The Doctor Weighs In

By Dov Michaeli MD, Ph.D

Have you ever looked at the list of ingredients on the foods you buy? I can guarantee that you’ll be hard put to find even one item that does not contain fructose in one form or another: it could be straight fructose, or masquerading as corn syrup, or sucrose (table sugar) whose content is 50% fructose. I recently checked 10 items in my foray to the local Safeway store; of the packaged foods, all ten contained fructose in one form or another. It's found in ketchup, fruits, jellies, pastries, and many processed foods. Even sugar substitutes can have high fructose corn syrup in them.

So what of it? Plenty.

Fructose and metabolic syndrome

One of the hallmarks of metabolic syndrome diagnosis is insulin resistance. What it basically means is the following: When glucose level in the blood gets to a certain level, glucose sensors in the beta cells of the pancreas initiate a commensurate release of insulin. The insulin binds to its receptors in the various tissues, and that results in uptake of the glucose by the cells and its utilization for energy and storage.

But something funny happens on the way to the insulin receptor when fructose undergoes metabolism: one of the end products is uric acid. Yes, the same compound that ends up in the urine, and that can cause such unpleasant things like kidney stones and gout. But uric acid turns out to do even more harm—it causes the cell to become insensitive to the message that insulin is trying to convey: take up more glucose from the blood. End result: increasing blood glucose levels, or hyperglycemia. And this, in turn leads to obesity and diabetes type 2.

The new food indexes

Beginning next year (and that’s in about 2 weeks) you will start seeing on the packaging of the foods you buy a new “index”: the nutritional value scale. One of these scales will use a numerical value, on a scale of one to one hundred, with 100 being the most nutritious. Others will use a star system, with 3 stars being the “best for you”. This is a laudable effort, initiate by academics specializing in nutrition science. But the subject of nutrition is so complex that I am sure each one of these scales will be subject to withering criticism. One of the reasons is that if real foods, no substance acts in isolation; grapes contain glucose, but dark-skin grapes also contain a high concentration of antioxidants. How do you balance the two? Or more relevant to the point of this article: apples, for instance, are high in fructose but also contain many other substances that far outweigh the latter’s deleterious effects. Will the new scales be able to account for that?

Caveat emptor

Be vigilant: check the label and look for fructose in all its disguises: corn syrup, corn fructose, or just fructose hiding in plain view. Sounds a bit paranoid? Next time when you in are the supermarket, do the experiment; check out the labels and you’d be amazed.

Interestingly, most food companies blamed the rising costs of corn (which nowadays is diverted to another political boondoggle—corn-based ethanol) for their poor financial results and the need to raise prices in the last two quarters. Corn, you might ask, in oat or wheat cereals? Yes, check the label: it is laced with corn syrup, which is nothing but a high-concentration solution of fructose.

Another interesting thought: could it be that our obesity/ diabetes epidemic is not entirely due to excess calories per se, but partly due to the ubiquitous fructose in our foods? This is quite conceivable; fructose is a food of extremely high glycemic value (namely, causes a rise in blood sugar) because of its high caloric content and because of its glucose resistance action.

So in this Christmas shopping season, here is one two-for-the-price-of-one bargain you should definitely pass up.

By Dov Michaeli MD, Ph.D

It is a well-known phenomenon: people under stress hit the fridge, and gorge on candy and fatty food. A gallon of ice scream in one sitting is not unheard of. But people who think deeply about such things asked themselves: why don’t they (people under stress) gorge on veggies? And what is the nature of the connection between stress and obesity? Is it simply overeating equalsobesity, or is there a deeper connection, involving the brain? After all, stress is a mind thing.

The physiology of acute stress

Almost every physiological action in our body is controlled by two systems: the autonomic nervous system, and the endocrine system.

The autonomic nervous system has this name because it is, well, autonomic: it marches to its own drum, if you will, independently of our whims, wishes or commands. This system is made up of two sub-systems: the sympathetic and the parasympathetic. Basically, they are the Yin and Yang of the autonomic nervous system: the sympathetic nerves secrete noradrenaline, a close relative of adrenaline, and it does everything you’d expect it to do: it accelerates the heart rate, increases blood pressure, in short: it readies the body to react to acute stress situations. My favorite example: you spot a lion coming at you. You want to supply ample blood to your muscles so you can run for your life, or if you are foolish enough, fight the lion; hence the increase in heart rate and blood pressure. The parasympathetic system secretes the neurotransmitter acetyl choline , and it has exactly the opposite action: it slows down the heart and reduces blood pressure.

The endocrine system reacts to stress by releasing two ‘stress hormones’: cortisol from the brain and adrenaline from the adrenal gland. Their action is similar to that of the sympathetic nervous system: increase blood pressure and heart rate.

The other type of stress

So far so good; but how does increased heart rate cause obesity? The answer is: it doesn’t. What I just described is the response to acute stress, and our bodies are well-adapted to handle it. But modern life added another type of stress: chronic stress. And here, a peptide, called neuropeptide Y, or NPY, comes into play. Its existence has been known for several years, but its function was largely unknown. It is expressed throughout the brain, but is especially abundant in circuits that regulate feeding and response to stress. Not surprisingly, like many other brain hormones, it is also secreted in tissues outside the brain that are involved in metabolism; it is secreted by sympathetic nerve endings in adipose tissue. Its function there has only recently been defined by Kuo and his coworkers. It increases adipogenesis (formation of fat tissue) by triggering both the formation of new adipocytes (fat cells) from immature preadipocytes, and by increasing the blood supply to the adipose tissue by formation of new blood vessels (a process called angiogenesis). Even more intriguing: the new fat tissue was not formed just anywhere in the body; it was formed in the abdomen, and specifically around the internal organs of the abdomen. This is exactly the fat distribution that is implicated in the genesis of metabolic syndrome. And to clinch the case: it does it only under severe chronic stress conditions. When mice were subjected to 2 threatening and severe chronic stress protocols, they secreted NPY; when they were subjected to non-threatening mild stress—no NPY. In biological experiments demonstration of a relationship between the “dose” (e.g. severity of the chronic stress) and “response” (e.g. secretion of the peptide), lends credibility to the observation, simply because in biology almost everything is dose-dependent.

Why do we prefer sweets and fats?

