The living state and cancer

ALBERT SZENT-GYORGYI

Abs~ac~ The surrounding world can be divided into two parts: alive and in-
animate What makes the difference is the subtle reactivity of living systems. The
difference is so great that it is reasonable to suppose that what underlies life is a
specific physical state, `the living state'.

Living systems are built mainly of nucleic acids and proteins, The former are
the guardians OF the basic blueprint while the business of life is carried on by pro-
teins. Proteins thus have to share the subtle reactivity of Living systems. A cfosed-
shell protein molecule, however, has no electronic mobility, and has but a low
chemical reactivity. Its orbitals are occupied by electron pairs which are held firm-
ly. The situation can be changed by taking single electrons out of the system, This
unpairs electrons, leaves half-occupied orbitafs with positive electron holes, mak-
ing the molecules into highly reactive paramagnetic free radicals, The reactivity of
the system depends on the degree of its electronjc desaturation. Electrons can be
taken out of protem molecules by `electron acceptors' in `charge transfer'.
When life began, our globe was covered by dense water vapour. There was no
light and no free oxygen. Electron acceptors could be made out of trioses by con-
centrating their carbon atoms as carbonyls at one end of the molecule. The
resulting methylglyoxat is a weak acceptor which made a low level of development
possible. When light appeared, free oxygen was generated by the energy of
photons. Oxygen is a strong electron acceptor. Its appearance opened the way to
the present tevel of development. The transfer of electrons from protein to o~y-
gen is effected by a compler chemical mechanism which involves ascorbic acid,

What is tife? This is the main probtem of biology. Many have asked this
question, but nobody has answered it. Science is based on the experience that
nature answers intelligent questions intelligently, so if she is silent there may
be something wrong about the question. The question is wrong because life,
as such, does not exist. What we can see is material systems which have this
wonderful quality of being alive. What is this quality? This is the problem. It
must be a very fu~damenra~ quality because it allows us to divide the whole
surrounding world into two parts: `animate' and `inanimate', alive and not-

3


4                                              A. SZENT-GYORGYI

alive. The division is sharp and unequivocal, which suggests that the living
state is a special physicochemical state, a state which can be described in terms
of exact sciences and has to fit into the great order of the universe, having
been created by the same forces as the universe itself. We must search for an
understanding and an answer to our question with a wide natural
philosophical outlook and fit life into the great scheme of creation.

What makes the difference between `animate' and `inanimate' is the
wonderful subtle reactivity and flexibility of the animate. So our first ques-
tion has to be: where to look for the physical basis of this reactivity, in what
substance? The two main components of our body are nucleic acids and pro-
teins. The nucleic acids are the guardians of the basic blueprints of structure,
while the business of life is carried on by the proteins. So we can expect the
proteins to share the subtle reactivity of life. Proteins are macromolecules,
built from simpler constructional units: the amino acids. I could never believe
that the wonderful subtlety of biological reactions should be brought about by
clumsy, relatively unreactive macromolecules without the concurrence of
much smaller and more mobile units which could hardly be anything else than
electrons. But electrons are mobile only on a conductor and so, more than 30
years ago (19411, I proposed that proteins may be conductors. As far as any
attention was given to it, my proposition was unanimously rejected. It was
pointed out to me that already a large number of proteins have been isolated
and thoroughly studied, none of which showed any signs of electrical conduc-
tivity.

This was a powerful argument and nothing could be said against it, but as
time went by it became clear to me that science had overlooked here a very im-
portant circumstance: that proteins are the most versatile substances capable
of performing the most different functions. On first approach, we have to
distinguish between two kinds of functions: very simple ones which can be
performed by single molecules in molecular dispersion, and more complex
ones which can be performed only by integrated systems of molecules. These
latter perform the great biological functions by which we know life, like mo-
tion and secretion or nervous activity. Such integrated systems have to be, by
definition, insoluble. The simple primitive functions, like maintenance of
osmotic pressure, or enzymic activity, which could be performed by single
molecules in solution, in molecular dispersion, demanded no electronic
mobility. But only these simple molecules were readily soluble, and for their
analysis the protein chemists needed solutions. So what they did was to ex-
tract from tissues the soluble proteins, call the extracted tissue `the residue',
and send it down the drain. With them they sent down the systems responsible
for the higher biological functions, which had complex electronic structures.


