Prof. Wei Hsueh
people know of Dr. Benveniste for his famous or
infamous research on the so-called “memory of
water”. Not too many, including biological
scientists, know of his earlier achievements in
allergy and inflammation research. Dr.
Benveniste in fact was the discoverer of
platelet-activating factor, or PAF. (He first
gave the name “platelet-activating factor” to this
compound, but later he changed it to “paf-acether”,
which was widely used in European publications. The
American scientists, on the other hand, stagnantly
stick to the original name).
Platelet-activating factor is the first, and so far
the only, natural phospholipid mediator. It
has very potent pro-inflammatory actions. Less than
2 micrograms (that is 1 millionth of a gram) per kg.
(of body weight) of PAF can induce circulatory shock
in rats, mice and rabbits. I first heard of
this powerful substance in a scientific meeting,
when I was only a few years out of postdoctoral
fellowship training and had just started my own
lab. My post-doctoral training was in
prostaglandins and thromboxane (lipid mediators) at
that time. This newly discovered substance,
PAF, is so potent, that it makes thromboxane, a
strong platelet-aggregating agent, “look like a
dish-washing liquid”, as my former mentor, Dr.
Needleman, jokingly said. I did not hesitate
to switch my focus from prostaglandins to PAF, and
subsequently, almost my entire career in scientific
research, which was continuously supported by NIH
for more than 20 years, was based on PAF. It
is a pity that Dr. B. gave up research on PAF to
concentrate on his other less conventional research,
for I believe that there may be a whole family of
phospholipid mediators with important
pathophysiological functions waiting to be
discovered. With time, this group of
compounds may become as large and as important
as the eicosanoid family (the study of which, by the
way, won the Nobel prize for some investigators in
1982). Unfortunately, the advance of this area
of research staggered and slowed down, after
Jacques, its leader, abandoned the field.
I first met Dr. Benveniste in person during an international PAF meeting in Hilton Head, U.S.A. At that time, he was at the top of his fame, renown, and influence as a scientist. His papers were published in the top-rate journals such as Nature and Journal of Immunology, and he was hailed as the discoverer of a new, important lipid mediator. In this meeting he impressed the audience by his success, brilliancy, intellectual daring, cutting wit, and good looks. He was the center of attention, respected by the old and admired by the young, and everything he said made people ponder. Students, post-docs and young scientists waited in line to get a chance to talk to him, hoping to gain some wisdom. At that time, I was only at the beginning of my research career and had just obtained a RO1 grant from NIH (a grant for independent researcher). Although I was working in a well-known medical school, Northwestern University, my lab was in the Children’s Hospital, an isolated lab, which is 3 miles away from the main campus. That was before Children’s Memorial hospital built its own research institute, and I was more or less working alone, in isolation. You could imagine that I was anxious to get advice and guidance from established researchers. Dr. Benveniste was kind and generous and was never stingy in giving valuable advice and suggestions for my research, and we soon established a regular, although infrequent correspondence. A few years later, I think it was in 1987, in an international meeting in Taipei, Jacques first mentioned his unconventional work on high dilution and basophils to me. He told me that the paper would soon be accepted by the prestigious journal Nature. Being young and naive, my rejoicing at the good news was genuine and heartfelt. Indeed, who would not have expected that such a ground-breaking research should bring nothing but fame and success, and perhaps even a Nobel prize!
Well, you all know what followed. The unthinkable and unexpected happened. The disastrous “Benveniste affair”, the infamous investigation by Nature, led by the chief editor, with the assistance of a professional “witch-hunter” from NIH, and a magician (a magician!). It was disaster after disaster. Things turned upside down. Gradually, everything was taken away from him: his budget, his staff, and finally his lab. Till today I can’t understand how come the scientific community in France and in the world turned a completely deaf ear to the success of his subsequent experiments that confirmed the earlier results of the Nature paper? The study, as you all know, was performed in collaboration with none other than Dr. Spira, a leading statistician in France, and the data were supported by impeccable statistical analysis.