The mice in the experiment secreted NPY only if allowed to eat fatty or sugary food. Regular mouse chow did not support secretion of the hormone even under severe chronic stress conditions. We know that high calorie food triggers the reward circuits in the brain. In fact, chronic feeding of high calorie foods activates all the circuits and brain centers that are involved in addiction. That, in turn, induces more eating, which increases the degree of addiction, which… you get the drift. Bottom line: obesity.

The details of the connection between secretion of NPY and high calorie food still need to be worked out. Why didn’t regular, low calorie food have the same effect? What are the specific neural circuits involved in this calorie/reward/peptide axis of evil? What is the mechanism for the specific accumulation of fat around internal organs? Will withdrawal of high-calorie food result in reversal of the accumulation of fat back to normal?

Obviously, many unanswered questioned are triggered by this research. But this is the hallmark of good science: every answer raises many more questions.

In summary

NPY is the link between stress and obesity. Its action:

• Secreted from the sympathetic nervous system only under conditions of chronic severe stress
• Increases adipogenesis by triggering adipocytes formation from preadipocytes, and by increasing blood supply to the adipose tissue
• Secreted only when high calorie diet is available
• Involves the activation of reward circuits in the brain
• And last but not least, it induced a state of metabolic syndrome (obesity, insulin resistance) in the experimental mice.

What is the relevance of this research to human obesity/metabolic syndrome?

Obviously, this phenomenon needs to be demonstrated in humans. Demonstration that NPY levels are markedly higher in chronically-stressed individuals will be a big step forward. Inhibition of secretion of NPY through drugs or stress reduction techniques will add weight to the hypothesis.

The big prize: demonstration of weight reduction through reduction of NPY secretion will be a boon to us and to our strained health care budget.

Here is a thought that may have occurred to you: can our increasingly stressful lifestyle be partly responsible for the obesity/metabolic syndrome epidemic?

Another thought: rather than wait for the results of these experiments to yield the ultimate proof, why not toss out all the sweets and high calorie foods, and stock the fridge with “good for you” veggies? No activation of the reward system in your brain=no NPY secretion. Not very appetizing solution, I know. I’d rather wait for the results of the human experiments, and then decide.

Epilogue

My estimate is that to carry out the required experiments in humans would cost about $10-20M. To develop and clinically test an NPY inhibitory drug could cost anywhere from $50-100M. Can the health care mavens quickly calculate what would be the ROI (return on investment) on this sum?

By Dov Michaeli MD, Ph.D

Every Sunday morning we have a family ritual: 8-9 in the morning it’s “Meet the Press”, 9-9:30—the Chris Matthews Show. And while the TV is blaring and we OD on politics, we walk on the treadmill or step on the elliptical, do abdominals and pushups, do Yoga and lift weights—in short: we indulge our political and fitness addictions simultaneously, and feel self-righteous and quite superior to the flabby unwashed masses.

I love to watch Chris at his best: benignly opinionated, urging his guests to express their opinion on a political subject before pronouncing the Matthews ‘truth’ (“Tell me something I don’t know… here is what I think”), full of lively energy; the man is manifestly enjoying exposing hypocrisy, mendacity, stupidity and other ills of our political leading lights.

So guess how surprised I was when I found out that Chris Matthews makes stupid mistakes, like any one of us. As I sorted through today’s mail my eyes fell on the cover of the latest issue of Diabetes Forecast. There he is on the cover, smiling his heart-melting Irish smile, over the title: “Chris Matthews: the Hardball host goes head-to-head with type 2”. I guess for the readership of this magazine there is only one sort of “type 2”— diabetes. Chris was interviewed by Dan Gilgoff, the politics editor of Beliefnet.com and author of The Jesus Machine: How James Dobson, Focus on the Family, and Evangelical America are Winning the Culture War. (I can’t resist a digression here. Dan, don’t fret: Dobson, Focus on the Family, and Evangelical America are losing the cultural war!).

The interview was an eye-opener for me. I have to admit, I used to attribute much of the American people’s lack of sophistication in health matters to poor education. No more; here is a highly educated individual, possessing an uncanny capacity to ferret out ignorance, stupidity, and dishonesty who betrays an incredible degree of ignorance when it comes to his own health.

Here are some excerpts from the interview, along with some gratutitous comments.

Q. You knew for years that you had diabetes but did very little about it.

A. … I had malaria after coming back from a trip to South Africa in 2001, but what I kept [hearing about] from my doctor was my high blood sugar levels. And I said, “What does that have to do with anything?”

Comment: Chris, with your sharp ear to nuance and encrypted messages—what did you think your doctor was trying to tell you? And you, doctor, were you too pressed for time to press your point home? By the way, going to South Africa without taking the Malaria pills? Did you think you were beyond the reach of lowly creatures such as mosquitoes?

Q. But you more or less ignored your diabetes until even more recently, right?

A… I also wasn’t doing any kind of dieting. I was aware of a general need to skip some things. The toughest habit is going to an airport in the morning when you haven’t had breakfast and seeing the pastries there. Hunger is the best chef—you see a couple pastries and have that and a cup of coffee for breakfast. There was a time when I’d have a hamburger and French fries for lunch with a beer or white wine, and I’d have cheesecake for dessert. It was pretty outrageous.

Comment: I agree. Many a time did I find myself struggling to walk past the Peet’s and Starbuck’s Coffee stands at the SF airport, without succumbing to the temptation of the pastries. But where was your doctor? How come you weren’t warned about pastries, hamburgers, French fries, beer or white wine for lunch? This is inexcusable.

Q. Did you consider reforming your diet after learning about your high blood sugar levels?

A…. I didn’t say, “Wait a minute, this is something I can reasonably deal with.” I didn’t understand the importance of it or the doability of it—that I could solve this problem, that it would be over, and I would be just like everybody else….

Comment: That he didn’t understand the importance of it is in part his doctor’s fault, and in part Matthews’ own dismissive attitude when confronted with inconvenient facts.

Q. You stayed in the hospital a few days. How scary was it?

A. When you have three doses of morphine and it still hurts, you begin to worry.

Comment: And I am sure you went back to your TV show, blasting any and all comers for their lack of clear solutions to our health care problem. Chris, it is people like you who are part of the problem.

Q. You’ve certainly lost a good bit of weight in the past year.

A. On my scale at home I’ve gone from around 235 to about 205, and I think I can lose some more if I do a little more exercise. I really haven’t done any exercise to lose all this weight, just changing what I eat.

