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| | Interviews with Nutritional Experts: Lipoic Acid Against AIDS: Newly discovered mechanism of antioxidant protection | |
Interview with Dr. Lester Packer
as interviewed by Richard A. Passwater PhD
Dr Lester Packer has chatted with us about antioxidants twice before
in which we discussed the "conventional" mechanisms by which antioxidant
nutrients protect us against disease. This month, we will review the exciting
new area of research that reveals how antioxidants affect our health by
influencing gene expression. Gene expression is the process in which our
genes control what our body makes and how well it is made. Every protein
made in the body is determined by our genes. Whether we produce more of
what is needed or not is part of the picture, but it is also important that
what we make is correct. If our genes are damaged we could produce cancerous
cells. Or our cells might not make an adequate number of LDL receptors to
take cholesterol from the blood stream. In fact, every aspect of body chemistry
and health is influenced by our genes, and now we understand more of the
role of antioxidants in gene function.
Dr. Packer has made many important discoveries about how antioxidants function,
including how various antioxidants work together synergistically. In our
previous interviews we have discussed oxygen radicals and other reactive
oxygen species (ROS) and how they can directly harm body components. Now
we will discuss how free radicals and ROS can alter many body processes
and both directly and indirectly affect health or cause disease.
Dr. Packer is a professor in the Department of Molecular and Cell Biology
at the University of California at Berkeley. His research in the area of
biological oxidation and bioenergetics has emphasized studies on the role
of oxidants and antioxidants in biological systems. He is one of the world's
leading researchers on vitamin E and biological antioxidants. His recent
research has elucidated new areas in the biochemistry of vitamin E -- the
vitamin E cycle. This is relevant to the understanding of new enzymic reactions
of vitamin E, the vitamin E radical, and the biological consequences of
the action of vitamin E. His recent research concerns the prevention of
oxidatively-induced injury in biological systems by antioxidants and how
antioxidants such as vitamin E and lipoic acid affect gene expression and
cell regulation. These investigations are helping to develop a new and broader
understanding of biological antioxidant defense mechanisms.
Dr. Packer has edited more than fifty books, authored over five-hundred
scientific articles, and has organized numerous conferences in the area
of his research interests. He serves on the editorial boards of three scientific
journals, and currently is President of The Oxygen Club of California, President
Elect of the international Society for Free Radical Research, and Vice President
of UNESCO's Global Network on Molecular and Cell Biology.
We will use Dr. Packer's exciting new research on stopping human immunodeficiency
virus (HIV) replication as a paradigm. Dr. Packer has found that lipoic
acid protects Nuclear Factor kappa-B (NF kappa-B) from activating the transcription
factor that causes HIV to replicate. We will discuss the importance of NF
kappa-B later, but suffice it to say now that the protection of NF kappa-B
is very important. If NF kappa-B is activated, then it in turn can activate
or damage genes, which in turn determines our health. The discovery of this
relationship has only very recently come to light and scientists are very
excited as they realize more than ever that antioxidants have great implications
for our health.
Passwater: Dr. Packer, we have mentioned alpha-lipoic acid in both
of our previous chats. Let's discuss it in more detail. Alpha-lipoic acid
is a metabolic antioxidant. It is a disulfhydryl coenzyme that is a co-factor
in at least two major energy producing reactions in the body and it is a
powerful antioxidant that is readily transported through cellular membranes.
Your research has focused on its role in the antioxidant cycle. Please review
again for us how alpha-lipoic acid helps recycle other antioxidants.
Packer: Alpha-lipoic acid has a low redox potential, which means
that its reduced form, dihydrolipoic acid, very readily donates electrons
to other compounds. So, for example, it can reduce oxidized glutathione
to reduced glutathione. It also appears to perhaps directly reduce the vitamin
E radical, formed when vitamin E quenches lipid peroxidation, back to vitamin
E. And it will reduce the semidehydroascorbyl back to ascorbate (vitamin
C). That, in turn, links it to vitamin E, because vitamin C can also reduce
the vitamin E radical. So you can see that all these antioxidants are tightly
interlinked, with alpha-lipoic acid playing a role in recycling many of
the key antioxidants in the cell.
Passwater: How do the roles of lipoic acid differ from that of another
antioxidant coenzyme, coenzyme Q-10?
