PAULING - 1

I was happy when Mrs. Gimbel and Dr. Rinkel invited me to come to
participate in this meeting, and I have been happy to attend the symposium on
the chemical basis of mental disease,/and to be associated with the Manfred
Sakal Foundation, because of its dedication to the job of diminishing the amount
of human suffering in the world.

Recently, the world has been changing at a tremendous rate. Techno-
jJogical advances are such that the world is not the same one year as it was the
year before. Tremendous weapons of destruction are developed. The stresses
under wk which people live become ever more oppressing. There hana SS es from the
centers of governments a special sort of trvationaltty. Frere’ ere are ¢ poeple of
dogma 4 sod Sevetatsonf, the old principles of conduct. ne are forced to strive
for a fundamental, ethieal, and philosophical principle under which we can live,
if the world is going to survive.

I think that the fundamental J ethical principle that everyone can accept
is that of the minimization of human suffering. This is not the same as maxi-
mizing the amount of happiness in the world. If we take money as the criterion,
to increase the income of, say, a billion people by a hundred dollars a year is
not at all equivalent in the amount of happiness that it causes to decreasing
the income of the other two billion by half of that amount. It is the, suffering,
A human suffering .t J that we have to pay attention to.

As the means of commmication and transportation, telephones, telegraphs,
the press have developed in the world, the nature of the human race has changed.
No longer are individual human beings the units. They are now bound together
by these means of communication in the same way that the cells of an individual
human body are bound together by the nerves that interconnect them, in such a way

that the whole human race is becoming one organism, and a special ethical
PAULING - 2

principle will have to be developed under these circumstances. But it mast not

be an ethical principle that places the survival of society or the race above
the value, the worth of the wee human being. vote ETS,
Now phere are many causes of human suffering. In some parts of the
worl / starvation, malnutrition, infectious diseases are the Pea causes;
but everywhere mental disease is an important cause, and watenge halt of oe
hospital beds in the country are occupied by mental patients. Mental disease
causes a purkke particularly great amount of suffering for two reasons:
First, 1t may continue in an individual year after yeary te~-famctusties—jer causing

hin
great suffering for mamy and his friends and relatives. And second, often it

 

attacks some of the wets most able of our people, «
(Tt may well be that schizophrenia is an especially significant disease
for the most able intellectuals. This is a disease that we must attack. We mst
cut down on the amount of suffering caused by mental illness.

I am grateful to the psychiatrists. For several years, eif-e-~derep

voor have had close contact with them,

 

yrs because I became interested Se

 

ers in the question of how mam chemistry might contribute to medicine,
might be used in diminishing the amount of human suffering, and lected that
mental disease was the field in which there was the greatest need of effort.

ABAL DS I am grateful to the psychiatrists, even though they do a ralter,

poor jobf/ because they don't know how to do any better. They use crude methods,

oN
insulin shock, electropshock therapy, damaging the whole human organism in the

hope that the new changed individual will be in some way improved.
PAULING - 3

“Ry pays
eee Bie tre Oion drugs,

ebtGiwed-set through any process of nakiosinctlean » ieccmmnae under-

 

standing of the

 
 
 

nature of the oe habeph 3 sete
found at, oat tor some patients, enms

I hope that the psychiatrists will not have to work poneer under wtathe

terrible handicap of extreme ignorance, and I am encouraged by the epgisssn

 

A wustate presented at this symposium) information: Yabout meet interest iawn
Vadueiaeriggge about abnormalities in the biochemistry of schizophrente in-

as compared

 

with other human beings.

on am encouraged to believe that the time will come before long, in ten

\
eet twenty years when, if enough there

will be come significant fundamental, basic understanding of the nature of the
eins JAbiatee: group of diseases that classify as schizophrenia, ont ener
mental diseases, comparable to that oat exists now for a few other 74 diseases
that are called molecular diseases.

I believe that most mental diseases are molecular diseases, the result
of a biochemical abnormality in the human body. St EE T think that the
psyche, thetseensciousnegg, the mind, is a manifestation of the structure of the

prain, an electrical oscillation in the brain supported by the material structure
u ' ()

 

of the brain, eapabie=a" be

abnormality in the aieyigg chemical structure of the brain itself usually

we made abnormal by an

spConnOOO nec gop xm cae xa SEE hereditary in character, sometimes

Qa
caused by see abnormality in the environment.
PAULING - 4

  

aX
Eallagra is an example of 2 disease pe

mental manifestations A Was prevalent years ago. It wos 2 a deficiency disease, “\artea
OD, aol of vitamin » nicotinic acid. This discovery has led to the solu-
tion of the ppllagra problem in many parts of the world.