When I met Jacques again in a meeting a few years later, I thought he would have looked defeated and dejected. I was certain that he would give up his unorthodox research, and return to the main stream. It was quite the contrary. Jacques appeared highly spirited, and told me that he had launched a new research project using electronically transmitted signals to stimulate human neutrophils. In the project, he used a well known neutrophil-activating agent, PMA (phorbol myristate acetate), and transmitted it electronically to neutrophils, then measured the oxygen radical production (which is an index for neutrophil activation). I myself was in inflammation research, and neutrophils have always been at the center of my interests. Besides, I was very curious about his new, revolutionary theory. I had all the equipment for measuring neutrophil activation in my lab, the only thing I lacked was the equipment to “transmit” the signals. He said he’d mail it to me. When I opened the package a week later I was shocked. I was expecting a piece of gleaming, fancy equipment, something like what we see in the science fiction movies, but what I got was a small black box containing a simple coil of homemade wires. I immediately tested it on rat peritoneal neutrophils, as I customarily used rats and mice on my experiments. To my surprise, I did see a difference between the control and experimental groups. However, my results were not always consistent. After discussing with Jacques, I realized that the difference was probably due to the way neutrophils were prepared. Since the volume of rat blood is small, it is difficult to harvest rat neutrophils from blood. I used a standard technique of neutrophil collection from the peritoneal cavity. As you know, neutrophils do not reside in the normal peritoneum unless there is inflammation, so I had to induce an inflammatory response by injecting sterile casein into the peritoneal cavity before collecting the neutrophils. Thus, the neutrophils I collected were not normal “resident” neutrophils, but were “elicited”, and were probably already in an activated state. This may explain the inconsistency of the results. Anyway, that was our first collaboration. I discontinued the collaboration because of the different systems we used. You may want to ask why didn’t I also use human blood neutrophils. Well, this is because human research in the U.S. is strictly regulated. To obtain any human tissue, even blood from volunteers, you need to submit a protocol to the Institutional Review Board (IRB). I was afraid that if I submitted the protocol to the IRB, the committee would probably think I was out of my mind, and would never pass the protocol. Anyway, Jacques did complete the study in collaboration with Dr. Yolene Thomas, an established biological scientist and immunologist in France, and the paper was later accepted for publication.
Jacques’ next step was even more bold and revolutionary. He wanted to transmit the biological signals digitally and recorded them in a computer. The preparation he used was a semi- in vivo system, an isolated, perfused guinea pig heart. This is a commonly used system by pharmacologists, called the Langendorff preparation. By injecting various vasoactive substances into the coronary artery of the isolated, perfused heart and measuring the coronary flow, you can quantitate the vasoconstriciting or vasodilating effect of the agent. A classical testing vasodilating substance is acetylcholine, which is the physiological mediator of the parasympathetic system. Atropine blocks the action of acetylcholine. In this experiment, Jacques recorded the signal of acetylcholine using a transducer and a computer with a sound-card. The signal was then amplified and “played” back onto water. He then injected the signal-carrying water into the isolated heart, and found that the coronary flow increased. In the next step, he pretreated the heart with atropine, and repeated the experiment. If the effect of digital Ach was blocked by atropine, then the observed effect should be specifically of Ach. This preparation resembles the in vivo system, and should have more relevance to the real physiology.
Later he did a similar set of experiments using ovalbumin-immunized heart stimulated with digital ovalbumin. After his initial success with these experiments, he asked me if I would like to record the signals in Chicago and send them to his lab. He mailed me the instructions, and I recorded ACh, OVA and water and sent them back to him either in disks or via e-mail, as attached files. Because the experiment and the theory behind it was too fantastic, Jacques decided that the only way that he could convince people was by doing it in a blinded fashion. For this he asked me to participate again. To me this time it was more like a fun game. He first recorded the signals of various substances on his computer. Then he e-mailed me the files. The files came labeled as “water”, “ACh”, “OVA” etc. I randomized and blind-coded them as #1, #2, #3, etc, and sent them back to him via e-mail. He would then test them on the isolated heart and e-mailed me his result, such as #1: water; #2: ACh, #3: OVA, and so on.
I have to admit that I was somewhat skeptical at the beginning. But to my surprise, most of the time his answers were correct. If you apply statistics to the result, the chance that this was a coincidence was very small. However, there is one thing I couldn’t understand. That is why the answer was not 100% correct. It seems that the system needed some “debugging”, and I don’t know whether or not Jacques finally made it work all the time.
This peculiar discovery may sound something of only casual interest for the curious, but if you think about it carefully, you’ll realize that its potential impact is enormous. I’m a M. D., so let’s focus on the potential medical applications. As you know, most drugs have some associated toxicities, including the most commonly used, counter-top drugs like aspirin. A digitally transmitted medicine may have all the benefits but little adverse effect, not mentioning its convenience: Doctors could prescribe and apply medicine via computer or phone to the patient. I will not go to the potential applications in industry and perhaps even in the military. That is outside my field.
Most importantly, this discovery changed our entire traditional concept about biology. Classic biology dictates that all biological actions require binding of the specific receptor by its agonist (compared to a lock-and-key mechanism), which triggers “signal transduction” pathways. Jacques’ theory says that such direct interaction is not only uneconomical (as it requires a lot of “trial and error” match after random encounters of the molecules with their receptors), but also unnecessary. He hypothesized that molecular signals are transmitted by electromagnetic means, i.e., via low frequency waves that co-resonate with the receptor, pretty much like the tuning of a radio. A water milieu is ideal for carrying this kind of EM waves. This hypothesis may sound wild, but if you sit down and think about it, there is some basis for it. Again, let me give you a clinical example. We all know that people who are allergic to a specific allergen can develop a rapid response, even life-threatening anaphylactic shock, in minutes or seconds, when exposed to a minute amount of the allergen. If you remember that an average adult person weighs 60-80 kg, (more in the U.S.), and the amounts of allergen ingested or exposed to can be in the range of a millionth of a gram or less, you’d wonder how can such a minute amount of substance travel through layers of tissue (such as the skin or gut), get into 5 liters of blood, highly diluted, react with antibody, get out of the blood vessels into tissues, find mast cells, and finally find its receptor on the cells surface to bind, and to release histamine and other mediators, all in a few minutes or seconds after exposure. You’d wonder how all these phenomena can be considered plausible under the classic concepts of biology. However, if you apply Jacques’ theory, the rapidity of the response and the extremely low concentration of the stimulus would make sense. I have been doing inflammation research for more than 20 years. We all know that to mimic the in vivo response by in vitro systems often requires a much higher concentration. Using PAF as an example, 3 micrograms/kg of PAF can kill a rat or mouse, but if we want to stimulate culture cells with PAF, we’d need at least micrograms/ml concentration level. We use the term “amplification”, “priming”, “synergy”, and “positive feedback” to explain the super-efficiency of inflammatory phenomenon in vivo. The truth is no one knows exactly what’s going on. Perhaps eventually all these can be explained from the standpoint of electromagnetic theory.