THE LIVING; STArE ANDC`ANC`ER                               5

If we were able to detach the integrated proteins that perform the vital fUnC-
tions, extract, precipitate, purify and crystallize them, I doubt whether they
would still have the subtle qualities which characterize life and could tell us the
difference between `animate' and `inanimate'.

Having decided to focus on proteins our next question is: in what dimension
to search? Present-day biology is a molecular biology, which searches for
answers mainly in the molecular dimension. Our body is built of molecules,
so its reactions have to be molecular reactions, but molecules are built of
atoms, and atoms are built of nuclei and electrons. So there is another dimen-
sion below the molecules which has been disregarded by biology.

The electrons surrounding the nuclei are in `orbitals' which, in a way, can
be looked on as boxes containing electrons in pairs. The two electrons of the
pairs spin in opposite directions, compensating each other's magnetic
moments, which makes them coupled. The electron pairs in their boxes are
held firmly, have no mobility or high reactivity. In inanimate systems all these
boxes in the ground state are occupied, making `closed shell molecules'. An
electron placed on such a molecule would find no place to go to. Shockley
(1950) compared such a closed shell molecule to a completely filled parking lot
to which no car could be added and in which the cars would have no mobility.
It is difficult to see how such a clumsy closed shell molecule could produce the
subtle reactivity of living systems. A molecular reaction between two of them
would mean only sharing a superficially-lying electron pair. So the question
arises whether there is a possibility of transforming such a clumsy unreactive
macromolecule into a highly reactive unit with a measure of electronic mobil-
ity.

Returning to Shockley's parking lot, if we take out one single car we could
make all other cars mobile, and having created an empty place we make shuf-
fling possible. By taking out a single electron from the closed shell molecule
we could create a `positive hole' in it, opening the way to the shuffling of elec-
trons. Taking out single eiectrons:we also have to uncouple electron pairs
and leave the earlier partner of the eliminated electrons with an uncompen-
sated magnetic moment behind. A molecule containing such uncoupled elec-
trons is a `free radical', and radicals are known to be very reactive. We have
upset the balance of the whole molecule, It seems natural that the more single
electrons we take out, the more we upset the balance and make all electrons
more mobile and reactive. By desaturating the molecule electronically wealso
do something very important, discovered lately by Laki & Ladik (1976): we
greatly increase the interaction between the molecules. These forces which
hold structures together are usually summed up as `van der Waats
attractions'. By desaturating the molecule, we thus strengthen the forces by


6                                          A. SZENT-GYORGYI

which molecules can be linked together to give higher and more complex
structures capable of increasingly complex and subtle reactions: we have
opened the way to development and differentiation, opened the way to evolu-
tion. Without desaturation, these forces are very weak and could not hold
structures together against normal molecular agitation. This leads us to the
first rule of electrobiology: the living state is the electronically desaturated
state of molecules, and the degree of development and differentiation is a
function of the degree of electronic desaturation. Electronic desaturation is a
central problem of biology, and so the next sections will be devoted to the
chemical mechanism of this process.

CHARGE TRANSFER AND PERMITTIVITY

Electrons can be taken out of molecules by other molecules by means of
`charge transfer'. If two molecules are held close together so that their or-
bitals overlap, the two form a single electronic system in which the electrons
can rearrange themselves. If an electron in molecule A can decrease its free
energy and increase its entropy by going over to molecule B, it will tend to do
so, leaving its own molecule behind with a positive charge.  Molecule A;
becomes a donor, while the `acceptor' molecule B acquires a negative charge.
The transfer of a whole electron to another molecule, where it stays put, is a
rare event which occurs only in `strong' charge transfer. What mostly will
happen is that the transferred electron or electrons oscillate between the two
molecules. Depending on various factors the oscillating electrons may not
divide their time equally between the two molecules but may spend, say, 1%
more on A than on B. It is customary to say, in such a case, that only one
hundredth of an electron has been transferred. Such a partial transfer of elec-
trons may play a very important part in biology and contribute to the subtle
adjustment of biological reactions. It may have also a major importance for
the mechanism of evolution.*

Here we meet a difficulty: by transferring an electron we create two elec-
trically charged free radicals (Fig. 1: A and B). Electrically charged free
radicals are exceedingly reactive and it is doubtful whether this reactivity is
compatible with life. There is a way out. Let us suppose that before transfer-
ring the electron from B to A we incorporate B into A, as shown in Fig. 1C. In
this case the transfer of electrons could take place as before and transform
both molecules into reactive free radicals, but no net charge would be

*It is believable that by sending out `fractions of electrons', molecules could explore
simultaneously a number of situations and would stay only where they can decrease their free
energy, increase their entropy and do something useful.