Comment: Chris, I watch you every Sunday on TV. You need to lose a minimum of 20 more lbs. You may rid yourself of the daily insulin injections, and as a bonus, you’ll wow the beautiful female political commentators on your show if you lost 40 lbs, and exercised!

Q. Why your aversion to exercise?

A. Don’t have any time. When am I going to do it?

Comment: What a lame excuse. There are people who run multi-billion dollar enterprises who find time to exercise. You make time, Chris. Get up one hour before you normally do, and just do it. It is going to grow on you, it will energize you to go after the bad guys, and you’ll feel sick on days that you skip—I guarantee it.

Q. As a public figure, do you feel obligated to send a message about diabetes?

A. What people ought to be told about diabetes is that if they have it in the family or sense that they’re on the road to it, they should go to their doctor and ask him what he thinks and actually listen to the doctor like they would use [their] financial advisor.

Maybe it’s an Irish thing—we like to think we can talk our way out of things or that we can avoid them. But I’ve come to respect doctors a whole lot through this whole thing because they know what they’re talking about and they’re telling you to do something for your own good.

Comment: You are right, Chris; people ought to listen, even more than to their financial advisor. It is a matter of their health and life—pretty existential stuff.

But you are wrong about it being an “Irish thing”. I have had Russian patients come in with a list of medications and treatments they had decided they needed, and all attempts at telling them otherwise were a waste of time. My own father would go to the doctor only to tear up the prescriptions he was given and treat himself with his grandmother’s nostrums. And my Rabbi told me that when your Celtic forefathers had no idea that the emerald island even existed, the Jews of Ireland already suffered from diabetes. And why did they have diabetes? Because they didn’t listen to their (Jewish) doctors.

See you next Sunday on TV.

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

By Dov Michaeli MD, Ph.D

How many of you watched a sumo wrestling match? I’d bet not too many. Let me tell you—it is absolutely fascinating, but for reasons that have nothing to do with the sport per se. The rules are very simple, almost childish. Two wrestlers face each other in a circle and push and shove attempting to have the opponent step outside the circle boundary. It reminded me of a game I used to play in elementary school, where two kids, hopping on one leg were pushing on each other trying to have the opponent land on both feet.

There were two things that fascinated me about the sumo match I saw in Tokyo.

The ritual

Sumo goes back hundreds of years in Japanese culture, and has its roots in ancient religious rituals. Coming to think of it, the classical Greek Olympic Games were also part of religious rituals.

When the two sumo wrestlers get into the arena they launch into an elaborate “dance”, bowing and embracing each other. Being the cynical Westerner that I am, I thought all this display of respect a bit phony; why can’t they just get down to business without wasting time on archaic rituals? My Japanese friend set me straight. These rituals are very meaningful to modern Japanese spectators just as they were to ancient ones. They connote the philosophy that being civil to each other cannot be checked out at the door even when one is going to engage in fierce combat. In one of the matches a Croatian wrestler who apparently was ignorant of the importance the Japanese attach to the ritual, went through the motions without conviction; a murmur of disapproval wafted through the audience.

The other ritual is just as interesting. Both wrestlers cast salt on the circle’s ground. Even my Japanese friend was at a loss explaining its meaning. I later found out that, like in virtually all cultures, salt held great importance and was a symbol of well-being and friendship. Hence the custom of greeting with bread and salt. And hence the expression “salt of the earth”. What the wrestling ritual meant was probably both: an homage to the opponent as “salt of the earth”, and wishing him (there are no female sumo wrestlers, yet) prosperity and well-being. But enough of obscure rituals; this is a health blog.

The other fascinating thing

I was watching those grotesquely obese behemoths (400 lbs is considered light weight) and wondered what awaits them when their career would be over in a very few years. Are they all going to get type 2 diabetes? Is their mortality rate due to heart disease astronomically high?

To put things in perspective—these wrestlers are not fat slobs, they are just fat. In medicine we classify them as morbidly obese, yet there was nothing morbid about them; they had humongous heft, and enormous power. They are usually recruited from Japanese villages by scouts who scour the countryside in search of extremely fit, strapping young farm boys. They bring them to the Big City, subject them to a grueling regimen of physical training that would put the Marines boot camp to shame, and basically force-feed them. The rationale is simple: winning in the arena depends on momentum, and in high school physics we learned that momentum= mass x speed. So they build up their mass, and they train them for speed, agility, and overall fitness.

Once they retire from the sport these gladiators don’t sink into a morass of depression, alcoholism, overeating, and disease. Most of them are kept on as ushers, ticket takers, etc.; and they keep in shape. I saw some of them, and I wouldn’t advise Schwarzenegger to tangle with any of them. I inquired about their health status after retirement, and to my surprise they were pronounced hale and fit into their 70s and 80s. I did not have an explanation. Received wisdom dictated that these people are sitting ducks for diabetes and heart disease.

The answer, finally

I have to admit that every time I preached the benefits of weight control and the penalty sinners would inevitably have to pay, I had this nagging doubt: what about those sumo wrestlers?

In a recent JAMA article scientists from the University of South Carolina in Columbia looked into the issue of adipocity (fatness) vs. cardiorespiratory fitness as determinants of death. In a 12-year study, researchers found that among 2603 American adults over 60 years old, those who engaged in cardiovascular activity were living longer than those who exercised less, even when they had the same amount of body fat. Previous studies have shown that both the level of cardiovascular fitness and the amount of body fat played a role in the health of older Americans. But this study shows that cardiorespiratory fitness helps adults over 60 live longer, regardless of body fat.

The authors conclude: In this study population, fitness was a significant mortality predictor in older adults, independent of overall or abdominal adiposity. Clinicians should consider the importance of preserving functional capacity by recommending regular physical activity for older individuals, normal-weight and overweight alike.

So there, finally: the puzzle of the healthy sumo wrestlers solved. But more importantly for us soft and overweight weaklings: exercise, exercise! It is literally a question of life and death.

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

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

In 2005, a team of investigators at the Center for Disease Control and Prevention, or CDC, published a paper that shook the foundations of our long-held beliefs; they found that death rates due to overweight (BMI 25-30) and obesity (BMI >30) were actually lower than death rates due to underweight. The paper came under withering criticism by scientists and nutritionists who had been preaching the gospel of weight control. “Libertarian” organizations funded by the food industry, such as “Food Freedom”, piled on with glee. Their basic message: you can’t trust those scientists; just let the consumer beware (and, I presume, let Darwin and the forces of the “free” market weed out those who did not).