It’s a supreme irony that such an original and reasonable hypothesis has had better reception outside than within the scientific circle. I guess lay people like it because the phrase “memory of water” has a poetic sounding tone. - In fact, I saw a play (written by a British playwright) in Chicago, called “Memory of water” (it had nothing to do with science or Jacques’ theories). But the scientific community almost uniformly turned a deaf ear to it. Why? I think there are several reasons. First, biological science and medicine in the west, since the time of renaissance, have been based on anatomy and alchemy. Anatomy progressed into histology, ultrastructure, and now down to the molecular level –the most fashionable molecular biology nowadays is really nothing but anatomy of the genes. Alchemy evolved into chemistry. Thus, almost all of our understanding of western medicine is based on anatomy and chemistry. Knowledge of biophysics, with the exception of a little mentioning of electric impulses in neurophysiology, is deplorably deficient. A famous Chinese classic, “Red chamber dream” said that women are made of water, and men are made of mud. The truth is, as we all know, that all humans, in fact all beings in the animal kingdom, are made of water. The majority of our being is water. The sad truth is that, no one in biological science knows much about this molecule, which is the essence of life. There are perhaps physicists among the audience here. I wonder if even physicists have a complete clear understanding of its mystery. We have no idea what state water is in the body and how it behaves in various pathophysiologic conditions. As we know, anatomy and chemistry do not explain everything in biology. When I was in medical school, acupuncture was considered voodoo medicine, scoffed by our professors and academic members of the medical societies. Why? Because there’s no anatomical or biochemical foundation for it. It always puzzled me how come so many people that we knew got better after acupuncture treatment. We were told it was due to “placebo effect”, but we knew placebo didn’t work that well in medical studies. Now acupuncture is accepted in all medical communities, even in the U.S. We now even know the acupuncture points of rats, (When you stimulate the acupuncture point, the physiological response can be recorded objectively), but we still don’t know the anatomical localization or have a clear scientific explanation for it.
Another reason for the rejection of an unorthodox theory by the scientific community is the current system and environment. In the U.S., scientists, from very early budding stage, are encouraged to go deep rather than broad. I was a member of the NIH study section for 5 years. I saw so many grants with brilliant, original ideas were shot down, because they were not “focused”. And only when the grant was revised and made concentrated on a specific aspect in depth, then it was accepted. This method has both its strength and weakness. The strength is that it will create many super-specialists. The weakness is that it makes scientists tube-visioned, and sometimes, narrow minded. The other problem is the peer review system to evaluate publications and grants. Admittedly, this is probably the most fair system so far, but it is certainly not a flawless one. If the peer-review is composed of the same tube-vision people, how can you rely on them to open their arms to revolutionary ideas? Further, since these people also decide the future of young scientists (because they make decisions on the papers and grants), people are afraid to openly support a heretical theory, for fear of jeopardizing their own careers. This is one reason I especially admire Jacques. He had a strong character and a will of iron. He looked down upon the worldly opinions with contempt, and he kept on going, despite all the difficulties and obstacles. Once he asked me what I thought about this seemingly crazy perseverance. I jokingly said that to be a prophet is admirable, to fight the Inquisition is courageous and heroic, but there is an uncomfortable risk of being burned alive at stake in the public plaza. He answered: “But I have a very demanding mistress, and I’m obsessed with her. My entire being is completely filled with the image, the profile, the enticing yet elusive face and intermittent smile of this woman: Science. I can’t help what I’m doing”. Now, here is the reply of a true scientist. People get into science for various reasons: fame, fortune, power, job security, escape, or simply for promotion (in academia), but real scientists are motivated by a passion for science. Such are the true idealists.
There has been too much said about the “Benveniste affair” and the “memory of water”, so I won’t spend much time repeating it here. All I wish to say is that Jacques’s idea about the electromagnetic transmission of molecular signals is not only original, but also of colossal importance. Biology has been, for centuries, concentrated first on the structural and chemical aspects up to this day, and studies on physical signaling are deplorably lacking. It took a true visionary to see it, and it was an honor for me to have been associated with, however peripherally, his research endeavor in this field. Whether confirmed true or not, his theory, to say the least, should awaken the imagination of the scientific world in this coming century. But, if proven true, it could be the greatest advance of biological science in hundreds of years.