Packer: Coenzyme Q-10 appears to be more limited in its antioxidant
capacity than lipoic acid. Coenzyme Q-10 can recycle vitamin E, and may
also be able to directly quench lipid peroxidation. But, since it's fat-soluble
as opposed to being water-soluble, it's pretty much limited to lipid (fat)
environments. Alpha-lipoic acid and dihydrolipoic acid have some solubility
in water, and so can quench radical reactions in both lipid and aqueous
environments. Between them, they have been shown to scavenge (inactivate)
hydroxyl and peroxyl radicals, as well as hypochlorous acid, singlet oxygen,
and nitric oxide. They also are able to chelate transition metals, which
are involved in oxidative reactions. And, of course, there are the recycling
effects on other antioxidants. SO lipoic acid really has quite a diversity
of functions when compared with coenzyme Q-10.
Passwater: Lipoic acid was discovered as an essential coenzyme in
1951, when it was realized that it was an essential component of enzymes
involved in mitochondrial electron transport (energy) reactions. It wasn't
until about 1988 that researchers also realized that it can also act as
a powerful biological antioxidant.
Packer: That's right. At first it was thought that alpha-lipoic acid
was a vitamin, but later it was shown to be synthesized in the body. But
the body is very stingy about synthesizing it, making only enough for its
metabolic role, so there is no free alpha-lipoic acid in the cell. It's
the free alpha-lipoic acid that acts as an antioxidant, because when it's
bound in mitochondrial enzyme complexes where it performs its metabolic
role, it really has no access to areas where oxidative stress may be occurring.
Passwater: Why is lipoic acid such a universal antioxidant? What
are the important features of its chemical structure?
Packer: The structure of lipoic acid is analogous to octanoic acid.
Lipoic acid is 6,8-dithiolane octanoic acid (also 1,2-dithiolane-3-valeric
acid or 1,2-dithiolane-3-pentanoic acid). And the molecule being small and
lipid-like in character but also having a hydrophilic (water-soluble) portion
renders its both water soluble and membrane soluble. Thus, the molecule
readily crosses cell membranes. Once it gets inside of cells, it can be
acted upon by cell enzymes. These reducing enzymes are mainly those in the
mitochondria, but there are also enzymes of the cytosol like glutathione
reductase that will also reduce lipoic acid.
Passwater: The body has chosen the basic eight-carbon chain to make
this molecule soluble. Why does the body choose sulfur to attach to this
basic carbon backbone to make lipoic acid an antioxidant? The body could
have simply added hydroxyl groups such as with monophenols like vitamin
E or polyphenols such as bioflavonoids. Not that I expected you to have
been here at the time the decision was made. There is something special
about all these sulfur compounds in the body. I have often written about
them in this column. Sulfur is the eighth most common substance in the body.
We have sulfur-containing vitamins (e. g., thiamine and biotin ), sulfur-containing
amino acids (e. g., cysteine, methionine and taurine ), sulfur-containing
antioxidants (e. g., lipoic acid and glutathione ), and countless proteins.
Packer: Sulfur is a key component in the structure of proteins and
in the function of proteins. So the final (conformational) status of a protein
is critical for its function. Take for example insulin, a small protein
that has three disulfide ( -S-S- ) linkages in it. If any of these of disulfide
linkages are broken or "reduced" by having hydrogen added to the
sulfur atom to form disulfhydryl groups ( -SH-SH- ), insulin completely
changes its structure and loses its activity.
Passwater: Does it have anything to do with the thiols being the
expendable antioxidant units in the antioxidant cycle where vitamin C recycles
vitamin E and (alpha-lipoic acid) recycles vitamin C and so on down the
chain ? Aren't the thiols and NADH or NADPH the units that are ultimately
consumed in free-radical termination as the other antioxidants are recycled
by the self-sacrificing thiols?
Packer: Yes, but the thiols like glutathione can exist in its oxidized
disulfide
(GSSG ) form or its reduced glutathione (GSH) form. The oxidized form can
be reduced by glutathione reductase. The same enzyme can also reduce alpha-lipoic
acid. Of course it works much more rapidly on glutathione. The enzyme derives
its reducing power from NADPH -- which is ultimately derived from glucose
metabolism. Metabolism drives the reduction of these essential antioxidants
in the body and the thiol status is really critical not only in the cytosol
but on proteins.
