Prof. Wei Hsueh
March 2005
Most
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.