The Doctor Weighs In

By Dov Michaeli MD, Ph.D

The aspirin story

The discovery of aspirin is a fascinating story (to me, at least). In 1853 the French chemist Charles Frederic Gerhardt (yes, I’m sure he was French) studied a group of organic chemicals called anhydrides (an=without, hydride=water). Among many molecules of this group he synthesized one called acetyl salicylic acid, or ASA. He then put the vial containing the white powder on a shelf, and forgot about it. And there it sat for over 40 years until 1897, when a German chemist named Felix Hoffmann, working for Bayer, the German chemical and pharmaceutical company, rediscovered the compound using a different synthetic procedure, tested it for analgesia, and voila! It was used as an analgesic and antipyretic (fever-lowering) since then.

But the story doesn’t end there. Nobody knew how aspirin worked. It was only in 1971 that it was discovered that aspirin works by inhibiting the enzyme cyclooxygenase (COX). For that discovery John Robert Vane, working for the Royal College of Surgeons (no, he was not a surgeon; he was a real scientist), received the Nobel Prize. What’s the big deal about this enzyme? It is a critical enzyme in the synthesis of a group of substances called prostaglandins, which are mediators of inflammation and pain. So aspirin very quickly became the mainstay of treatment for arthritis and other inflammatory diseases. In its soluble form, sodium salicylate, it was used in the treatment of Crohn’s disease, or colitis, a devastating inflammatory disease of the colon. And within a few short years a new group of COX inhibitors, called NSAID (non-steroidal anti inflammatory drugs), was synthesized. Famous members of this group are ibuprofen (Advil), naproxen (Naprocyn), and others.

But wait, wait, there is more. In the late 70s, it was discovered that low dose aspirin or NSAID inhibit platelet aggregation, which was the basis for using them as a preventative for myocardial infarction.

This is quite a remarkable demonstration how learning the molecular details of biology and pharmacology can lead in totally unexpected directions, and to undreamed of new therapies.

New respect for the humble DEET

Who doesn’t know DEET? Certainly nobody who has ever gone on a hiking or camping trip. I personally experienced the wrath of a cloud of mosquitoes when I forgot “to DEET”. We were on our way to watch the chimps in Africa , and my memory of that particular outing is total body itch. If there are species that I wouldn’t shed tears if they became extinct it is the mosquitoes.

Like aspirin, DEET was synthesized a long time ago (over 50 years ago), and notwithstanding the long-held reasonable assumption that it is a mosquito repellent, nobody really investigated its mode of action. That is surprising, given the medical importance of mosquito-borne diseases, such as malaria, dengue fever, yellow fever, and more.

In the latest Science magazine a group of molecular neurobiologists from Rockefeller University published a report on DEET’s mode action. And surprise, surprise: it is not a repellent. It doesn’t smell bad to the mosquito. In fact, it doesn’t smell at all.

Female mosquitoes (and fruit flies) smell lactic acid in our sweat, and carbon dioxide and a certain alcohol (1-octen-3-ol) in our breath. Those three odorants evoke in the little pests the equivalent of a Pavlovian response—but instead of drooling they home in like heat-seeking missiles.

How do they smell it? For each of the 3 odorants there is a specific receptor on mosquitoe’s antennas. Once a molecule of say, lactic acid lands on its receptor, it triggers an electrical discharge in the olfactory nerve leading to the brain. And there, a behavioral pattern is unleashed that sends the blood sucker hurtling toward the source of the odor.

DEET works by occupying the receptors, so that the odorants cannot bind. Result: the insect is unaware of them, no chemical attraction, no bite.

Could the aspirin story be repeated?

I think so. DEET was discovered the old fashioned way; chemists synthesized thousands of compounds which were then tested for any activity imaginable. This approach gave us most of the drugs being used to date. But it also has a weakness: because the drug was discovered by the hit or miss approach and not by designing it to bind to a specific target, its binding to the target molecule was essentially accidental and almost never was at a maximum. It was good enough, and was rushed to market. Now that we know the molecular details of the mode of action of DEET, chemists can synthesize new classes of molecules that will bind more specifically and more tightly to the receptors. In other words, they can create less toxic and vastly more effective compounds that will protect us from insect bites. This is important, because DEET is toxic to infants. But even more important, blood-feeding insects transmit many of the world's deadliest diseases. Malaria alone infects an estimated 500 million people annually, leading to the deaths of about 1 million people per year! These are mind-boggling numbers. Spraying or dabbing on a new and improved version of DEET, could turn out to be a powerful means of malaria control. Bill and Melinda, are you listening?