The most serious criticism of the study was that it was not even a prospective study, let alone a controlled one. It had a retrospective design, the least reliable of epidemiological studies. Furthermore, it relied on death certificate reports, notoriously inaccurate and many times misleading. Just as one example, a patient dying of a heart attack would normally have his cause of death listed as myocardial infarction, without mention of the underlying type 2 diabetes. It also flew in the face of a huge body of literature showing excess mortality due to obesity and its link to type 2 diabetes and its cardiac and kidney complications, as well as some of the biggest cancer killers such as colon, breast, esophageal, uterine, ovarian, kidney and pancreas—all obesity related cancers. I might add that recently prostate cancer was added to the list.

In a paper published in the Nov 7 issue of JAMA, the authors of the 2005 study went back to the same data bases they had used, in order to determine which causes of death are associated with underweight and which are associated with overweight and obesity.

The envelope, please…

The group with normal weight (BMI 20-25) were considered the baseline and the groups over or below this range were compared to them.

The diseases associated with overweight and obesity were not surprising; the usual suspects were identified, again: heart disease, kidney disease, type 2 diabetes and cancers related to excess weight.

What is intriguing is the relationship of underweight (BMI less than 18.5) to disease; to my knowledge, this kind of information has not been available before this study was published. These people suffered excessive mortality rates from acute and chronic respiratory disease, injury, as well as some cancers that are not related to excess weight, and miscellaneous other diseases (Alzheimer’s, Parkinson’s).

Critique

The study is revealing, especially in its identification of underweight as not healthy. Jewish and Italian mothers, please stand up and say in unison: I TOLD YOU SO.

What could explain the lower rate of mortality associated with overweight than that associated with underweight? No answer is offered by the survey, but what comes to mind is that modern medicine is simply too good at warding off death. We can now keep patients with heart disease and kidney disease alive with all kinds of wonderful drugs and procedures. Even colon and breast cancers, major killers in the not-too-distant past, are now more like chronic diseases, thanks to early detection, chemo- and biological therapy. And bear in mind: the study measured death rates only; it did not attempt to measure the prevalence of disease that has not resulted in death during the study period. 

What could explain the underweight association with disease? A study of this kind cannot establish causality, but one can speculate (especially when not subjected to the jaundiced eyes of peer reviewers). Two things come to mind: muscle mass and immunity. BMI below 18.5 almost by definition means that some of the lost weight comes from loss of muscle. One of the most important muscles, when it comes to infectious diseases, is the diaphragm. When this muscle is weak, respiration is weak, lungs are not ventilated completely, and before long pneumonia ensues. Bedridden patients, elderly people, patients with AIDS, cachectic (wasted) patients with advanced cancer—all are susceptible to respiratory infections. In fact, this is the most common cause of death in such patients. Likewise, low nutritional status is associated with defective immunity to infectious diseases. But, as I said, this is sheer speculation.

What about the validity of the study as a whole? None of the deficiencies that plagued the original paper, namely retrospective design and reliance on death certificates, have been cured. The methodology is identical, the data base is identical—the only difference is that here we get an analysis of the diseases associated with out- of- the- normal body weights.

Dr, Flegal, the senior author of the study, was quite cautious in her assessment of the study . According to Dr. Flegal, "The take-home message is that the relationship between fat and mortality is more complicated than we tend to think." On the other hand, experts like Walter Willett, professor of epidemiology and nutrition at the Harvard School of Public Health, "dismissed the findings as fundamentally flawed, saying [that] an overwhelming body of evidence has documented the risks of being either overweight or obese." He called the findings "rubbish."

Well, well, I wouldn’t go that far. The study did contribute some valuable information on underweight and its relationship to disease. And it provoked controversy—which is great; this is how science is done and how progress is made.

By Dov Michaeli MD, Ph.D

Here is some exciting news from the Biotech world: the time is fast approaching when your personal DNA sequence will be readily available.

So what’s the big deal? Read on.

The human genome project

In 2003, the first complete genetic blueprint was published with great fanfare (President Bush, believe it or not, was present at the announcement). At the time, scientific pundits, journalists, and self-appointed crystal ball-gazers, fell over each other proclaiming the benefits of this scientific feat. Indeed, the possibilities were, and still are, simply huge. People expected the advances to come tumbling down almost immediately; it did not happen. Why? Money! It cost about 3 billion dollars to complete the first sequencing in 2003. At that price, it would have cost about $900 billion to sequence everybody's DNA in the US. Come to think of it, that’s not that much more than the Iraq war is costing us…

Fortunately, bright and competent people are engaged in this enterprise. The J. Craig Ventner Institute announced two months ago that it had completed the sequencing of, well, J. Craig Ventner’s genome. Cost: $60 million, or 2% of the cost of the original Human Genome Project’s DNA sequence.

Want more? There are now at least four companies that are racing to develop machines that will sequence a person’s genome for $10,000, or 0.017% of the cost for the Ventner sequence. In fact, the first one to reach the mark will win a $10 million prize offered by the X Prize Foundation. At this price we could have everybody’s DNA sequenced for a total national cost of $3 billion—chump change, about 2 week’s worth of a dirty little war.

What’s the big deal about sequencing everybody’s DNA?

For this you have to understand what DNA is made of. It is made of 4 chemicals, or bases, A, T, G, and C, strung together. Every three bases code for an amino acid, and those, strung together, make up the proteins that carry out all the functions that keep us alive and well. The sequence of these bases, and hence the equence of the amino acids they code for, is highly variable.  So, to be able to read the genomic blueprint, you have to determine the sequence in which they appear. The number of possible permutations in the order in which the bases, and amino acids, is arranged  is essentially infinite.There are about 100 million bases in a chromosome, and there are 23 chromosomes—so you can appreciate the enormity of the task.