THE LIVING STATE ANDCANCER

7

(J-0 @J

  A          e          C

FIG. I. A and B symbolize charge transfer: C stands for doping,

generated, the transfer having taken place inside the complex. Such incor-
poration with intramolecular charge transfer is called `doping', which is one
of the most important reactions on which the electronics industry is built, in
which poor semiconductors are made into strong ones by doping them with
electron donors or acceptors.

The creation of life demanded `donors' and `acceptors'. How do we find
them? The universe has been transformed into one coherent system by the
periodic chart of atoms of Mendeleev, the top rows of which are reproduced
in Fig. 2. Where do donors and acceptors fit into this system? As we alLknow,
this chart, which contains all the elements, consists of horizontal and vertical
rows. Each horizontal row begins and ends with a noble gas. The noble gases
are the most stable ones, and all physical systems tend to acquire stability. So
all elements tend to resemble a noble gas by having the same number of elec-
trons in their outermost shell. The elements on the right side of the chart have
less, those on the left side have more electrons than the nearest noble gas; and
so the former tend to take up electrons and the latter tend to give off elec-
trons. Thus the former become electron acceptors, the latter electron donors.
According to the table the best acceptors are fluorine and the other halogens.
In fact, they are too strong as acceptors to be used by life, so for a good
biological acceptor we have to turn to the next column, headed by oxygen, the
universal biological acceptor.  The energy driving life is derived from the
transfer of an electron from hydrogen to oxygen.

Charge transfer depends to a great extent on the dielectric constant, E, of
the solvent, which decides its permitt~vity. A high e corresponds to a high per-
mittivity, and a low t to a low permittivity. A given E may both promote and
impede charge transfer in which positive and negative charges have to be
separated. Such separation will be promoted by a high t which depolarizes the
charges and so facilitates separation. At the same time, for charge transfer to
take place, the two interacting molecules have to be held together in close
proximity by conventional forces which are electropolar. So a high e


8

A. SZENT-GYORGYI

FK;. 2. Top lines of Mendeleev's periodic chart of atoms. To make the figure correct it would
have to be cut out and roiled into a spiral in which the two neons overlap.

will tend to depolarize and disrupt such complexes, interfering with charge
transfer.  One special case of complex formation is dimerization (or
polymerization in general), which can greatly promote charge transfer, as
shown in Fig. 3. In Fig. 3, A represents a charge transfer complex in which
the charges have been transferred to the ends of the particle. A dimerization,
as shown in B, will greatly depolarize and so facilitate the transfer. These op-
posing in~uences will allow some charge transfer to take place only at a cer-
tain t where the opposing forces balance each other most favourabiy. This is
illustrated in Fig. 4, in an experiment in which a series of test tubes were filled
with different solvents containing an increasing amount of water, the concen-
tration of water increasing from tube to tube by 10%. The far left tube con-
tained the pure organic solvent and the last one on the right, pure water. Then
in all tubes a charge transfer reaction was performed which could be recogniz-
ed by its colour. The + sign indicates the intensity of colour and charge
transfer. The organic solvents had a relatively low e (45 for dimethyl sulphox-
ide and 37 for dimethylformamide). As can be seen in Fig. 4, there was no
reaction in the pure organic solvents; the reaction gradually became stronger
as the F increased, then weaker again in pure water.

As will be discussed later, I believe that cancer, essentialIy, is a failure to
desaturate proteins and so substances which interfere with charge transfer
have to be carcinogenic. According to Fig. 4, water is a carcinogen. This car-

Ftc,. 3. x. A fibrous molecule with separated charges. IL The same dimerized. The figure is inten-
ded IO show that the separation of charges promotes dimerization and dimerization promotes the
separation of charges.