I often wonder why nature decided to use glutathione instead of lipoic acid
and I sometimes answer this by saying that I think lipoic acid could be
too much of a good thing for routine defense against radicals. It can be
too strong of an antioxidant for precise control under normal conditions.
The body doesn't like to use powerful antioxidants, it wants to hedge its
bets. So instead of having nanomolar concentrations of lipoic acid floating
around it has millimolar concentrations of the weaker antioxidant glutathione.
The body tries to flood the cell with many molecules of glutathione. The
level of glutathione is among the highest concentration of water soluble
substances in cells. In liver it is about eight millimolar. The more powerful
antioxidants are present in lower concentrations. Vitamin C is normally
present in lower concentrations and of course vitamin E in much, much lower,
a million times lower concentrations. The thiol system, (alpha-lipoic acid)
is unique in that it can talk to (chemically communicate with) proteins,
it can talk to vitamin C, and it may talk to vitamin E directly. That's
a very weak effect. And there are other key reductants that are very important
in cell regulation. One of them is called thioredoxin.
Thioredoxin is a very important protein that turns on and turns off pathways.
It does not directly link to the glutathione system. Reduced glutathione
cannot reduce thioredoxin but reduced alpha-lipoic acid can. So alpha-lipoic
acid it is unique in that it can talk to that system too. Its very versatile.
It gets around in all body systems.
Passwater: Lipoic acid is not considered to be a dietary essential
nutrient. Our bodies can make some lipoic acid, but do we make enough for
optimal health or should lipoic acid be considered "conditionally essential?"
Packer: The body makes only transient amounts--very trace amounts.
In fact, we know very little about how it is biosynthesized and that is
an area we should learn more about. We should know step by step exactly
how lipoic acid is made in the body. We don't know.
Passwater: Therefore we don't know the weak links in lipoic acid
production. Does your research indicate that there is benefit in exogenous
sources at least under certain conditions?
Packer: We are using lipoic acid in a therapeutic mode. We are using
it as an exogenous antioxidant to boost the antioxidant status of the body,
and as a unique and potent reductant to study various processes in which
reducing power is important.
Passwater: OK, there are two concepts I want to explore for our readers.
When as chemists we speak of antioxidants and "reducing power"
or "redox cycling" sometimes the jargon discourages some of our
non-chemist readers. Now they have the opportunity to have one of the best
and most energetic biochemistry lecturer explain these concepts.
Packer: When a compound is reduced, it gains an electron. When a
compound is oxidized, it loses an electron. Reducing power refers to a compound's
ability to donate an electron, that is, to reduce another compound. If a
compound donates an electron easily, it has high reducing power. If it hangs
on tightly to electrons, it has low reducing power.
When you talk about oxidation and reduction, there are always two compounds
involved, one which loses an electron and one which gains an electron. For
example, when vitamin E quenches lipid peroxidation, that's an oxidation
- reduction reaction. Vitamin E donates an electron to a peroxyl radical.
The vitamin E is oxidized, and the peroxyl radical is reduced. "Redox"
is just sort of a shorthand way of saying "reduction and oxidation,"
and redox cycles are groups of linked redox reactions. To take the vitamin
E example again, after the vitamin E loses an electron, it can be given
an electron by another compound, for example, vitamin C. Now the vitamin
C has become oxidized, and the vitamin E is reduced -- it's been cycled
back to its original form.
Passwater: When we think of the life process as so many electrons
and hydrogen atoms (protons) being moved throughout the body, we sometimes
forget that oxidation-reduction, electron transfer and acid-base relationships
are not the everyday concerns of non-chemists.
Now let me go back to your concept of "therapeutic value."
When increased reducing power is needed, is this limited to "therapeutic
use" or would there be conditions where increased reducing power
could optimize health above and beyond what is needed for growth and normal
maintenance?
Packer: Well the way I think about some of these things is that
the driving force in evolution was to support child-bearing and child-rearing,
reproductive capacity of a species, and once that had been dispensed with,
there is no longer any evolutionary need to keep members of that species
living. In fact, there are certain species known that after sexual activity,
the males die.
Nowadays more people are living longer because of improved nutrition, medical
advances in antibiotics, and so on. As a result, we are seeing an increased
prevalence of certain chronic and degenerative diseases that were fairly
uncommon before. Age-related diseases such as cataract, cardiovascular disease,
cancer, neuro-degenerative diseases and so forth are now considered normal.