But you can appreciate another fact. No system is 100% error-free. As they say in Washington, mistakes have been made. The mistakes in the formation of the DNA, for instance T instead of a G in a particular place, are actually quite common. They are called single nucleotide polymorphisms or SNP (pronounced ‘snips’, aka ‘point mutations’), and they are responsible for our individuality. This is why my daughter and son share a lot of traits with me and their mother, but are not identical to either one of us, and are not even ‘an average’ between the two of us. They are truly unique. This is also the reason why the fear that people will clone their offspring, or the DNA of some famous people, in order to obtain a perfect replica, is misplaced—they will never get it thanks to SNPs (and thank God, or evolution, for that). The first and last individual to come close was Narcissus—and look what happened to him: he became something else—a flower (called narcissus). Not even close.

As part of our personality/ individuality SNPs determine something important: our susceptibility to various diseases and our tolerance of different drugs. For instance, Ventner discovered from his DNA that he has a certain gene variant that increases his susceptibility to Alzheimer’s disease. Other variants are associated with cardiovascular disease, diabetes, basically all human diseases. Mind you, we are not saying that people with SNPs predisposing them to obesity will become obese. But they are predisposed to obesity, and most likely will have to work harder to ward it off.

Now you can begin to see the revolutionary importance of having a complete map of your DNA.

• You, and your physician, will know ahead of time what incipient diseases are lurking in the dark recesses of your genome. You can then take action. To avoid type 2 diabetes you can control your diet. To avoid heart disease you could adhere to a diet and exercise regime, get more frequent checkups, maybe even start on low dose aspirin as a preventative measure. The same goes for cancers, psychiatric disorders, etc, etc.
• Or consider this: we'll be able to tell which child really suffers from ADHD or bipolar disorder, and who is just ' being a kid'; no more fuzzy and subjective diagnoses, especially in psychiatry.
• We now know, from a field called pharmacogenomics, that people respond differently to different drugs. This too is controlled to a large extent by your SNPs. Some people take a drug called methotrexate for treatment of their cancer or rheumatoid arthritis and tolerate it without much of a problem. Others experience extreme fatigue, nausea, vomiting, anemia, infections and other unpleasant side effects. The answer my friend is written in the SNPs.
• There are certain drugs that work in some people and not at all in others. One of those is a cancer drug called 5FU, another is the anti acid drug Zantac. I still remember that many years ago the Japanese government refused to approve it in Japan unless the drug company conducted extensive clinical trials in Japan, because "the Japanese GI tract is different". We attributed it to plain old protectionism. It turned out that many Japanese indeed react to the drug differently—because of a unique combination of SNPs.
• Psychiatric drugs are currently prescribed on a hit or miss basis. Some patients go through four or five drugs, different doses of each, combinations of drugs etc. until the desired effect is achieved. Why is this great variability? you guessed it. Knowing the patient’s genetic makeup ahead of time could avoid this terrible process of trial and error.

I could go on and on, because the list is endless. But you get the idea.

The Pharmaceutical Industry

The business model of the drug industry depended on the discovery of blockbuster drugs, selling for billions of dollars a year. The industry is now changing its collective thinking. They realize that to make money they don’t have to treat millions and millions of people; they could make it by focusing on a much smaller population, and deliver a drug that is essentially tailor-made for it. The up front expense of clinical trials is enormous. The reason is that if the drug works on say, 50% of the people, you need many thousands of subjects enrolled in the trial in order to show a significant effect of the drug. But if you knew ahead of time the genetic makeup of the people who are likely to respond to the drug- then you’ll need only dozens, or a few hundred at most, to show the effect. The tremendous reduction in the cost of such a trial would make even a drug that is effective in only10% of the population highly profitable.

This is not a theoretical model anymore, it actually happened. A small percentage of patients with chronic myelogenous leukemia (CML) have a certain constellation of SNPs in an enzyme that is central to the disease. The drug company, Novartis, decided to develop a drug that would be specific for these people. They saw it as a public service rather than a commercial undertaking. The drug, called Imatinib, was tested in the first phase of the trial in about 25-30 patients, to prove its safety. But lo and behold, it was also 100% effective. On this basis the FDA quickly approved it. The company did not have to spend hundreds of millions of dollars and 15 years to bring it to market. This made it a very profitable drug.

The sociological effect

Without getting too deeply into the implications of these developments, here is a thought: we faithfully repeat the mantra that we are all unique individuals. Some truly believe in it, others (especially people in power) pay lip service to the concept, but in reality expect everybody to behave the same. Just ask any teacher who has to deal with a bright, but restless, child. Or the police officer who has no time or patience for idiosyncratic behavior. Or the despot who brooks no dissent. But once the concept of uniqueness of the individual ceases to be just a philosophical idea and becomes rooted in our Biology, maybe, just maybe, we’ll learn to accept our fellow humans as uniquely individual, deserving of all the legitimacy and respect we’d accord to ourselves.

Now that would be a paradigm shift!

By Dov Michaeli MD, Ph.D

Here are three headlines from today’s paper:

1. Front page: “GOP Losing Grip On Core Business Vote”. For obvious reasons.
2. Opinion page: “Immigration Losers” by Richard Nadler, President of Americas Majority Foundation, a Midwest public policy think tank (and I might add, a Republican organization in the mold of the Taft dynasty): “ …Republicans need to repudiate… the immoral, uneconomical goal of mass deportation”.
3. Opinion page: “The Future of Bioenergy”, by Juan Enriquez, managing director of Excel Medical Ventures, cofounder of Synthetic Genomics, and founding director of Harvard Business School Life science Project.

The first article Chronicles the takeover of the Republican party by the social conservatives, and the virtual disappearance of the fiscal conservatives/social moderates from the party. The second decries the xenophobic and punitive stance of the Republican party with regard to immigration issues. The last one calls for innovative approaches, using biology to solve the energy and global warming dilemmas we are confronted with.

Quiz: which newspaper was I reading?

1. The New York Times.
2. The Washington Post.
3. The Los Angeles Times.

Answer: none of the above. It was the Wall Street Journal, the bastion and mouthpiece of conservative (read: regressive) ideology, and a fierce opponent of anything liberal, such as fiscal responsibility and global warming. The editorial page had labeled the global warming issue as a liberal hoax, a figment of liberal scientists’ imagination, invented out of whole cloth and computer models.

But the purpose of this posting is not to harangue one particular political view. I want to highlight the salient points made in Enriquez’s article as to what Biology can bring to the table in solving our energy and climate problems. I had intended to write about this issue for a long time and this article was the catalyst.