THE LIVING STATE AND CANCER                              9

Fir;. 4. Intensity of the charge transfer reaction between methylamine and rn~t~y~~ly~~a~ in a
mixture af dimethyl sul~ho~ide or dimethylformamide and water. The first sample on the left
contains the pure organic solvent, the last on the right, pure water. The maximum of the reaction
is around r =60. Glycerol (bottom line) has no such maximum.

cinogenic activity of water around the living protein structure is eliminated by
the water structures the proteins build around themselves, which decrease e.
The e of water is 81.5; that of ice is 2, similar to that of paraffin wax.

The third line in Fig. 4 shows glyceroi. I showed many years ago (1949) that
the motility of muscle can be preserved for years in 50% glycerol. Up to now
this activity has been mystery. It seems to be the resuft of the favourable per-
mittivity of the solvent, which allows the conservation of electronic relations.

METHYLGLYOXAL

When life originated, about three and a half billion years ago, it was prob-
ably pitch dark on our globe and there was no oxygen, the earth being covered
by a dense layer of water vapour. There was no free oxygen. The oxygen was
present in bound form as water, carbonate, phosphate, etc, which is of no use
as an acceptor for protein. So if our rules of electronic biology are valid and
there can be no life without desaturation, and oxygen is the universal accep-
tor, then we have to supnose that life found ways of using the bound oxygen
as acceptor. Nature achieved this by taking a molecule of water out of triose
and crowding all the oxygens as carbonyf, GO, at one end of the mofecuie,
the hydrogens at the other. The substance formed is ~ethy~g~yoxal (Fig. 5).

Nature is simple but subtle (P. Ehrenfest, personal communication).
Methylglyoxdl is a unique substance.  There is no other substance with its
special characteristics, In spite of its small size it contains a reactive aldehydic
group, and a ketonic C=O, which has a Iow lying triplet orbital (Abdu~nur
1976), making it an acceptor. Triose is the smallest molecule which could be
transformed in this way.

That 1 have not lost myself in meaningless speculation and am still close to
the central problems of biology is indicated by the fact that more than sixty
years ago a most reactive and apparently ubiquitous biological enzymic


10                                                A. WENT-GYORGYI

system was discovered, `glyoxa/ase', which catalyses a two-step reaction using
glutathione as coenzyme. It can transform, at an extreme speed, methylglyox-
al into D-lactic acid. Nature does not indulge in luxuries, and if there is such a
widely spread and active enzymic system, it must have something very impor-
tant to do. But up to the present nobody has been able to find any use for it,
D-lactic acid and methylglyoxal not being known to have any major biological
function,

HC = 0

c=o

FIG. 5. Structure of methylglyoxal.

Methyiglyoxal can attack protein by means of its aldehydic C=O interacting
with an amino group of protein. Protein has but one typical NH2 group which
is in its lysine residues.* Before discussing this interaction I should like to
consider briefly a simpler model in which the protein's place is taken by the
simplest aliphatic amine, methylamine.

If aqueous solutions of methylamine and methylglyoxal are mixed, the ap-
pearance of a yellow colour indicates the formation of a Schiff base which
contains the chromogenic N=C link:

RI-C=O + H,N-R2- R'--C=N-RZ + Hz0

If the same reaction is performed in a solvent of lower permittivity, such as
methanol or acetone, instead of water, a purple colour appears. If
OSM-acetone solutions of two reagents are mixed, then the purple product
precipitates and can be isolated.  Pohl et al. (1977) measured its molecular
weight, which indicated a polymerization to a tetramer. In the electron spin
resonance (e.s.r.) spectroscope the purple precipitate gives a strong signal with
a rich hyperfine structure, showing that polymerization and charge transfer
have occurred. In the first instance the precipitate is colourless; it turns purple
in a fraction of a second, showing that the primary product of the reaction is a
colourless substance. The same can be shown also for the Schiff bases by us-
ing butylamine instead of methylamine. The colourless primary product is in

*The NH, in arginine residues is part of a guanidine group and has specific qualities and reac-
tions.


THE LIVING STATE AND CANCER                               11

all probability a hemiacetal.* At the high permittivity of water the hemiacetal
turns into the yellow Schiff base, while at a lower permittivity, such as that of
acetone or methanol, it polymerizes and turns into the purple charge transfer
complex.

