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.

Surprise – Adolescent Obesity Leads To Later Heart Disease and Diabetes

Well, probably not a surprise at all. The seeds of coronary artery disease (CAD) are laid down early and over long periods. But given our current pandemic of obesity beginning in childhood, should we worry about an epidemic of chronic disease like diabetes and CAD in the years to come? The clear answer is a resounding “Yes.”

There has been a long term study of military men in the Israeli Defense Force. An article in the New England Journal of Medicine, April 7, 2011 reports on what happened over an average follow-up of 17 years after army induction at age 17 for those who chose to remain in the military after the required three years. This amounted to 37,674 healthy men followed for about 650,000 person years. Among them, 1173 developed diabetes type 2 over time and 327 developed angiography-proven CAD. All by the age of 45.

Here is the baseline data:

Blood pressure, resting heart rate, fasting blood sugar, and low density lipoprotein (LDL – the “bad stuff”) and smoking incidence progressively increased with increasing BMI (BMI, a calculated ratio of weight and height) among the 17 year old inductees. High density lipoproteins (HDL – or the “good stuff”) declined as did the amount of weekly exercise with increasing BMI.



Here is the follow-up data:

Since this was a study of men beginning at age 17 and lasting an average of 17 years, it follows that the 327 cases of CAD and 1173 of diabetes were among relatively young men – aged 25-45 years old. When the investigators adjusted for age, family history of CAD, blood pressure, smoking status, LDL, HDL and triglycerides they found that an elevated BMI at age 17 was a significant independent risk factor for CAD. Indeed the risk increased by 12% for each increment of 1 unit of BMI. They also noted that CAD occurred even in those with BMIs that are generally considered within the acceptable range today.

BMI at age 17 also predicted for the later development of diabetes mellitus type 2 (DM) with risk increasing about 10% for each additional 1 unit of BMI. But with diabetes, it was the adult level (age 25 and beyond) that was associated with a greater increase in diabetes relative risk. Said differently, higher levels of BMI at age 17 correlate with higher risk of CAD and diabetes in early adulthood. Persistent elevations of BMI increase that risk. Elevation in early adulthood increases the risk of DM during early adulthood whether or not the person had a higher BMI at age 17.

My takeaway:

It is imperative to intervene now in the growing pandemic of childhood and adolescent obesity. Even modest increases BMI can predispose to later CAD and DM. Once developed, these are chronic illnesses that persist for life, are challenging to manage, are expensive to treat and have a high impact on both quality of life and longevity. Our children are our future; it is our obligation to protect them. And if that is not reason enough, then think of your wallet. The high costs of their care will have a very significant impact on each of us in our taxes and our insurance premiums.

The Incidence Of Kidney Failure Due To Diabetes Is Down – But We Should Not Be Pleased

Diabetes mellitus is the most common cause of kidney failure that progresses to end stage renal disease (ESRD,) meaning that the person requires dialysis or kidney transplant. ESRD is chronic and life long, is complicated to treat, has a major negative effect on quality of life and the costs are high.


So it was good news when the Centers of Disease Control reported that the incidence of ESRD among diabetics had declined by about 35% over the ten years ending in 2007. The reasons for the decline are not known but a few assumptions seem reasonable. More and more patients now keep good control of their blood sugar with careful monitoring and many also keep their blood pressure under control with anti-hypertensive medications. Further, it has been shown that angiotensin-converting enzyme inhibitors (or ACE inhibitors) and angiotensin-receptor blockers (or ARBs) slow the decline of kidney function in those with diabetes and early kidney failure. It is believed that as many as 80% of these patients are taking ACE or ARBs – a good thing. All of these may be the factors that have led to this decline of diabetes to kidney failure; or there may be others as yet not appreciated.

But the news really is not so good. The decline in kidney failure incidence was offset by a much increased absolute number of individuals with diabetes developing kidney failure. Why? Because there are so many more individuals developing diabetes now than just a decade ago – so there are more people at risk of and therefore developing kidney failure.

We can be pleased that secondary prevention approaches are slowing the onset of kidney failure among those with diabetes but we should be aghast that so many of our fellow citizens are setting themselves up for a high risk of diabetes as a result of obesity.

The message - the real need is to accelerate efforts to stop the epidemic of obesity (excess consumption of not very nutritious food compounded with a sedentary lifestyle, including in adolescents.) Obesity is the primary culprit leasing to the rapidly rising number of individuals with diabetes.