A paradigm shift

One of the deepest thinkers of the history of science was Thomas Kuhn who, in 1962, published his seminal book “The Structure of Scientific Revolutions”. In it he argued that we all share a certain view of the world (paradigm) at a given time, on which the science of the time is based. But then and insight occurs, which shakes the foundation of our old world view and on which a new paradigm is founded. For example, until the 17^th century Anatomy and Medicine were based on the writings of Galen, a Greek physician from the 2^nd century. For 15 centuries scientists and physicians did not bother to dissect an animal in order to observe and verify the Galenic dogmas handed down to them since antiquity. But then William Harvey, a British physician, had an insight: why not observe how blood flows-- which led to the discovery of the circulation. But more happened: the demonstration that Galen’s writings about blood flow were wrong led other scientists to question his other assertions, test them through direct observations- which led to the modern sciences of Anatomy and Physiology. In fact, the revolution did not stop there; people learned to view with suspicion “received wisdom” handed down by higher authorities. These momentous changes in world view were a “paradigm shift”.

We are changing our world view,again

When our agricultural practices, inherited from the time we began to cultivate crop plants about 10,000 years ago, no longer sufficed to feed an exploding population we invented better ploughs, bigger machines, synthetic fertilizers, powerful insecticides. But this solution finally reached its inherent limitations. In the 20^th century the world could not feed the hungry multitudes of China, India and Africa. Malthus was triumphant. But then another revolution took place.

‘We began to apply more Gregor Mendel and less Henry Ford. Plant geneticists like Nobel Prize winner Norman Borlaug found that altering plants biologically was even more powerful and efficient than brute-force mechanical solutions. By altering seeds, harvest cycles and climate range, Mr. Borlaug and his colleagues launched the green revolution. Poor farmers in China and India, who could never afford a mechanical solution, became net exporters using a biological solution.’

The new world view is that the cleanest and most efficient solutions to our environmental and energy problems will be provided by Biology.

Consider coal, the most abundant and most polluting source of energy we have. Hydrocarbons are, in essence, sunlight concentrated in plant, animal or bacterial matter. Be it coal, gas or oil, what we are extracting and burning is bioenergy concentrated in carbon. Molecular Biology, the science that launched a thousand medical advances, is now enabling us to convert coal into ethanol in the ground; no more mining, no more environmental degradation, no more millions of tons of carbon emission, no more global warming.

And how is this miracle going to be accomplished? By genetically engineering bacteria that will break down the hydrocarbons of coal (or oil, for that matter) and convert it into ethanol. This is eminently doable, the technology is already here—all we need to do is change our thinking from big engineering solutions to clean and elegant biological ones.

You ain’t seen nothing yet

In the August 3 2007 issue of Science, an article titled “ Genome Transplantation in Bacteria: Changing One Species to Another” was published by scientists from the Craig Ventner Institute in Bethesda Maryland . (In its previous incarnation as the Celera Corporation, it was one of the two teams that deciphered the human genome). The article begins thus: “ As a step toward propagation of synthetic genomes, we completely replaced the genome of a bacterial cell with one from another species by transplanting a whole genome as naked DNA” (italics mine).

The significance of this simple statement is hard for the layman to fathom. In fact, it is almost impossible to grasp the enormity of the consequences of such a statement. What it means is that it will be possible in the not too distant future to synthesize new organisms. Not preexisting ones—completely synthetic new species! Now think of it:

· Synthetic bacteria whose whole mission in life is to convert coal and oil into ethanol at a rate faster than we could extract the hydrocarbons from the ground. And much cleaner and enormously cheaper, to boot.

· Synthetic bacteria that will consume any pollutant or toxic material we manage to create.

· Synthetic bacteria that will consume prodigious amount of carbon dioxide from the atmosphere, and convert it into ethanol—a two’fer.

· Synthetic bacteria that will course our blood vessels and convert LDL into HDL particles, and consume triglycerides while they are at it.

· Synthetic bacteria that will be able to sense glucose levels in the blood and release the appropriate amount of synthetic insulin in response.

Need I go on? The possibilities of this scientific revolution are mind boggling. Our world view will become totally biological. Sounds like science fiction or at least a distant dream: not at all. In an interview Craig Ventner stated that his team will have the first synthetic bacterial “species” in 5-10 years!

There is an ancient Chinese curse “may you live in interesting times”. Science will convert the curse into a blessing.

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

By William H. Bestermann Jr. MD

Type 2 diabetes is a condition that costs Americans terribly in terms of death, disability, and health care expenditures. This chronic condition is a vicious cycle type of illness. Glucose control tends to deteriorate over time. Most of these patients also have problems with blood pressure and cholesterol. Only about a third of type 2 diabetics have their pressure, sugar, or cholesterol under control as individual risk factors. Only 7% have all three risk factors controlled simultaneously to conservative goals. This sad fact has dramatic consequences. The lifetime risk of a diabetic having a heart attack or a stroke is 80%. For each risk factor that is controlled to goal using the right medication, the risk is reduced by roughly half—so when we control pressure, sugar, and cholesterol the risk is reduced from 80% to 40% to 20% to 10%. Now maybe the risk is not really 10%, but it is very dramatically reduced and in 10 years of experience with 450 diabetics, I believe that I have seen a very important reduction in vascular events that has been achieved by aggressively controlling these risk factors..

Everything bad that happens to a diabetic is fundamentally arterial or vascular. Obviously the heart attacks, strokes and amputations are vascular, but even the kidney, nerve and eye damage relate to arterial damage as well. So the target here is not just the sugar or the cholesterol. The fundamental question is “how do we lower the sugar, cholesterol and pressure with the maximum benefit on the artery?” Furthermore, how do we accomplish this in such a way that the patient’s life is minimally altered and this is sustainable.

In this post, I will focus on sugar control. Everyone agrees that type 2 diabetes is at its core a life-style illness. As one of my colleagues in South Carolina said: “There is nothing that we can do for diabetes that you cannot outrun with a spoon.” In other words, if the patient does not make some effort with diet and exercise, it is difficult and perhaps impossible to get risk factors to goal. I have controlled the sugar in disabled patients, but it is more difficult. Type 2 diabetes is a disease of elevated blood sugar. It is self-evident that sugar consumption must be limited. Less widely appreciated is the impact of starch or carbohydrate consumption. Processed starch becomes sugar in 2 minutes once it is consumed. When a person eats 100 calories of white rice, in 2 minutes it is just as if he took a spoon and ate 100 calories of sugar out of the sugar bowl. The less processed a carbohydrate, the more slowly it is consumed.