METHYLGLYOXAL AND PROTEIN

If we represent the peptide chain of protein by a straight line, as has been
done in Fig. 6, then the lysine side-chain can be drawn as a straight line which
hangs out to one side, consisting of four carbon atoms with an NH2 at its
end.  This side-chain can be looked upon as a fishing rod, fishing for
methylglyoxal. Methylglyoxal molecules can be expected to attach themselves
to the amino group forming a Schiff base which is but slightiy weaker as an ac-
ceptor than methylglyoxal (J. Ladik, unpublished calculations).

FIG. 6.

While the lysine side-chain is stretched out it can take with its Schiff base no
electrons from the peptide chain from which it is separated by four saturated
carbon atoms, through which no electrons can be transmitted. However, the
side-chain is pliable and can fold. Otto et al. (1978) made a thorough study
of this folding and found that it will bring the Schiff base into touch with the
second-neighbour peptide bond of the peptide chain of the protein, enabling it
to enter a charge transfer reaction with it and take electrons from it. it will
form an n-p junction which will charge the Schiff base negatively, the peptide
chain positively, making it into a p-type conductor. t In many proteins, about

                          H
                          I
*CH,-NH, + 0= C-H--H,- N-COH
     h         1 1
                       H R

t It deserves consideration whether anaerobic life may not be based on an n-type conductivity.
The very first forms of life had to be anaerobic.


12                                               A. SCENT-GYOKGY I

each eighth amino acid residue is a Iysine (Fig. 7), and so the peptide chain has
a boosting station at every eighth amino acid. This lysine side-chain with the
attached Schiff base is the kernel of the mechanism proteins carry with them
for their desaturation.

If a solution of lysine is treated with methylglyoxal it turns yellow because
of the formation of a Schiff base. It can give no purple complex, not even in
alcohol or acetone, because the bulky molecule interferes with polymeriza-
tion. If a protein, such as casein, is treated with aqueous methylglyoxal, its
granules being suspended in methyiglyoxal solution, it turns yellow, but if the
amino groups of the lysine residues are methylated, the protein remains col-
ourless. If treated with a methanol solution of methylglyoxai, the colour of
the protein becomes darker, brown.  Since the lysine side-chains cannot
polymerize this darker colour has to be due to a more intimate compfexing of
the Schiff base with the peptide chain, due to the lower permittivity of the sol-
vent.

NH2
L-l,
iH,
iH*
i"2
CNH?
;OOH

FIG. 7. LyGne.

The brown cofour of the methylgiyoxal-treated casein is very similar to that
of the liver, which makes it seem likely that the liver actually owes at least part
of its colour to its electronic desaturation by methyiglyoxal. Fodor ef al.
(1978) have in fact isolated and identified the methylglyoxal linked to the liver
protein.

In the first period, life had to be based on a desaturation by methylglyoxal,
which is a weak acceptor, and so life, in this period, could have developed but
only the simplest forms which have left no traces behind.
Fig. 6 suggests that the Schiff base, being at the end of the lysine side-chain,
at a distance from the peptide chain, is formed in random water which pro-
motes the formation of Schiff bases. The association of the Schiff base with
the peptide link in the peptide chain may be promoted by the lowered dielectric
constant, lowered by the protein, which builds water structures around itself.


According to the theory presented, the desaturation of the peptide chain
should lead to an increase in its electronic conductivity. This conductivity has
been measured by Pethig 2% Szent-Gyorgyi (1977) as well as by Bone et al.
(1978) and found to be increased considerably.

The brown colour of the fiver indicates unpaired electrons and suggests that
protein radicals are an important part of the structure of liver cells. Pohl et al.
(1977) isolated these coloured proteins and found them to be paramagnet~c,
giving a strong e.s.r. signal, similar to the signal given by casein treated with
methylgIyoxa~. This suggests that the c.s.r. signals given by living material are
actually due to the protein radicals composing the cellular structures, and are
not entirely due to undefined free radicals in solution, as hitherto supposed.
The structural proteins in Pohl's experiments were isolated by homogenizing
the tissue in ice-cooled 50% ammonium sulphate and subsequent centrifuga-
tion. The sohrble proteins were isolated similarly in the centrifuge by 100%
saturatjon, after the structural proteins had been eliminated; the soluble pro-
teins gave but a very weak signal.