Let’s not forget the repulsive ticks; they are attracted to humans by exactly the same odorants. Lyme disease, tick-borne relapsing fever, Rocky Mountain spotted fever, tick typhus—these are all diseases transmitted by ticks. In the new world of global warming insect-borne diseases are going to become significant public health problems; Ebola and chikungunya are harbingers of what’s coming.

And who knows what else is waiting around the corner once DEET-like drugs are made? After all, did Hoffmann, toiling in the Bayer laboratory, ever dream of what aspirin would turn out to be?

By Dov Michaeli MD, Ph.D

Several months ago I received an alarming phone call from my nephew: he had terrific pain in his abdomen which caused him to double over. His stool was pitch black. It was obvious that he had an acute stomach ulcer, probably bleeding. What could cause this painful disease?

Since the late 19^th century doctors described the existence of bacteria in the stomach, but for a variety of reasons these reports did not gain traction, or were simply not believed. The bacterium, later named Helicobacter pylori was rediscovered in 1979 by Australian pathologist Robin Warren, who did further research on it with Barry Marshall beginning in 1981; they isolated the organisms from mucosal specimens from human stomachs and were the first to successfully culture them. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by infection by this bacterium and not by stress or spicy foods as had been assumed before. Their report was met with universal disbelief. I remember my own dismissive reaction when I read the first papers. An organism living in such an acidic environment (pH 2-3)? And not as a transient tenant, but a permanent resident? “everybody” knew that stomach ulcer is caused by stress…there must be some mistake here.

The experiment that changed everybody’s mind was when Barry Marshall, in a dramatic effort to convince the medical world, swallowed a petri dish of H. pylori, showed with gastric biopsy that the bacteria indeed colonized his stomach, developed gastritis within weeks after swallowing it, eradicated it with a combination of bismuth subsalicylate (Pepto Bismol) and metronidazole (Flagyl), and a second endoscopy 10 days later confirmed that the gastritis resolved. It was only then, in 1994, that NIH ( the National Institutues of Health) published an opinion stating that most recurrent gastric ulcers were caused by H. pylori, and recommended that antibiotics be included in the treatment regimen. In 2005 Warren and Marshall were awarded the Nobel Prize for their work.

What is H.pylori?

This bacterium is wonderful example of biological adaptation. It burrows into the mucous layer (a gel-like mucus layer) of the stomach, and that’s where it stays. But to survive in this hostile environment it had to somehow protect itself from the acid. Urea is normally secreted by the epithelial cells (these are the cells lining the stomach). The bacteria secrete an enzyme, urease, which breaks down urea to ammonia and CO 2 . Ammonia does a wonderful thing for these bacteria: it neutralizes the acid in the vicinity, thus allowing them to thrive in this forbidding environment. But it does something else: it kills the epithelial cells that come in contact with it. Thus it, and some other proteins secreted by the bacterium, cause gastritis (inflammation of the stomach lining) and eventually, an ulcer.

What about the acid?

We are not completely blameless--H. pylori gets some help from us in causing gastritis and ulcers. Once the mucous layer is damaged by  bacterial colonization, the epithelial cells lie bare and defenseless against the destructive effects of the acid. This can explain the relationship between emotional upset and ulcer disease: stress hormones cause an increased secretion of acid. Coffee has also been shown to increase acid secretion.  Unfortunately, decaffeinated coffee is not going to help;  chemicals that cause increase in acid secretion are present also in decaf. The same is true for excessive alcohol consumption; it damages the mucous layer, and exposes the cells to acid. add to that H. pylori--and you are in trouble.

Eradicate! eradicate?

H. pylori is an ancient organism that has lived in human stomachs probably since the beginning of our species, about 4 million years ago. It is disseminated with the drinking water, and probably infected 100% of the human population before sanitary conditions became widespread in the 19^th and 20^th century. As we saw, the ulcer formation is really incidental, collateral damage, to the ingenious secretion of urease and neutralization of stomach acid. Even more alarming, it is now generally accepted that H. pylori is responsible for most cases of stomach cancer. So obviously, if we just treated this pesky bacterium to a dose of antibiotics-we’d solve the problem once and for all. Indeed, while the incidence of H. pylori infection in humans is decreasing in developing countries, presumably because of improving sanitation and increasing use of antibiotics, in the United States the incidence of gastric cancer has decreased by 80 percent from 1900 to 2000.