Based on the results of many animal and human intervention studies, it is
clear that antioxidants play a role in slowing the development of these
diseases.
The use of nutritional antioxidants above and beyond the amount needed for
treating deficiency has a clear rationale when you think of aging and lifestyle.
We are living longer, but it is important to maintain good health longer
as well. It is not age -- the passage of time per se -- that causes these
diseases, but the effect of oxidative stress over time that causes the so-called
age-related diseases. With better protection against oxidative stress, we
can prevent or at least postpone these diseases.
Passwater: The prevention of age-related disease is not often considered
in "classical nutrition" even though it is vital to body maintenance.
It does involve the optimization of health nonetheless. Those traditional
nutritionists who only look at reproduction and growth into adulthood miss
many of the requirements for maintaining optimum adult health. Optimal adult
health should be considered as part of the official RDA's, but it isn't.
Packer: Well, this idea is still fairly new, and the people who set
the RDA's are, understandably, quite conservative about changing their approach.
One key issue is whether there are any undesirable side effects to taking
antioxidants at the doses that produce optimum health. There is little evidence
that there are any side effects in taking large doses of, for example, vitamin
C and vitamin E. As the results of long-term studies which are underway
now continue to come in, I think the tide will shift toward perhaps recommending
a higher level of some nutrients as being shown to be consistent with optimal
health.
Passwater: Recently you have published some interesting results about
the role of alpha-lipoic acid in T-lymphocyte function. What are you observing?
Packer: I am particularly interested in T-lymphocyte function because
in viral infection, T-lymphocytes show oxidated stress. This is particularly
a concern in HIV infection. Several studies have demonstrated that HIV-infected
T-lymphocytes are deficient in glutathione which is their primary antioxidant.
So these cells are really under oxidative stress.
One strategy has been to try to overcome the intracellular glutathione deficiency.
Glutathione is not transported into HIV-infect T cells and the HIV-infected
T cells do not produce enough to overcome the oxidative stress occurring
within the cells. N-acetyl cysteine has been used in one approach to stimulate
glutathione production within the cells, but lipoic acid supplementation
seems to be a much better approach.
Passwater: Who first tested this concept?
Packer: In 1989, a group of investigators in Germany led by Dr. A.
Baur reported that the replication of HIV in a T-lymphocyte cell line could
be prevented by lipoic acid. They were looking to reduce the oxidative stress
in the T cells when they made this important observation.
Since the mechanism whereby lipoic acid prevented HIV replication was not
obvious, and we were working with lipoic acid we realized that this was
something we should take a look at. It turns out that one of the transcription
factors that is very important in producing a long-term repeat structure
of the proviral of DNA requires the activation of the NF kappa-B. The transcription
factor is known to be activated by reactive oxygen species.
As an example, the transcription factor can be activated by ultraviolet
energy or by hydrogen peroxide. Various receptors that generate reactive
oxygen species like tumor necrosis factor- alpha, interleukin-2, or lympho-toxin
all activate NF kappa-B.
Passwater: You mentioned NF kappa-B. Our readers will want to learn
about your research showing how alpha-lipoic acid protects NF kappa-B which
in turn, protects genes and inhibits HIV replication. I'll review the basics
as most nutritionists still haven't even heard of NF kappa-B yet. Alpha-lipoic
acid has the ability to protect the genetic material, DNA, in the cell nucleus.
A gene is a "block" of DNA that operates as a unit within a chromosome
to control a specific cell function by regulating the production of a specific
protein. There are about 100,000 genes in each of the 46 chromosomes in
the nucleus of cells. Genes are capable of reproducing themselves at each
cell division and they are capable of managing the formation of body proteins
trough processes called gene expression and regulation. Any factor that
interferes with normal gene regulation can profoundly influence health and
lifespan. Free radicals and other reactive oxygen species can influence
gene expression and regulation.
You have shown that alpha-lipoic acid can play an important role in gene
regulation. Genes can be activated by a protein complex called Nuclear Factor
kappa-B (NF-kappa-B). This activator can bind to DNA in genes and cause
changes in the rate of expression of specific genes. Usually these are genes
associated with the acute inflammatory response. Old animals, including
man, have more NK-kappa-B bound to their genes than do young animals. The
most studied effect of NK-kappa-B has been its effect on the immune system,
but it is also known to lead to such things as defective skin cells and
aged skin, but apparently can also lead to defective cells in all body organs
which results in decreased function of all body systems. Such effects could
be due to "overdoing" the inflammatory response.