The history of life was divided into two parts by the appearance of fight. fn
the first, dark period the globe was covered by dense water vapour, and the
atmosphere had to be reducing. There was no free oxygen, and there could be
no stable electron acceptors. Accordingly, life could reach only a very low*
degree of development, which has left practically no traces behind. The pro-
tein in this period had to be desaturated by methylglyoxal, which is a weak ac-
ceptor and could develop only the simplest forms of life, the main function of
which had to be the proliferation which made Iife percnniat. This unbridled
proliferation had to be favoured by the low level of cohesive forces and the
poverty and simplicity of structures. I have called this first dark proliferative
part `the c~ period'.

This situation changed when, because of cooling, the water vapour con-
densed and light could reach the surface of the globe. What life did with this
light was to use its energy for the separation of the elements of water, produc-
ing oxygen, which is a strong acceptor, and so could start up the development
and differentia~jon~ the end result of which is us. I have called the second;
light oxidative part of life's history the 6 period. The cohesive forces
generated by the electronic desaturatian led to the building of increasingly
complex structures with increasingly complex and subtle reactions.

Cohesion and structures interfere with proliferation, so when the cell
divides it has to lower its cohesive forces and dismount part of its structure,


14                                         A. SZENT-GYC)RGYI

These changes can be summed up as a partial return to the CY state, which is the
ground state of life. It has to be the more stable state, having the lower free
energy and higher entropy. So the (Y - 6 transformation had to be kept
reversible. After it had completed its division, the cell had to build up its /3
state again. So in the @ period the unbridled proliferation was replaced by
regulated growth. Should the cell, after completing cell division, find the way
of return to the 0 state perturbed, it has to persist in the proliferative CY state
and continue to divide when no division is needed, leading to a tumour. This
also explains why very rapidly dividing cells resemble one another, be they em-
bryonic, cancerous, or simply very rapidly dividing normal cells.

The more complete the return to the CY state, the faster the proliferation and
the lower the cohesive forces will be, and the more malignant the tumour pro-
duced.

ASCORBIC ACID

Free oxygen, 02, is a strong electron acceptor and so its appearance in the /3
period opened the way to a higher degree of electronic desaturation, and to
the corresponding higher degree of differentiation and development. If
nature develops a new method, as a rule, she does not throw the old one out,
but simply adds the new one to it, improving it. So, in the p period,
methylglyoxal was not replaced by 02, but the 02 was added to it, boosting up
its acceptor strength.

However, oxygen does not interact with protein, nor does it interact with
methylglyoxal. So in order for it to be used as an acceptor for protein, a link
had to be developed by which the oxygen could be linked to methylglyoxal,
transferring to it part of its acceptor power. This link had to have very
specific qualities: it had to be able to make a bond simultaneously both with
oxygen and methylglyoxal and had to have an electronic mobility by which it
could transfer the acceptor strength of 02 to the ketoaldehyde. This new
substance, which nature developed when light and oxygen appeared, is ascor-
bic acid, discovered by me in the early thirties. Later it was found to have an
antiscorbutic activity, and to be identical with the then unknown antiscorbutic
component of fresh vegetables called `Vitamin C'.

In a remarkably short time the chemical nature of ascorbic acid was cleared
up and the substance became available at low cost in crystalline condition in
an unlimited quantity. But while we have learned everything worth knowing
about its chemistry, its biological function remained unknown, preventing
medicine from making full use of its remarkable reactivity. We can control
only what we understand. Even a simple question, such as the magnitude of


THE LlVtNG STATE AND CANCER                              15

the recommended daily dose, has remained unsettled, oscillating between
megadoses and a few milligrams.

The development of ascorbic acid is one of the landmarks of evolution, as
was the appearance of light and oxygen. That ascorbic acid readily interacts
with oxygen can be shown by placing a sample of its Na salt into the e.s.r. spec-
trometer in the absence of oxygen. On admission of air the typical free radical
signal appears, consisting of a doublet with a splitting of 1.75 gauss. Each
part of the doublet has a further triplet splitting of 0.175 gauss.

That ascorbic acid can readily interact with methylglyoxal has been shown
by Fodor, who will describe his observations later in this symposium (Fodor ei
at., pp. 165-169).

The great mobility of the unpaired electron inside the ascorbate radical can
be demonstrated by e.s.r. which shows that this electron can interact with
many of the protons of ascorbate.

