Intuition, in my view, is the faculty that allows the mind's eye to visualize what is invisible to the naked eye. It is that element of human perception that celebrates the mystery of life. Knowledge grows first by intuition and then by analysis. Some intuitive insight always precedes all major breakthroughs in human perceptions, experimentation, and analysis. This has been true of physical sciences, creative arts, agriculture, finance, and, of course, medicine.

The practice of medicine is artful application of some facts of biology to the care of an individual. We live in the Information Age. But how large is the body of knowledge from which a clinician is required to select some facts to be used in designing a treatment plan for his patient? Consider the following quote from a recent issue of Nature:

[T]he Protein Data Bank now contains some 13,000 unique structures into which proteins can fold.1        

It seems certain that the above number will grow exponentially during the next several years. Consider the following quote from a recent issue of Science:

Robotics and computers promise to transform structural biology into a high-speed effort dubbed "structural genomics," in which researchers will churn out thousands of proteins structures in the next five years.2

The March of A Million Proteins

Beyond the sheer numbers, proteins in human biology fold and unfold, and so change their functionalities. Many of those that have been characterized are versatile molecules, playing changing roles under different conditions. In this "post-genomics" period, the "hot" field now is proteomics. There are an estimated one million proteins in the human body. Now consider another quote from a recent issue of Nature:

Analyzing the entire set of proteins of an organism is a far bigger challenge than anything in genomics...The inside of a cell is a crowded and dynamic place, where proteins are perpetually being created and discarded...Indeed, there is no such thing as proteomics—it will differ significantly not only between individuals (much more than do their genome), but also within one individual before and after, say, a millennium party.3

Later I cite the example of macrophage migration inhibitory factor (MIF) to show how astoundingly diverse those roles can be. Beyond that diversity is the matter of proteins assuming different functions under different conditions. Thus, the human body may be seen as an enormous kaleidoscope with a million pieces (of proteins only), with each piece capable of myriad functions. When a single piece in that kaleidoscope changes in one way, everything else changes in some way.

For a clinician, the variables influencing functions of individual proteins, fats, sugars, minerals and vitamins are simply too large to feel secure applying the knowledge learned in the laboratory (mostly in animal species) to the sick. This is the case at present. Within the next few decades, it is entirely safe to predict that hundreds of thousands of proteins will be characterized. How may we expect a clinician to cope with that explosion of knowledge then?

Some will undoubtedly look to computers for the final answer. Indeed, it is tempting to think of the analagy of instant management of huge bodies of financial data with super computers by the folks at Wall Street. However, I am also reminded of a friend who recently lost a lot of his money in trading and decided to abandon the market. "I make money only if others buy what I buy first. Lately, they have not done that," he ruefully told me.

A physician must, of necessity, select some facts and establish some order of priority of how those facts may be applied—by some pattern of practice that his patients are willing to accept—read buy, in the Wall Street lingo. It is evident is that Americans in increasing numbers are not buying the prevailing model of Star Wars medicine governed by computers. One-third of prescriptions written in the United States are simply not filled.

We physicians make difficult clinical decisions by some internal methodology that we often cannot explain. When pressed to do so, we struggle to rationalize.. That clearly is intuition at work. What can be more alluring and compelling than the subject of intuition for a physician? Having worked with physicians of various nationalities for more than four decades, I know that is so. And yet, the very subject of intuition is regularly shrugged off—or worse, derisively dismissed—by professors in our medical schools and in the editorial offices of medical journals.

Ask an experienced surgeon what would happen if he always made his decision to operate for suspected appendicitis only by analysis of clinical and laboratory data and exclude intuition. He will tell you that would substantially increase the number of normal appendices removed as well as cases of perforations of appendix with peritonitis due to delay in surgery. I know that. I trained as a surgeon.

Ask an experienced cardiologist what would happen if he were to be barred from using his intuition. What would be the outcome if he were to make his decision about whether or not a patient has a serious coronary emergency only by analysis of clinical and laboratory data? He will tell you that would substantially increase the number of persons admitted to the coronary care unit without a myocardial infarction as well as persons with infarcts who are sent home. I know that. I saw many cardiac crises in the emergency department.

Ask an experienced pathologist what would happen if he always made his decision to diagnose or rule out malignancies in biopsies only by analysis of clinical and laboratory data and kept his intuition out. He will tell you that would substantially increase the number of cancers that go undiagnosed as well as those that are diagnosed by mistake. I know that. I diagnosed more than 40,000 malignant neoplasms.

Then ask naturopaths, herbologists, and acupuncturists if they can subordinate their work to some algorithms of numbers and measurements. They will look at you in disbelief. How and when did a physician's intuition fall into servitude of analysis of body fluids or tissues in the care of the sick? Enter Mr. Flexner.