If I am not simplifying your research too much, this gene activator, NK-kappa-B,
is held in check by other protein sub-units called I-kappa-B proteins. When
an I-kappa-B protein binds to NF-kappa-B, the complex cannot pass from the
cell cytoplasm through the porous two-layered membrane of the nuclear envelope
into the nucleus where the genes are located. The goal for health is to
not allow excess NK-kappa-B to be released from the complex, and
to permit the body to control its release by normal processes. However,
free radicals, peroxides, and ultraviolet energy can induce the inactive
complex to dissociate and allow the NF-kappa-B to penetrate into the nucleus
and damage DNA.
Packer: Basically, that is correct. The activation of NF kappa-B
transforms it from a trimeric protein that is in the cytosol to a heterodimer.
The inhibitory protein that was associated with NF kappa-B is destroyed
by a protease enzyme and is separated from the NF kappa-B. Then the heterodimer
migrates through the nucleus and finds the DNA and leads to gene expression.
Antioxidants by virtue of the fact that they may inhibit reactive oxygen
species should in principle be able to inhibit activation of this transcription
factor. And in fact this is what we found.
Passwater: Several antioxidants can reduce the free radicals in various
compartments of the body. Antioxidants such as the bioflavonoids have relatively
large molecular sizes which make it difficult for them to be transported
through cellular membranes. An advantage of alpha-lipoic acid is that it
is relatively very small molecule and is readily transported through cellular
membranes including the nuclear membrane. Thus, it not only can terminate
free radicals in the blood stream and on the cellular membrane, alpha-lipoic
acid can protect NF kappa-B in the cytosol and even protect the DNA in the
nucleus.
Packer: We have done studies on lipoprotein oxidation, ischemia reprefusion
injury, and molecular biological effects with ginkgo biloba extract which
contains lots of bioflavonoids. We find that activation of NF kappa-B is
not inhibited by ginkgo biloba extract but other transcription factors are.
So we think the bioflavonoids in ginkgo biloba may be important but it doesn't
seem to protect on NF kappa-B. However, that doesn't rule out that some
bioflavonoids may have antioxidant action that may affect NF kappa-B. There
are thousands of bioflavonoids .
Passwater: Let's follow up on your comment that alpha-lipoic acid
supplementation appears to be a better approach to preventing the transcription
of HIV than using N-acetylcysteine.
Packer: We have also seen that vitamin E can inhibit activation
of NF kappa-B but it depends on how the reactive oxygen species are generated.
If they involve lipid-derived radicals in the activation, then it would
be natural that vitamin E would be very effective and we find this is the
case. Therefore that is what is probably involved. But if the reactive oxygen
species didn't involve a lipid environment, you would not expect vitamin
E to work.
Passwater: How about vitamin C?
Packer: Vitamin C does not seem to inhibit NF kappa-B.
Passwater: How about co-enzyme Q-10?
Packer: Nope. Can't get it there. The body can't get it to the nucleus
where it would be effective.
Passwater: How about N-acetyl cysteine?
Packer: N-acetyl cysteine does work. It gets into the cytosol and
nucleus and does have antioxidant activity. It does prevent NF kappa-B activation.
But I have not seen any studies with Coenzyme Q-10 at all.
Passwater: You mentioned alpha-lipoic acid can interact at several
points - it is multi-functional.
Packer: It can be multi-functional. Yes, exactly. We have been trying
to identify the various sites in which alpha-lipoic acid may be important
in the activation of this nuclear transcription factor. We have found at
least two sites at which this may work and we believe there may be more.
But the two most important ones we found are the activation of NF-kappa-B
itself, which we believe is due to quenching by the reduced form of lipoic
acid and the quenching of free radicals or other reactive oxygen species.
The second way in which we think alpha-lipoic acid is important is in the
oxidized form. When lipoic acid enters a cell, it enters as the oxidized
form and then it gets reduced, resulting in a mixture of the reduced and
the oxidized forms. The oxidized form oxidizes SH groups on the heterodimer
that are needed to bind the heterodimer to DNA . The oxidation of those
groups may prevent the binding of the DNA.