However, there are always coseqences; some of them unintended. Parallel to the decrease in H. pylori infection there is an increase in the incidence of acid reflux from the stomach into the esophagus. And even more alarming: esophageal cancer is now the most rapidly rising cancer in the U.S. and Europe.

Fortunately, in most cases we can deal with this problem quite easily: we have now powerful drugs that are called proton-pump inhibitors, such as prilosec, that inhibit acid formation in the stomach and its reflux to the esophagus.

So here is another example of the delicate balance between us and our environment, in this case our internal environment. Recent studies showed that gut bacteria may contribute to obesity or even to our mood. So before we indiscriminately eradicate the flora that inhabited us for millions of years and upset the delicate biological balance we live in, we should carefully consider the consequences.

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

By Dov Michaeli MD, Ph.D

I remember a wonderful lecture at UCSF, about 30 years ago, by Dr. Dennis Burkitt, on “Diseases of Civilization”. Dr. Burkitt was a missionary doctor in the bush in what at the time was Rhodesia (today’s Zimbabwe ). He was also an extraordinarily astute clinical observer (he was the first to describe a hitherto unknown cancer, aptly called Burkitt’s lymphoma). At the end of the lecture somebody asked whether Africans in the bush, being free of modern world stress, are healthier. Dr. Burkitt retorted that wondering every night whether that was the night the lion was going to have you for lunch is hardly an anxiety-free thought. The message was that stress recognizes no boundaries of geography, education, income, sex or national origin.

What is stress?

To paraphrase Potter Stewart, a supreme court justice who grappled with the definition of pornography: “I know it when I see it”. But there is a more ‘scientific’ definition: Psychological stress occurs when an individual perceives that environmental demands tax or exceed his or her adaptive capacity”. Interestingly, an elaboration of this definition includes two elements: high psychological demands coupled with low decision latitude. In other words, stress as we commonly understand it, high and unrelenting demand, is not enough. It is the lack of control, the feeling of helplessness, which tips the scale to the feeling of stress.

Can psychological stress cause disease?

I have to admit: being a firm believer in the physical causes of disease, I was highly skeptical. I readily admitted that stress could exacerbate disease; I have seen countless cases of acute asthma attacks or acute MI precipitated by acute psychological stress. But chronic, low intensity stress? I wanted to see hard evidence.

The title of a recent article, and an accompanying commentary in the JAMA, “Job Strain and Risk of acute Recurrent Coronary Heart Disease Events”, tweaked my curiosity. The authors followed 206 patients who have had an MI, for a period of 2.5 years following their initial episode. After statistically adjusting for 26 potentially confounding factors (smoking history, hypertension, high LDL etc.) they concluded that job strain increased the risk of recurrent coronary heart disease or CHD by 100%!

How can it happen?

There are many theories, but the most plausible and the best documented is the stress hormone theory. We have two systems that get activated during stress: the HPA (hypothalamic-pituitary- adrenocortical axis) and the SAM (sympathetic- adrenal- medullary) systems. HPA secretes cortisol, SAM secretes epinephrine aka adrenaline. Both are known as stress hormones.

 If stress is so common in life, how is it that evolution allowed the hormonal response to stress to be so deleterious? And the answer is: it didn’t. Besides facilitating the fight or flight response, they increase innate immunity, our first line of defense against pathological invaders, and decrease the inflammatory response. But all this is true for acute stress (e.g. the lion is coming at you). Chronic stress is something quite different. For reasons yet unknown, chronic stress causes a decrease of the immune response and an increase of the inflammatory response—exactly the opposite effects of acute stress. Whatever the reasons may be—the effect is destructive. As an example: coronary heart disease is basically an inflammatory process, and chronic stress aids and abets it. Furthermore, macrophages, which are white blood cells that are central to the formation of a coronary plaque, were recently discovered to secrete their own adrenaline, adding insult to injury.

Does a low dose of NSAID (non-steroidal anti inflammatory drugs) to prevent CHD make sense now?

What other diseases are associated with stress?

