels. This layer of cells can be implanted in the bladder of children with a defect. Once more I need to note that it is still early days in these studies but they do raise exciting possibilities.

            The message here is that adult stem cells are being used today for life threatening and life impairing diseases with excellent success and are being studied in other diseases with exciting prospects for the future.

Medical Megatrends – Stems Cells – Part I of III

             New cells to replace those destroyed in diabetes type 1, cells to help heal a heart attack, cells to cure leukemia – this is the promise of stem cells. Some of this is happening now; more will be available in a few years.

Stem cells will usher in the era of regenerative medicine, allowing the creation of cells, tissues and organs to treat or cure diseases and injuries. This will be a fundamental alteration in our approach to medical care and a transformational medical megatrend. And it will be very “personalized medicine” to provide the specific individual with custom tailored new cells and tissues for organ repair or replacement.

Extensive use of stem cells as therapy is still in its infancy. Call it infancy  because  there is so much basic science still to be understood, that it will be quite some years before we will see stem cells being used on any sort of regular basis to treat diabetes, Parkinson’s disease, or heart failure after a heart attack. But time flies, many investigators are hard at work and the science may advance quickly.

There are exceptions; stem cells are being actively used for a few situations and have been for many years. Among them are “bone marrow” or stem cell transplantation for diseases like leukemia, some cancers being treated with very high doses of chemotherapy or some individuals, especially children, with immune disorders.

            Since stem cells have the potential to be of ever increasing importance to medical care, albeit not for a few years, it is important to understand just what a stem cell is, generally how the various types of stem cells differ from each other and how they are either found in the body or produced in the laboratory. The key characteristics of stem cells are that 1) they can replicate themselves and 2) they can become mature cells that make up the tissue and organs of the body.

Embryonic stem cells are found in the earliest divisions of the fertilized ovum and can become any of the body’s approximately 200 types of cells (liver, lung, brain) and they have the capacity when placed in tissue culture in the laboratory to divide and to replicate themselves indefinitely. We call them pluripotent in that they can become any of the various types of cells in the body. Think of them as the most fundamental cellular building block that can create the tissues and organs of our body.

            Adult stem cells, as the name implies, can be found in the bodies of adults (or newborns and children for that matter.) They also can self replicate but when placed in tissue culture it has not been possible to have them replicate indefinitely as embryonic stem cells do. Adult stem cells generally only can differentiate into one type of the body’s cells or tissue, i.e., are unipotent. For example muscle stem cells only become muscle cells but not liver cells. But some adult stem cells, such as those from the bone marrow, can become multiple but not all types of cells. Stem cells obtained from the umbilical cord of a newborn baby are more like adult stem cells in that they can develop into some but apparently not all cells types. In effect, they are further along in the chain of differentiation.

There are also other types of stem cells that as of now are being produced in the laboratory and which have many of the attributes of embryonic stem cells – nuclear transfer, induced pluripotent, and protein-induced pluripotent stem cells, among others. To create the nuclear transfer stem cell, an unfertilized egg is obtained from a woman’s ovary. The egg has its nucleus extracted by a micropipette and then has the nucleus of an adult cell inserted in its place. This nucleus might be obtained from a skin cell taken from the arm of a patient with a particular problem such as diabetes. The newly created cell is placed in culture and with the appropriate signals begins to act like an embryonic stem cell in that it will divide and replicate itself and with the appropriate signals the daughter cells can become various body cell types. The hope is that these cells, genetically identical to the patient who had the skin biopsy, could be grown up into a vast number of – in this example – pancreatic islet cells and used to treat this individual patient’s diabetes. 

The induced pluripotent stem cell (or iPSC) also has many of the embryonic stem cells’ characteristics. It is produced by taking a person’s cells such as from the skin of the arm and then stimulating them by inserting a few key genes, using a retrovirus. These genes reprogram the cell to revert to what is similar to an embryonic stem cell. The concern of course is that it is induced using a virus. More recent experiments have found that certain proteins can reprogram the cell just as can the virally-inserted genes. These stem cells are known as protein-induced pluripotent stem cells (piPSC). Both are being evaluated to determine if they can be as effective as embryonic stem cells. With each of these three techniques, a clear hoped for advantage is that a person can donate his or her own cells for transformation into stem cells and from there into whatever cell is of interest, such as pancreatic islet cells that secrete insulin. Such cells transplanted back into the person would be recognized as “self” and not trigger rejection with a graft vs. host response by the body. This concept with each technique is therefore all about “personalized medicine.” 

Next time I will delve more deeply into adult stem cells followed the next time by embryonic stem cells. But in the meanwhile think of stem cell science as one more of those truly transformative medical megatrends that will revolutionize the practice of medicine in the years to come and in the process improve the healthcare of you and your family.