So we have identified two sites at which lipoic acid may be important. Yes,
it very much is a multi-functional kind of thing. It would be hard for me
to conceive that vitamin E or bioflavonoids could work in that same way.
But nevertheless they could work to some degree if they were effective in
quenching the reactive oxygen species. They should work.
Passwater: Let's turn to improving cellular glutathione levels in
healthy people. We mentioned that HIV-infected cells could not transport
pre-formed glutathione into the cell interiors and that they could not produce
enough glutathione inside the cells to meet antioxidant needs. The study
of absorption and bioavailability of glutathione supplements is quite complex
and fraught with experimental artifacts such as the measurement system inducing
stress which results in the body responding with localized increases in
glutathione. As our understanding of glutathione biochemistry increases,
we are better able to discern the meaningful data from the obstinsible procedural
artifacts that confound the issue. Dr. Dean Jones of the Emory University
School of Medicine will discuss the role of oral glutathione absorption
with us in an up-coming interview. You have edited several books on glutathione.
What is your experience with attempting to improve cellular glutathione
levels by increasing dietary glutathione levels?
Packer: Dietary glutathione does not significantly increase intracellular
glutathione levels. Glutathione does not cross cell membranes. Mitochondrial
glutathione exists in isolation from cytosolic glutathione. In oxidative
stress, some tissues expel oxidized glutathione (GSSG). Intestinal absorption
is considered vanishingly small.
However, the late Dr. Al Meister of Cornell found that the monoester of
glutathione, though not absorbed from the diet, can be absorbed if injected
intraperitoneally (injected into the peritoneum, the thin membrane that
lines the walls of the abdomen), and will bolster the glutathione content
of many tissues. Dr. Meister also developed a di-ester of glutathione which
may be even more effective than the monoester of glutathione.
Passwater: As Dr. Jones will explain in a future article, dietary
and supplemental glutathione do have important roles such as in the detoxification
of peroxides in food and providing a very safe form of cysteine. Studies
have shown that oral glutathione has appreciably reduced oral cancer rates.
However, oral glutathione is of negligible value to HIV-positive and AIDS
patients who need to boost their intracellular glutathione. What would the
advantage of alpha- lipoic acid be for improving intracellular glutathione
over a system that would work on improving the absorption of glutathione
or its esters?
Packer: Let me give you an example. I am writing a paper right now
with a colleague. Dr. V. G. Ravindranath and her colleagues. We've carried
out a joint study on cerebral ischemia reperfusion injury. In these experiments,
we restrict the flow of blood through the carotid arteries for 30 minutes
and then the restriction is released and we watch what happens to the animals.
Eighty percent of these animals die in 24 hours. If they are administered
the monoester glutathione there is no significant reduction in mortality--just
a few percent but no significance. Only 20 percent of the animals die if
they are treated with lipoic acid. It is the most remarkable effect ever
found in cerebral ischemia in a model system. What happens? During reperfusion,
glutathione levels drop in the brain; but you give alpha-lipoic acid you
raise the glutathione levels in the brain. So alpha-lipoic acid is able
to bolster the cellular glutathione levels not only in this system but we
have seen this in lymphocytes also.
Passwater: I believe Dr. Leneord Herzenberg and his team are currently
conducting a clinical intervention trial giving NAC to HIV-positive and/or
AIDS patients. Recently, I chatted with Dr. Luc Montagnier who shared his
plans with our readers that he will be using NAC and other antioxidants
in HIV-positive patients. Have they seen the evidence suggesting that alpha-lipoic
acid may be more effective?
Packer: Yes they have because I have lectured in Dr. Montagnier's
department and I have recommended to him that in a multi-center antioxidant
trial that is being proposed in France that they include alpha-lipoic acid
in the cocktail. He knows about it very definitely, but, he hasn't gotten
to the point of using it yet.
Passwater: Well your research is always so very exciting. Thank you
for sharing it with us.
All rights, including electronic and print media, to this article are copywrited
by © Richard A. Passwater, Ph.D. and Whole Foods Magazine (WFC Inc.).
| Richard A. Passwater, Ph.D. has been a research biochemist since 1959. His first areas of research was in the development of pharmaceuticals and analytical chemistry. His laboratory research led to his discovery of......more |  |
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