Encapsulated Pig Islet Cells For Diabetes Type 1 – A Trial

Here is a follow-up to the post on islet cell xenotransplantation for type 1 diabetes mellitus. A group in New Zealand has been studying the use of islet cells derived from pigs which have not been genetically modified. The cells are encapsulated to protect them from immune cells. The company reports that they are self regulating (meaning that they will produce insulin as needed based on the body’s blood sugar levels) and efficient at secreting the insulin produced into the patient’s body. The investigators report on one patient that is now nearly 10 years since transplantation with persistent functioning islet cells. Dr John Baker and Living Cell Technologies are conducting the human trial after having tested their product in multiple animal models. The material below, taken from the US National Institutes of Health Clinical Trials web site [http://tinyurl.com/2fmcnp6 ], was prepared by the company and its investigators:

“Intraperitoneal islet transplantation has the potential to ameliorate type 1 diabetes mellitus and avert the long-term consequences of chronic diabetes which cannot be achieved by conventional insulin treatment.

As donor human islets are not available in sufficient numbers, porcine islets are the best alternative source as they are recognised as the most physiologically compatible xenogeneic insulin-producing cells. Although the use of pig-derived cells raises the risk of xenotic infections, this can be minimised by obtaining cells from designated pathogen-free (DPF) animals bred in isolation and monitored to be free of specified pathogens. The worldwide experience to date in more than 200 patients who have received transplants of pig tissue has not demonstrated evidence of transmitted xenotic infections.

As animal-derived tissues have to be protected from immune rejection when transplanted into humans, transplants are usually accompanied by immunosuppressive therapy. However, porcine islets are preferably transplanted without the use of immunosuppressive drugs which cause significant morbidity. To protect them from immune rejection, the islets can be encapsulated in alginate microcapsules which permit the inward passage of nutrients and glucose and the outward passage of insulin. Alginate-encapsulated porcine islets transplanted without immunosuppressive drugs have survived rejection for many months in animal studies, and have been retrieved from a diabetic patient over 9.5 years after intraperitoneal transplantation and shown to contain viable islets that stain positive for insulin.

DIABECELL® comprises neonatal porcine islets encapsulated in alginate microcapsules. DIABECELL® has been safely transplanted in healthy and diabetic mice, rats, rabbits, dogs and non-human primates. Following DIABECELL® transplants, the requirement for daily insulin was significantly reduced in diabetic rats and non-human primates.

The optimal dose and frequency of transplantation of the current DIABECELL® preparation for the treatment of type 1 diabetes in humans can only be determined in clinical trials. The intention of this phase I/IIa clinical trial is to obtain at least 52 weeks safety and preliminary efficacy data in type 1 diabetic patients following transplantation of a single low effective dose of DIABECELL® into the peritoneal cavity.”

The results of this study, still a few years off, will be of great interest to those whose diabetes is hard to control with standard insulin approaches.

More on Transplanted Pig Organs – Xenotransplantation

Although xenotransplantation has not progressed far enough to allow transplanting a pig organ to a human, there are other exciting opportunities in the works for xenotransplantation in the not to distant future.

Individuals that develop liver failure often die before a suitable donor can be found or before the damaged liver can heal on its own. There is no artificial liver comparable to the dialysis machine for kidney failure. But using a specially develop pig liver outside the body to cleanse the person’s blood of noxious compounds is a possibility. There have been some positive results using a normal or a genetically modified pig liver for such “extracorporeal” perfusion until a donor organ is available or until the patient’s liver recovers on its own.

Progress has also been made with genetically modified insulin-producing pancreas islet cells for treating diabetes. One approach is to place the transplanted islet cells into a “capsule” that allows insulin to exit out and nutrients like glucose to enter in yet keeps immune cells that would destroy the islet cells at bay outside the capsule.
Further progress in xenotransplantation is likely but there are significant barriers to success. Genetic modification of the pig is possible but it is not yet clear all of the modifications that will be necessary. Concurrently, work is progressing to develop immune modulation with drugs just as is done to suppress the immune system with human to human organ transplants. Further development of encapsulation may aide the process, especially with islet cell transplantation for diabetes.

Despite all of the progress to date, the barriers to success are very real and only time will tell if xenotransplantation will become a truly viable path to organ replacement