The Flexner Tragedy
I believe one can trace the tragedy of excluding intuition from a clinician's work to an amazingly bad judgment of Abraham Flexner, a man engaged to study medical education by Carnegie Foundation on behest of the American Medical Association.4

Flexner evidently was neither a scientist nor a clinician. His 1910 report, the so-called Flexner Report, did more damage to the health of Americans than any other single document. (The only other single report that comes close to its pernicious influence is that of the 1940 Nutrition Board that promulgated the abominable notion of limiting essential nutrients to their putative Required Daily Amounts. None of the persons on that Board was a practicing nutritionist. I discussed that important subject in RDA: Rats, Drugs and Assumptions.)

Flexner undertook a study of 139 allopathic and eight osteopathic medical schools. Much to the liking of those at the helm of the AMA, he pronounced all eight osteopathic schools substandard and unfit to provide medical education. The AMA took full advantage of the report and through a "standardization of hospitals" plan promulgated by the American College of Surgeons in 1918, managed to ban doctors of osteopathy from all American hospitals. Exalting the Flexner report to the status of the bible of "scientific" medicine, the AMA also used that report as a lethal weapon to effectively squelch all other healing arts. As went the United States, so did Europe and the rest of the world.

One of the silly aspects of the Flexner Report that is rarely discussed is that it recommended that the United States allow only thirty four-year medical schools, each enrolling 300 students. That would have reduced by 50% the number of young doctors leaving those schools. For the 1910 American population of 91 million, his plan would have amounted to two physicians per 100,000 persons. But the most pernicious influence of the Flexner Report was not that it secured a lasting medical monopoly for the AMA. For decades, it put a physician's intuition in servitude of laboratory tests.

Flexner and his disciples essentially trashed all healing arts in the United States. The only model they approved of was that of drug therapies evaluated under what they considered were "controlled" conditions. That model lasted for decades and essentially left no room for a clinician's intuition in his work. Intuition, they pronounced, was the crutch of the feebleminded, the one who did not have the diligence or discipline to learn their model of drug medicine.

It was in that setting that the "Flexner tragedy" took form. In the past, the atomism- vitalism debate had largely been a matter of amusement for the philosopher and the experimenter. The Flexner tragedy was played on a national scale with real physicians cast in the role of mindless messengers of the science of pharmaceutical companies. (The bag men for drug companies, as one young doctor recently put it.) Flexner declared osteopaths incompetent and pronounced all healing arts "unscientific." What basis did he have for his pronouncement? Intuition of a homeopath did not fit into his model. Had he studied homeopathy to find whether it works or not? He dismissed a naturopath's intuition in favor of his own. Had he studied naturopathy before trashing it? He rejected a herbologist's intuition and experience. Had he evaluated that? And acupuncture? How could a generation of clinicians take that from a non-clinician? How could many more generations of clinicians robotically accept his dogma? And for decades?

Of course, intuition in medicine had been dealt many blows long before Flexner. The old atomism versus vitalism debate—the ancient Greeks thrived on it—was revived during the 1600s. Proponents of vitalism seized the opportunity and laid claim on the former. Life, they pronounced, could only be created and perpetuated by a vital force that governed organic matter in living beings— humans, animals, and plants. Later chemists decided to divide matter into two forms: organic and inorganic.The stage was then set for the proclaimed victory of materialists when, in 1828, Friedrich Wohler claimed that he had synthesized urea, the first organic compound from inorganic raw materials. To many, that put the last nail in the coffin of vitalism. But vitalism persisted. At the turn of the century, it was fashionable among scientists to ridicule vitalism. (Indeed, some even today snicker at it. Consider the following quote from a recent issue of Nature:

Vitalism was an attempt to reconcile rationality with a sense of wonder.5

The author—unwittingly, it seems to me—holds rationality and a sense of wonder to be two discrete elements of the human experience which some lesser souls try to link together. Confusion about what the rational is persists.

It is not surprising that Flexner, a theorist and a non-clinician, mistook a clinician's intuition as a form of vitalism in 1910. What is surprising is that he failed to realize that his model was inconsistent with great medical arts of the Chinese and Indians. Various healing arts function in their respective cultures. Flexner proposed to destroy all medical cultures except the drug culture. What is astounding is that the main body of physicians of his time failed to see that transparent folly and did not dismiss it outright. Or, perhaps it was merely an economic issue for those at the helm of the AMA who declared Flexner a saviour.

Now consider the following quote from the September 11, 2000, issue of Time:

Many patients suffering from high blood pressure were probably surprised last week to hear that one of the most popular classes of drugs for treating their condition—calcium channel blockers—was being blamed for some 85,000 avoidable heart attacks and heart failures a year. Their doctors were less likely to be surprised. [Italics added].6

I use this quote to make two points. First, what should be our take on the science of thousands of papers published to show calcium channel blockers were safe? Second, what can be said about the editors who rejected all papers describing clinical outcome of nondrug therapies for controlling hypertension with natural remedies simply because those studies were not blinded and controlled? How can anyone blind treatment plans that include water therapy, meditation, exercise, nutrients, and avoidance of metabolic sugar and insulin roller coasters?