Depression is the most obvious one. To cite some compelling statistics: approximately 20-25% of persons who experience major stressful events develop depression. And when a cohort of depressed persons was examined, it was found that 50-80% have had a major “life event” in the preceding 3-6 months. To close the loop: most depressed individuals suffer from a depressed immune response and from chronic, low grade inflammation. Based on this we still cannot conclude that there is a cause and effect relationship here; but it is an intriguing correlation nontheless.

HIV/AIDS has also been suggested to progress faster, even when taking anti HIV medications, if the patient is under chronic stress. Again, one shouldn’t be surprised if the explanation will turn out to be a depressed immune response.

In Conclusion

On the biological level, this is yet another demonstration of the mind-body relationship. In fact, a whole field of research called psychoneuroimmunology (I know, it’s a mouthful, but if you break it up to its component words, psycho-neuro-immunology, it makes sense) is thriving and is uncovering new connections between brain, mind and immune response on an almost daily basis.

On the clinical level, the strengthening evidence of the effect of stress on health and disease suggests new modalities and approaches to treatment.

What is most intriguing and potentially far-reaching, are the societal consequences. Now that we accrue more and more evidence on the effects of stress on health, it would make economic sense to pay attention to the work environment. An enlightened manager would insist on stress reduction in the workplace in order to increase productivity. Conversely, could a company be found liable if an employee is subjected to an abusive supervisor and suffers a heart attack? The medical evidence is already here.

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

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!

A recent study from the Mayo Clinic, published in the Journal of the National Cancer Institute (JNCI, vol. 99, p. 825, 2007), looks at the relationship between the use of aspirin and non-aspirin NSAID (non steroidal anti inflammatory drugs) in postmenopausal women and the incidence of death from cancer, heart disease, and death from any cause.

How the study was done

The investigators studied data on about 22,500 women who were enrolled in the Iowa Women's Health Study, a long-term health study of women living in Iowa. Starting in 1986, the women completed surveys periodically about their medical history, diet, physical activity, smoking, and other factors every year until 1992. In that year, the women also reported their use of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. They were then followed, without filling out additional questionnaires, until 2002.

And the results were…

· Women who took aspirin were 13% less likely to die of cancer.

· They were 25% less likely to die of heart disease.

· They were 18% less likely to die of any cause during the study.

· Non-aspirin NSAID had no effect on mortality.

What’s wrong with this picture?

Plenty. Let me count:

1. The study was observational; such studies are fraught with problems, and are not very reliable. For instance, the investigators did not study the effect of aspirin by giving the drug, and following them for the study period (known as a prospective study). They got their data from a questionnaire filled out by the participants.

2. The study started in 1986 and ended in 2002—16 years in duration. And only at one point in time (1992) were the participants asked to recall their aspirin use. The quality of such recall has been shown in several studies as flawed.

3. The questionnaire did not ask about the frequency and dose of the aspirin. And even if they did, such data would have been of questionable utility. Would you trust your own recollection of your aspirin intake several years back? Or even the prior 6 months?

4. The study was restricted to postmenopausal women, mostly white. Does this finding extend to other population groups?

5. Only aspirin had an effect on mortality. Non-aspirin NSAID, such as Advil, Motrin and Aleve, had no effect. This finding is conflict with other studied showing non-aspirin NSAID having a survival benefit similar to aspirin. Both types of drugs have a similar mode of action; they are anti-inflammatory drugs, targeting the same metabolic pathway ( prostaglandin synthesis). If however, this observation stands up to repeat studies, it would be a great contribution, which may uncover some subtle differences of clinical importance between aspirin and other NSAID.

Should you start taking aspirin?

Obviously, this is at best an incomplete study. On this basis alone, it would be inadvisable to start taking aspirin on a daily basis. Admittedly, other studies suggest that daily aspirin is beneficial, to a small degree, in the prevention of breast cancer and colon cancer, as well as heart disease.

But consider these two facts:

· Aspirin is not harmless. It can cause all kinds of stomach problems, like gastritis (inflammation of the lining of the stomach) and ulcer. It can also cause bleeding problems, including hemorrhagic (bleeding) stroke.

· Why take medicine for a 13% reduction in cancer mortality when you can eat well (five helpings of fruits and vegetables a day) and exercise (30 minutes walk, six times a week) and cut your risk of death from breast cancer by 50%! See my earlier post, "Women with breast cancer can lower their risk of dying by 50%." The same type of protection has been shown for colon cancer, and for heart disease.

As far as I am concrned, the choice is obvious.

Dov Michaeli MD, Ph.D