The Doctor Weighs In

By Dov Michaeli MD, Ph.D

Stem cell research is hot, and getting hotter. Big deal, you might think. This esoteric topic may be important for some scientists, or maybe a few politicians—but what’s in it for me? Let me tell you right off: a lot more than you can imagine. Just consider the statistics, and do the math of your odds requiring one day stem cell therapy.

Heart disease:

• Almost 1 out of every 2.4 deaths in the USA result from cardiovascular disease, or CVD.
• Since 1900, CVD has been the leading cause of death in every year but one - 1918. In that year, the main cause of death was the Spanish Flu pandemic.
• About every 29 seconds an American will suffer a coronary event.
• About every 60 seconds, someone dies from one.
• At least 250,000 people die of heart attacks each year before they reach a hospital.
• It is a myth that heart disease is a man's disease. In fact, cardiovascular diseases are the number one killer of women (and men). These diseases currently claim the lives of more than a half a million females every year - more than the next 16 causes of death put together.

Diabetes (type 2):

· As of 2005, 20.8 million people—7.0% of the population—had diabetes; According to recent CDC figures, there are approximately 798,000 new cases of type 2 diabetes annually in USA, most are Type 2 diabetes.

· According to the WHO figures, there were 173 million cases of type 2 diabetes worldwide in 2002.

· Type 2 diabetes confers a two to four-fold greater risk of coronary heart disease among men and a three to five-fold increased risk among women.

· Diabetes also magnifies the effect of raised cholesterol levels, raised blood pressure, smoking and obesity and so influences coronary heart disease risk indirectly.

· Number of deaths with diabetes as underlying cause of death climbed form 34,500 in 1980 to 62,000 in 1996—an increase of over 44% in 16 years.

· Diabetics use medical resources at a higher rate than average nationwide. Diagnosed diabetics constitute about seven percent of the total population, but diabetes costs account for about 13-14% of all health care expenditures. Diabetes treatment costs about $113 billion a year - more than three and a half times as much as the care for non-diabetic patients.

Alzheimer’s disease:

· There are now more than 5 million people in the United States living with Alzheimer’s. This number includes 4.9 million people over the age of 65 and between 200,000 and 500,000 people under age 65 with early onset Alzheimer's disease and other dementias. This is a 10 percent increase from the previous prevalence nationwide estimate of 4.5 million.

· Every 72 seconds, someone develops Alzheimer’s.

· Without a cure or effective treatments to delay the onset or progression of the Alzheimer's, the prevalence could soar to 7.7 million people with the disease by 2030. By mid-century, the number of people with Alzheimer's is expected to grow to as many as 16 million, more than the current total population of New York City, Los Angeles, Chicago and Houston combined.

· As the prevalence impact of Alzheimer's grows, so does the cost to the nation. The direct and indirect costs of Alzheimer's and other dementias amount to more than $148 billion annually, which is more than the annual sales of any retailer in the world excluding Wal-Mart.

Parkinson’s disease

· There are about 1.1 million people in the U.S. diagnosed with Parkinson’s disease. This is a rate of about 360/ 100,000 people. The rate for people over 65 is about 3%.

· The most detailed report on the economic impact of PD was prepared in 1998 for the Parkinson's Disease Foundation. This study estimated the per-individual yearly cost of PD in 1997 at $24,041 ($24,425 in 1998). Based on a prevalence of one million affected individuals, the total economic burden was calculated at $24 billion.

So there you have it. I listed only four diseases that may be amenable to stem cell therapy. The reason I included the costs of these diseases is to highlight the cost to you, in the form of health-care insurance and direct costs, before you die.

What is a stem cell?

Just think of it as the stem of a plant, which gives rise to the branches and leaves. The developing embryo is formed by a few cells that have the potential to develop into any of the body’s almost 200 cell types. We call such cells ‘pluripotential’, and when their origin is from an embryo they are called ‘embryonic pluripotential cells’. It turns out that every fully formed tissue-- be it blood, neurons, heart—maintains a small reservoir of pluripotential cells, albeit less “pluri” than the embryonic ones, because they are destined to develop into only one or a few specific tissues. This is biology’s form of insurance, in case a certain tissue is in need of repair or regeneration. Alas, in the course of evolution we lost our capacity to regenerate new heart muscle or new brain cells, although the cells are still there, dormant.

The big debate the country went through was over the use of cells derived from a (discarded) blastula (an early stage of embryonic development, consisting of a spherical layer of around 128 cells surrounding a central fluid-filled cavity). Some people saw it as tantamount to murder; others saw the tilting of the moral balance in favor of a discarded agglomeration of 128 cells over the suffering of millions of living people as incomprehensible, if not unconscionable.