I now return to the subjects of the complexity in medical knowledge and making difficult clinical judgments.

MIF: A Molecular Chameleon Par Excellence

The names of proteins and peptides usually reflect their functions when first discovered. Later studies generally reveal biologic activities entirely distinct from those first recognized. That, of course, calls into question conclusions drawn from the initial observations. New hypotheses are then advanced in light of new findings. That cycle repeats itself continually. Science, we are told, advances by trials and errors, and is self correcting. This should be fully acknowledged and heeded in clinical medicine, but rarely is. New drugs are almost always introduced with claims of finality of the proposed basis of their mechanisms of actions. The belief about the putative mechanisms harden into medical "science." Indeed, many editors of medical journals hold that no papers must be published until the data support the proposed mechanisms of action of the pharmacologic agent in question.

Macrophage migration inhibitory factor (MIF) is one of the best molecules to illustrate the above view. This cytokine was the first to be discovered in the early 1960s and may be the last to be understood.7,8 Indeed, it is unlikely that its myriad roles in clinical medicine will ever be fully delineated. Consider the following:

MIF is a proinflammatory cytokine under some conditions and an anti-inflammatory agent under other conditions.9-12 It is a key player in innate immunity in some ways and a regulator of acquired immunity in others.7 It promotes death of some types of cells during inflammation13 and at the same time allows other cells to bypass apoptosis.14 It supports cancer cells by promoting angiogenesis15 and inhibits them by its regulation of antitumor T cells.16 It is involved in the release of insulin from the beta islet cells17 and influences carbohydrate metabolism at the peripheral cellular level.18 It is released by the pituatry to participate in the systemic reactions to stress, and so influences the adrenal response.9,19 Glucocorticoids suppress the inflammatory response and so would be expected to inhibit the generation of MIF. The reality is opposite of that. Instead, those steroids in low concentrations increase its production by macrophages.19 It functions as a thiol-protein oxidoreductase and structurally resembles bacterial isomerases,20 making it likely that it also indirectly serves as an antibiotic (by competitive inhibition of isomerases). Like most proteins participating in immunity, it mates with its receptors to initiate its work7-9 but—interestingly, when circumstances require it to go on by itself—it is also capable of performing solo.10

Uptake of MIF by cells occurs not only with specific receptors but also by endocytosis—a process by which extracellular substances are engulfed by being wrapped around by a cell's outer membrane followed by its inclusion in membrane-bound vesicles. MIF then binds to to Jab1 protein in the cytoplasm. That protein induces phosphorylation of growth and transcription factors. (An example of the former is c-Jun and of the latter is AP-1.) Both types of factors activate the expression of proinflammatory genes. Interestingly, Jab-1 also binds to and facilitates the degradation of p27Kip1 which, in turn, arrests the cell division cycle. That is one way in which Jab-1 rescues serum- starved fibroblasts. However, when overexpressed, MIF inhibits Jab-1 (leading to higher levels of p27Kip1) and exerts a regulatory effect on pro-inflammatory effects of AP-1.10

Beyond the matter of its many discrete and opposing biologic phenomena associated with MIF, there is an even more matter of the bell-shaped dose-response curve of MIF with respect to most of its effects. That dose-response pattern also includes the inhibtion of macrophage migration for which it was so named. The MIF concentration under specific conditions may inhibit or augment the specific biologic effect under consideration. It is noteworthy in this context that extracellular levels of MIF range is very wide—from about 4 ng/ml in normal blood plasma to 150 ng/ml in patients with septic shock21 —and makes all predictions about its diverse roles exceedingly difficult, if possible at all.

What further insights into the workings of MIF—the first discovered and the most intensely examined cytokine so far—will the next few decades bring? It is my strong sense that the mystery of MIF will grow, and not diminish, in the coming years. And what implications for the sick will that knowledge carry? Undoubtedly, such insights will open new possibilities for drugs that block one or more of the effects of MIF and benefit the acutely ill for days or months. The essential point, in my view is this: It is highly unlikely that such blockade approach will restore the health of those with chronic nutritional, ecologic, and degeneratory disorders for years and decades.

Returning to the subject of intuition, Webster defines intuition as the act or faculty of knowing without the use of the rational processes. That does not seem quite right. Intution, to me, is a voice from within—some higher level of communication. I do not see how anyone can separate that from the rational processes, as those putting Webster dictionary together did. One needs a light to make sense of one's life. For me that light is God. Now, if that troubles some in "scientific medicine," I feel helpless about it. Certainly, no one with real interest in the healing phenomena will find the matters of intuition and inner light in a clinician's work troublesome.