Some understanding of nutrition is vital. Formal dietary instruction by a certified diabetic instructor is helpful but I see substantial variation in what patients are told. As a practical matter I have found the South Beach diet to be very useful and just bought the book for a friend at Walmart for $12.00. I have recommended that diet for patients and found it very effective with sustainable effects on weight and sugar control. Dr Agatson, the author, is a cardiologist famous for developing the cat scan calcium score we use to determine cardiac risk. He teaches two very important concepts. First, we have to learn to limit starch and to eat our starch in the form of whole foods. Second, we need to limit fats, especially animal fats and trans fat. This program is attractive because it is effective, widely available, and supported by recipe books and pre-packaged items.

Next we come to drug therapy. Doctors are trained in the treatment of diabetes with medication by learning about all of the medications that are available, and then they are left to decide which of these many medications they will use and in what order. There are several different classes of oral drugs with multiple drugs in each class. There are multiple types of insulin with differing durations of action. There is no real protocol that is universally agreed upon as best practice.

Type 2 diabetes is the later stage of the metabolic syndrome. Most type 2 diabetics have been metabolically abnormal for decades. They have been resistant to the effects of insulin for years and just before they become diabetic they have been maintaining their normal sugar by producing levels of insulin in the blood that are three times normal. As time goes on they are unable to sustain that level of insulin production and when insulin levels fall the sugar begins to rise. At the time of diagnosis, insulin production has fallen by 50% and the loss of the ability to produce insulin is aggravated by poor sugar control—a built-in vicious cycle. When it comes to diabetes, we just do too little too late.

In recognition of this fact, there was a recent consensus algorithm published in Diabetes Care. This is a joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. They emphasized the importance of diet and exercise as first therapy. Most notably in my view the authors went on to say, “The authors recognize that for most individuals with type 2 diabetes, lifestyle interventions fail to achieve or maintain metabolic goals, either because of failure to lose weight, weight regain, progressive disease, or a combination of factors. Therefore, our consensus is that metformin therapy should be initiated concurrent with lifestyle intervention at diagnosis.” Most medications for diabetes cause weight gain. Metformin has modest effects in assisting with weight reduction and it is the only medical treatment for diabetes that is proven to lower the incidence of heart attack and stroke by 40%. That effect is on a par with the best cholesterol and pressure treatments.

If treatment with metformin fails, it is generally because insulin production is at least relatively inadequate. The most effective and rational next step is to instruct the patient in a self-adjusted insulin shot using Lantus or Levemir. In the protocol I use, the patient is able to rapidly bring the sugar safely down and most patients are at goal with this reasonably simple approach. It seems to me that the proven vascular benefits of metformin would be preserved in these patients since all we are doing is replacing insulin that they cannot make themselves. Most patients are really surprised at how easy this is to work with and how much better they feel when their sugar is controlled.

The American Diabetes Association recently published Proceedings of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. The proceedings are published in a July 2007 supplement to Diabetes Care.

The experts participating in this conference have recommended the following screening strategy for Gestational Diabetes Mellitus (GDM):

Risk for gestational diabetes should be ascertained at the first prenatal visit.

Low risk:

• Member of an ethnic group with a low prevalence of GDM
• No known diabetes in first degree relatives
• Age < 25 years old
• Weight normal before pregnancy
• Weight normal at birth
• No history of abnormal glucose metabolism
• No history of poor obstetrical outcomes

If all of the following characteristics are present, low risk women are not required to have blood glucose tested routinely.

High risk:

• Severe obesity
• Strong family history of type 2 diabetes
• Previous history of GDM, impaired glucose metabolism (e.g., insulin resistance, metabolic syndrome, or type 2 diabetes), or glucosuria (glucose in the urine)

Perform blood glucose testing as soon as feasible if one or more of the high risk factors are present. If GDM is not diagnosed, blood glucose testing should be repeated at 24-28 weeks or at any time a patient has symptoms or signs that are suggestive of hyperglycemia.

Average risk (everyone who is not low or high risk):

Perform blood glucose testing at 24-28 week on all average risk women

New to the screening guidelines this year is the inclusion of “normal weight at birth” to the list of requirements to be considered low risk. This was added because of evidence that women who were at the extremes of birth weight have altered insulin action and/or insulin secretory capacity that may predispose them to the development of GDM as adults.

There is an increasing prevalence of GDM in the US that appears tied to the increase in obesity and type 2 diabetes incidence. Because impact of GDM on both the mother and the fetus can be ameliorated with aggressive treatment, it is imperative that all pregnant women seek early prenatal care, have their risk for GDM assessed, and have glucose tolerance testing as outlined above.

By Dov Michaeli MD, Ph.D

The theory that selenium is ‘good for you’ has just suffered a body blow—supplementation actually causes an increase in the prevalence of type 2 diabetes.

Why is selenium a food supplement?

The theories range from the sublime to the ridiculous. I still remember that runners swore by selenium as a performance enhancer. It didn’t do it for me, so I asked for the evidence. In a word: there was none.

Another ‘theory’ is that selenium is important in the prevention of HIV/AIDS. Evidence? Sub Saharan Africa has a low selenium content in the soil, and a high incidence of HIV. The exception is Senegal , where the soil content is high and, wouldn’t you guess, HIV incidence is lower. Enough said.

A more serious theory is that it acts as an antioxidant. True enough, in vitro (in the test tube) it works as advertised. Oxygen free radicals are injurious to cells, to organs, and probably to the whole body. In fact, one of the leading theories on the causes of aging and its attendant diseases is the damage wrought by those pesky radicals. One of the enzymes that is tasked with ‘sopping up’ oxygen free radicals is called glutathione oxidase and selenium is a cofactor or necessary part of its structure—without it the enzyme cannot function. Wouldn’t you then assume that selenium supplementation should be ‘good for you’? Indeed, severe deficiency of selenium can result in myocardial necrosis (Keshan disease); it is so rare, you’d be hard pressed to find it in many medical textbooks.

The reason selenium deficiency is so rare is that we need it only in trace amounts. The daily requirement is about 70 mcg, and we can get all of it and a lot more, from nuts, legumes, meats and fish.