Also, the spectrometer gives valuable information about the interaction of
oxygen, ascorbate and methylglyoxal, which information has hitherto been
utilized only to a small extent. If methylamine and methylglyoxal solutions
are mixed a very strong signal appears with a rich hyperfine structure. In the
presence of ascorbate the signal is much stronger, showing that the ascorbate
catalyses charge transfer, without changing the character. If casein is treated
with methylglyoxal in the presence of ascorbate, a new signal appears (P.C.R.
Gascoyne, personal communication), indicating that the ascorbate is built
into the charge transfer complex-an observation which may have far-
reaching biological consequences and introduces new viewpoints into the
medical use of the acid.

Most fascinating and complex spectroscopic reactions have been found by
my colleague Jane McLaughlin (unpublished results). If both cuvettes of the
spectrophotometer contained a mixture of a 0.0256~ solution of methylglyox-
al and methylamine (0.077M), and 0.0077M-ascorbic acid was added, a very
strong absorption appeared around 400 nm, which disappeared slowly (Fig.
8). A second peak appeared around 500 nm. In the absence of oxygen the ad-
dition of ascorbic acid m$de no difference, showing that it catalysed the
charge transfer between 02 and methylglyoxal. If no ascorbate was present,
admission of oxygen to the mixture of methylglyoxal and methylamine in-
hibited the appearance of the absorption spectrum.

Oxygen, essentially, brings the hfe-giving light into the living system.
Ascorbic acid catalyses this reaction. It is involved in bringing matter to life.
This opens up new aspects of the medical application of ascorbic acid.
The actual role played by oxygen in these reactions is yet unknown and
demands more study on the basic level.  It is possible that the 02 molecule


A.SZENT-GYORGYI

355 400     500    600
      "in

FIG. 8. See text for explantation (p. 15).

simply takes an electron over and dissociates off, but it seems more likely to
me that it takes over only parts of an electron and remains attached to the
charge transfer complex. If, in this ease, the oxygen pressure is decreased, the
oxygen may dissociate off, upsetting the electron balance in the whole charge
transfer mechanism. This may explain why consciousness instantaneously
fades out if the oxygen supply to the brain is cut off. This suggests also that in
the comatose state after a heart attack the infusion of ascorbic acid and
artificial respiration might be indicated.

Two cardinal symptoms of a cancerous transformation are a low
paramagnetic susceptibility and a low cohesion. Both are the consequences of
a defective desaturation of the structural proteins, due to the loosening up and
disorganization of the chemical machinery, a shift towards the o( state.

A cell is a strongly integrated system and all its reactions are coupled to one
another. In the normal cell the reactions are coupled in such a way that activi-
ty improves activity. Desaturation promotes further desaturation, and exer-
cise makes us stronger, but coupling is a two-way street, and factors which in-
hibit normal interactions may be coupled in such a way that they cause further


THE l.IWNG STATE ANTI CANCER                              17

inhibition. An inadequate desaturation may inhibit desaturation. This can
push the cell into a vicious circle which the cell is unable to break, and Ieads it
into a state of disorganization, landing it in the proliferative CY state. If the
situation is not corrected this situation may become constitutive, irreversible.

To be able to correct a deficiency we need a still better and more detailed
knowledge of the chemical machinery of electronic desaturation, which can be
achieved by basic research. The blindfold search for a cure for cancer seems a
hopeless waste. Until correction becomes possible the best defence against
cancer is keeping the machinery in perfect working order. More than sixty
years of research on living systems has convinced me that our body is much
more nearly perfect than the endless list of ailments suggests. Its shortcom-
ings are due less to its inborn imperfections than to our abusing it.

One factor which deserves special attention is ascorbic acid, for the supply
of which we depend on food, the expensive nature of which is not a guarantee
of its quality. Some experiments suggest that this acid is not merely a catalyst
but that it is built into the machinery-and is part and parcel of it. Since we
are building and rebuilding this machinery all the time, a continuous supply of
ascorbic acid is important. A machinery built without ascorbic acid cannot be
corrected by suddenly administering megadoses. Correction of defects may
take the better part of a year.

The ideal of medicine is the curing of all diseases. The ideal should be full
health, which leaves no room for any shortcoming. In the U.S.A. we are still
losing the battle against cancer: every day there are eight hundred casualties,
I strongly believe that cancer is accessible to a complete analysis on the basic
level, and that understanding it means also the ability to control it.

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18                                          A. SZENT-GYOKGYI

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