The new discovery: genetically manufactured stem cells

Last week Shinya Yamanaka of the University of Kyoto reported that his team has created pluripotent cells from human skin cells, or fibroblasts. On the same day, a team of researchers led by James Thompson at the University of Wisconsin, Madison, reported the same. Do you get the sense that there must have been a fierce race underway to reach this goal? You are absolutely right. Here is what happened.

Last year Yamanaka discovered that introducing four proteins called transcription factors into mouse skin cells ‘reprogrammed’ the cells into embryo-like state. There are thousands of different transcription factors in every cell nucleus, and their function is to regulate gene expression. The discovery that only four transcription factors can induce such a profound change in the character of a cell is astounding. But this was in mouse, and there are basic differences between human and mouse cells. Yamanaka knew that his publication would trigger an intense race to accomplish the same feat in human cells. He worked 16 hour a day, seven days a week, and reported last week that the same four factors produced the same results in humans. The cells were taken from the face of a 36-year-old Caucasian woman. He repeated the exercise with cells from joint fluid from a 69-year-old man with similar results.

Back in Madison James Thompson read Yamanaka’s mouse experiment with more than passing interest. After all, he was the discoverer of the method to propagate human embryonic stem cells. He immediately set out to repeat Yamanaka’s experiments in human cells, with two differences. The first was the source of the skin cells: he obtained them from foreskin, which is fertile ground for a lot of internet jokes but is otherwise of no import. The other difference is important; he used four transforming factors, but only two of the ones used by Yamanaka. He avoided one factor, c-myc, because it is associated with cancer. The fact that he could use different transforming factors suggests that in the future, scientists will have great latitude in the formation of ‘induced pluripotent stem (iPS) cells’, maybe of different traits and capabilities.

The future is bright

These were the first two teams to reach the finish line. Many more are still racing. With researchers crowding into the field rapid advancements are certain. As several scientists ecstatically stated, this is a paradigm shift in reprogramming cells, and will relatively soon result in patient-specific pluripotent cell therapy. Many obstacles remain, but all are surmountable; the big breakthrough has been accomplished. The grim statistics of heart disease, diabetes, neurological diseases, and probably cancer, will become a lot less menacing.

Dov Michaeli MD, Ph.D is in the biotech industry

By Dov Michaeli MD, Ph.D

The sometimes acrimonious debate over the use of human embryonic stem cells usually follows this outline:

Con : We respect all life, however primordial. The blastocyst is a potential human being and deserves all the ethical considerations of a living human.

Pro : The blastocyst is just an agglomeration of cells formed within one week of fertilization of the egg, still undifferentiated into organs such as a heart, GI tract or nervous system. There is nothing “human” about it. And in any event, these embryos are destined to be discarded by the fertility clinic.

Against the theoretical/ theological argument of respect for potential life, the promise of curing  presently incurable diseases is real, not theoretical, and the beneficiaries are live, suffering human beings, not cells in a dish with a vanishingly small potential of becoming a human embryo.

Con: We cannot play God and decide who should live and who should die. However small the potential of the potential for life—it is still there. And in any event, the potential for using embryonic stem cells for therapeutic purposes is theoretical at best. So far, not one therapy or potential therapy has been scientifically demonstrated.

The last argument has just been demolished

The online edition of the August 26, 2007 Nature Biotechnology published an article by scientists from the University of Washington and from Geron Corporation. They created a myocardial infarction in rats that mimicked the human variety in every significant detail. They then transplanted cardiomyocytes (heart muscle cells) derived from human embryonic stem cells into the infarcted or dead heart tissue and observed that:

· The heart was partially revascularized.

· Heart failure was reversed.

· Contractile function of the heart was restored to pre-infarction level.

What now?

• This experiment will need to be replicated, preferably by another research group. If the results of the repeat experiment confirm these spectacular results it will be tried in humans, whether in the U.S. or elsewhere.
• Could similar experiments with neuronal cells be far behind? In fact, some are already ongoing.

And the societal ramifications?

The somewhat esoteric, academic/ethical/moral debate will assume a much higher degree of intensity: every patient with heart failure or myocardial infarction will have a real life interest in the issue; for many it will be literally an issue of life and death. And the caregivers and families of Alzheimer's disease patients? And spinal cord injury patients? And cancer patients? For all of them and their families it will be an overriding political issue. We are talking about many millions of voters with a personal interest in the issue. Who ever thought that science might one day be the cause of a political earthquake?

Interestingly, the ones with the sharpest appreciation of this development are not politicians or government bureaucrats, but Wall Street investors who put their money where their mouth is. Here is Tobin Smith, one of the most insightful among them:

“ OUR TAKE: The implications of this study are mind boggling -- I mean simply breathtaking. This is the futuristic stuff that gives us the reason to buy GERN on pullbacks”.

Now, I wouldn’t rush out and buy Geron stock; it will be many years before they realize one dollar of profit. But the advance reported in this study is indeed breathtaking.

Dov Michaeli MD, Ph.D works in the Biotech industry.