If a little is good, isn’t more even better?

Absolutely not! Selenium has a narrow “therapeutic window”, meaning that above this narrow range it becomes toxic. Symptoms of selenium toxicity range from garlic odour on the breath, gastrointestinal disorders, hair loss, sloughing of nails, fatigue, irritability and neurological damage. In fact, in the midwest plains and the rocky mountains there is a weed aptly called locoweed, which concentrates selenium from the soil. Horses and cows grazing on it develop severe neurological symptoms mimicking BSE, otherwise known as Mad Cow Disease. So far no human cases of locoweed intoxication have been reported. But with new vegan dishes being invented every day in trendy restaurants, and more and more people grazing in them, who knows?

Add diabetes to the catalog of selenium diseases.

A recent article in the Annals of Medicine (21 August, 2007, vol. 147, pp.217-223) reports findings from a study called the nutritional prevention of Cancer. Patients were randomly assigned to receive 200 mcg of selenium daily for 7.7 years, or placebo. The study design was excellent: it was randomized, double blind, and the initial levels of selenium in the blood were measured before the onset of the trial, so that a reliable baseline was established for each individual. Follow up blood levels of selenium were measured throughout the trial period.

The trial was not designed to measure diabetes, and the investigators relied on medical records and oral reports. Nevertheless, the results were compelling. And surprising.

They found that among the subjects who took selenium supplementation, those with the top third selenium concentration in the blood had a 270% increase in probability of becoming diabetic over the placebo group.

About 35% of the U.S. population take daily multivitamins. The common concentration is only 20 mcg, which is 29% of daily requirement. No danger there. But 1% ( about 2.5 million people) take selenium supplements of 200 mcg a day. These are big numbers, and can go part way in explaining where non-obese type 2 diabetics come from .

What’s the take home lesson?

Do not take selenium supplements; there is no scientific basis to any of the claims of benefits to mega doses (200mcg and higher). There is compelling evidence that they are harmful. The low concentrations found in multivitamins (20 mcg) are most likely harmless. Whether they do any good is another question; there is no evidence that they do.

The bigger lesson from this study is that the whole food supplements field is rife with unsubstantiated claims, and outright falsehoods. Caveat emptor.

Dov Michaeli MD, Ph.D. is a biochemist and a drug researcher in the biotech industry.

By Dov Michaeli MD, Ph.D

In my previous posting I reviewed a paper published in the New England Journal of Medicine which showed that obesity can spread among friends and family just like any infectious disease. But unlike infectious diseases, physical proximity did not count for much: obesity did not spread among neighbors. It did spread among family members, regardless of geographical location. The strongest influence on the spread of obesity was friendship, in particular mutual friendship. This was a totally unexpected finding.

The paper had some unavoidable flaws. For instance, in assessing the effect of friendship, the investigators had data on an average of 0.7 “contacts” (or friends) per case. This hardly gives a complete picture of the social network of the average person. So, at this stage I am skeptical but hope I am wrong. I hope that additional studies will corroborate the basic finding of the relationship between social contacts and disease. Why?

Our current understanding of disease

We have been educated to look for physical explanations to biological/medical phenomena. As physicians we were taught to look for the “disease genes” ( for instance Huntington’s disease, sometimes called Guthrie’s disease after the famous folk singer Woodie Guthrie who died of this disease), or the metabolic dysfunction ( diabetes type 2), or environmental influences ( lead poisoning, pollution-induced respiratory diseases), or combination of those ( cancer as a consequence of genetic predisposition and environmental mutation-causing substances). We viewed with suspicion the ancient art of ‘alternative medicine,’ in my view justifiably so. When subjected to rigorous scientific examination, most if not all of those folk remedies turned out to be just, well, folktales.

But ‘hard science’ Medicine is also wanting, and the example at hand is the spread of obesity. Several genes that predispose to obesity have been identified, but they account for only a minority of cases of the ‘disease’. What accounts for the rest? We all answer reflexively: lifestyle. But that’s too glib. Why do some people have to fight mightily to avoid obesity, while others barely move off the couch with nary an ounce of weight gain? Again, metabolic differences sometimes exist, but many times they are at least not readily apparent.

Enter social networks

The surprising finding that friendships are powerful factors in the spread of obesity, if corroborated, would go a long way toward explaining the puzzle of the ‘obesity epidemic’. And not only obesity: many other diseases are now becoming susceptible to this analysis. Why is it that we are having an ‘autism epidemic’? Why is it that certain school districts have an inordinately higher prevalence of autism? No suspected physical agent, including the much abused vaccination of children, stood the test of rigorous examination. Increased awareness? Erroneous or loose diagnoses? They don’t account for the rise.

The possibilities are even more amazing. If you examine the genes of obesity and diabetes type 2, you’d find that these two diseases share at least three genes. Which raises the possibility that there exist networks of diseases, all interlinked. This may explain, at least in part, why a certain drug given for disease A would affect disease B, or cause side effects unforeseen by our knowledge of the drug’s mechanism. A wonderful example is the drug imatinib (or Gleevec), designed to work specifically on a mutation of the enzyme tyrosine kinase (called Bcr-Abl) that causes CML or Chronic Myelogenous Leukemia. Lo and behold, despite its great specificity it turned out to inhibit another tyrosine kinase called c-kit, that is responsible for rare a stomach cancer called stromal tumor. What’s the connection? The drug action uncovered an unsuspected close link between the two enzymes; both evolved from a common ancestor gene, and the two cousin proteins resemble each other like twins. But wait, there is more... even more unexpectedly, it was discovered that the drug activates a certain immune cell (IKDC) that is active in killing infectious organisms and tumor cells. The mechanism for that is largely unknown. This is only one example, but it hints at as yet- undiscovered complex networks of diseases.

Question: all these examples deal with molecular networks, which makes it intuitively easy to visualize interactions between molecules and the effect of these interactions rippling through the networks. But how would something spread through social networks? The answer: through memes.

Memes, and spread of ideas (and diseases)

What is a meme? The definition I like the best is from the Wikipedia:

meme , (IPA: /mi:m/ ) as defined within memetic theory, comprises a unit of cultural information, cultural evolution or diffusion that propagates from one mind to another analogously to the way in which a gene propagates from one organism to another as a unit of genetic information and of biological