April 22, 1996
Walking back from the bank to the hospital today I was prompted to
buy several large juicy navel oranges. I've been eyeing oranges for many
weeks now, but my wife and I have a long standing disagreement about
who picks the best ones. I thought the oranges she chose at a fruit
stand, just outside Half Moon Bay yesterday, were puny; she again
suggested I always pick the oversized, dried up ones.
Today, though, my oranges were winners: Sweet, juicy and large;
just the way I like them.
In the news the past several days, as you've probably heard, Vitamin C
requirements (RDAs, Required Daily Allowance, set by the National Research
Council, the nation's highest scientific authority) for adult males have
been revalued upward. Not modestly either: But three-fold, and still
the upper limit is poorly defined. It seems an intramural researcher
at NIH finally got the funding go ahead to do some of the experiments
which Linus Pauling and Albert Szent-Gyorgyi always longed to do
before the end of their lives, but were denied funding for.
It is notable that in this latest work (1), seven men in their twenties
were fed increasing doses of Vitamin C after being starved for
it in their diet. Although they never showed signs of scurvy,
each volunteer did report feeling uncomfortable when deprived
of Vitamin C. The NIH authors note that because the subjects
of their study were young men in their 20's, the results are
limited to this subject group.
The vivid image of Szent-Gyorgyi standing in front of Whitman Auditorium
in Woods Hole holding a bottle of glyoxyl in one hand and Vitamin C
in the other is permanently etched in my memory. I'll not easily
forget the hypothesis of 'radical scavenging' which Szent-Gyorgyi
put to us that day: He said that he and Pauling had been talking
about the central importance of OXYGEN in human metabolism
and explained that he had been concerned for a good deal of time about
reactions generating singlet oxygen. These, produced in abundance
during mitochondrial "charge transfer" in liver parenchyma, and other
aerobically active tissues, must absorb electrons pairwise in order to
avoid causing damage.
In 1931, Pauling discovered the superoxide radical, which, though
produced in minute quantities as an unwanted byproduct of oxidative
phosphorylation, has enormous destructive capacity if not defused (2).
During lectures given at UC Berkeley in the 80s, Pauling paid
tribute to the remarkable specificity of the enzymatic system that
neutralizes it: Superoxide dismutase; at the same time, however,
he noted that this enzyme does not defuse the lesser, but still significant
intracellular destructive capacity of singlet oxygen or the hydroxide radical
(and unkown to him at the time, the NO radical).
Superoxide dismutase transforms superoxide radicals to peroxide which can
then be eliminated as water after the action of peroxidase and catalase.
But what is the body to do with all the unpaired electrons such a process
would generate? Szent-Gyorgyi told that oxygen itself could absorb unpaired
electrons if only it were conjugated to carbon in the form of a double
carbonyl: the simplest such compound being glyoxyl, commonly found in human
liver, for this compound had sufficient electron delocalization to provide
something of an electron sink. And, the supply of glyoxyl is renewable
through the action of the glutathione-S-tranferase system, present in
liver mitochondria. Further, Szent-Gyorgyi told us excitedly, two
englishmen and a german, H.D. Dakin, H.W. Dudley and C. Neuberg had, in
1913 discovered that methylated-glyoxyl could be transformed to a potent
energy source itself, lactic acid, through the action of glyoxylase,
which they discovered in that year. So, in one fell swoop, Szent-Gyorgyi
had connected for us the relationship between oxygen radical and one
carbon metabolism. I promise I will discuss this relationship in the
next few weeks, when I write another essay, tentatively titled,
Folic Acid and I.
In comments honoring Szent-Gyorgyi on the occasion of his 82nd
birthday, Linus Pauling recalled Vitamin C's discovery by Szent-Gyorgyi
in 1928. Pauling noted that Szent-Gyorgyi had written in 1939 (4) that
although organisms were generally well adapted to their surroundings,
that the destruction of the natural environment endangered that
adapatation. "I have a strong faith in the perfection of the human
body", Szent-Gyorgyi wrote in 1939, "and I think that vitamins are an
important factor in its coordination with its surroundings. Vitamins,
if properly understood and applied, will help us to reduce human suffering
to an extent which the most fantastic mind would fail to imagine." (3)
On the day that I met him in Woods Hole, Szent-Gyorgyi told us he and Pauling
(three Nobel prizes) between them suggested that significant increases
in Vitamin C intake were almost certainly required by an adult body,
perhaps especially at times when oxygen production was increased.
Szent-Gyorgyi had insisted in a book he had written two years before,
that Vitamin C, especially when complexed with manganese in
the presence of oxygen, could synthesize a free radical form, as well and as
easily as it could form a dehydroascorbate, oxidized form in the
presence of copper or iron and in alliance with an enzyme he'd
discovered in plants in 1931 and named 'ascorbic acid oxidase.'
Szent-Gyorgyi insisted that it was in some sense the equilibrium between
the various oxidized and reduced forms of ascorbate which provided its
multifarious activities.
And yet, this week, fully 18 years after the memorable talk by
Szent-Gyorgyi which I just described, the Vitamin C RDA for men
has been adjusted three-fold upward.
It makes me wonder at the brazen inefficiency of the research
'establishment'...
The knowledge that both Linus and Albe died
without ever attaining a modicum of funding for their final
nutrition project confirms some of my worst fears about
our ways of deciding what research is worthy in this
country.
My hope in writing this is that our children will not suffer
because of the lack of wisdom of their leaders in
making decision about what to and what not to study.
Bert Gold
San Francisco
References
(1) Levine, M.; Conry-Cantilena, C.; Wang, Y.; Welch, R.W.; Washko, P.W.;
Dhariwal, K.R.; Park, J.B.; Lazarev, A.; Graumlich, J.G., King, J.;
Cantilena, L.R. (1996) Vitamin C pharmacokinetics in healthy
volunteers: Evidence for a recommended dietary allowance.
Proc. Natl. Acad. Sci. USA; 93, 3704-3709.
(2) Marinacci, B. (1995) Linus Pauling in His Own Words, New York, Simon &
Shuster.
(3) Kaminer, B., ed. (1977) Search and Discovery, A tribute to Albert
Szent-Gyorgyi, New York, Academic Press.
(4) Szent-Gyorgyi, A. (1939) On Oxidation, Fermentation, Vitamins, Health
and Disease. Baltimore, Williams and Wilkins.