Cin the # field of mental deficiency

SEE CEE, TOLecular mental disease

phenylketonuria, first identified 30 years ago by Dr. relies in Oslo, Norway,

  
 

here is some Understanding about

ie exampleg the disease yimey

who checked up on some mentally deficient children who had an odd enelif and )
found that there were some unusual substances present in their urine} se tee
further investigation by him and other scientists led to A iscovery that these
children lack an enzyme in the liver that cat 6 the oxpiation of an amino
acid, phenylalanine

d
stream and cerebrospinal fluid to high concentrations, Wherethe toagn interferes

to tyrosine, so that the phenylalanine puilage in the blood- ©
x i

\

with the development af and function of the brainyand leads to mental deficiency. /

Q ‘Foe oalng)

ae ce
 

about 20 different, acids: glycine » alanine, Aerine, tyrefine,

neletini cing, and 80 on, We eat me we need of—it, jnot quite
“Wene ran See Vn at

ssows tureeine, Bie enzyme ean catalyzes the oxidation of

Most people have two genes net they have inherited from

    
  

their parents that manufactuee the enzyzef in the liver to do

this job. One person in 80 has one gene that manufactures the

ANN Mees wd

enzyme and ,one damaged mata ted spiothy gene that went qmanun

 

Q cin VA) Lee very )
H , enzyme that a nermal person has, But—theebs enough to keep
A

them in good health,
 
  
 
  
      
  

great lotterys the child inherits, Ferre TE en 0G £ etrtne See

 

ani Lhe no bene ate of the two genes the father Apne of the two from the

mothers A quarter of the children ‘wheieloniejvens inherit ab rmal gene of the

father and RK abnormal gene of the mother, ettnceh 11 mamafacture the enzyme.
1 There is none of enzyme in the liver. As the child eate its

food the phenylalanine b

causing him to be
nentally deficient sasiaainigg= aw * evere eczema) and other me ofihe

   
 
 

1 > But when this ledge was gbtains?, it was e that te
pheowid—test fex this eficetees tra ae
eed o Jos

—couttediged Ye child do SNe
from whieh the wgx phenylalanine had been removed, ao
a a ‘kom manner, a pochepeenst—verysttippy anavineme—er

whe
Tis disease, which jp, responsible for 1 per cent

 

 

of the institutionalized mentally deficient individuals in the United States >

now may be brought under control because of the discovery about its nature.
ce owlhey
rt talk about artisense—that I know -more—abowt,

\
s<tivte molecular disease We

 

which I have a personal

 

connection, because its molecular nature was discovered by three of ny
students working in Pasadena 13 years ago.

Tt is a disease of the blood, aahmis ood important one. Perhaps
10 or 20 thousand people in the world die of ity Ch en are born with this
disease, they suffer for a few years and then aLey DoS wipe sopemeeey i
ore

   

This disease 1s a disease in which the # red cells of the blood are
twisted out of shape. Often, instead of being flat, they are twisted into a
sort of crescent shape that looked to Dr. ierrick in igi. sedetpige like a

xgimkesickle with which one cuts grass. He named 9% Sickle cell amenia. ¢—*>
K

 

Hemoglobin makes up 4 1 per cent of the weght of emedasihgem Q—

 

human being, =m

dnvesiigumait, It isa Pb deautitul protain, red, because the molecule,
which eae about 10,000 atoms = has 4 ton atome which are able to combine
with oxygen in the lungs and carry the oxygen out to the extremities.

The red cells of these patients with Sickle cell anemia have these red
cells which are twisted out of shape. They are only twisted out of plece in the
venous blood, not in the arterial blood. There they have the normal shape. As
you see, there is the cleavage.

It is highly younew? probable that it is the hemoglobin i molecule then
that is responsible for the disease, because in arterial blood you don't have
hemoglobin; you have instead oxygen; whereas in venous blood, there is something
different. If these patients manufacture a sort of hemoglobin was different
from that which normal individuals mamfacture, these might be sticky molecules,
self-complementary, such that they would clamp onto one another to form long
rods which would line up side by side to form a long needle-like thing.

It would be longer than the diameter of the red cell, and it would twist itself
out of shape. They would be sticky and get tangled up with themselves and

prevent the flow of blood through the capillaries and the various manifest&tions
m PAULING - 8

of the disease would ocecur.

So, Dr. Tunneau and Dr. Singer, and Dr. Welis, after a while, with
encouragement, carried out an experiment. They put a little drop of uxke
salt water, with electrodes at the ends -- a positive electrode and a negative
electrode -- and introduced a drop of hemoglobin froma normal human being.
In this colorless liquid, under the influence of the electric current, it moved
ever toward the positively-charged electrode. It had a negative electric

charge.

When a drop Ses of blood from a patient with the disease was put in
the trough, it moved over to the negatively-charged; if it had a positive
charge, it had to be different from the normal hemoglobin in the red cells of
normal individuals.

If you mixed these two and put a drop of the mixture in the electric
field, they separated; part of the blood moved this way; the rest that way.
Then when they got blood from the father of the patient and the mother of the
patient -- and gak Dr. Tunnesu of our laboratory put a drop of hemoglobin from
the father of the patient -- that blood split in half; half moved toward the
anode, and half toward the cathode; and similarly for the mother.

This made the nature of the disease clezr. The father and the mother
head one normal gene that manufactured normal hemoglobin. Each had a normal
gene, and each had an abnormal gene, and each of these genes manufactured ite
own kind of hemoglobin. Here we had an abnormal hemoglobin. And the patients
had inherited only the abnormal gene of the father and only the abnormal gene
of the mother.

Here was the demonstration, for the first time, of a disease of the

hemoglobin molecule that produced the manifestations of the disease Sickle
PAULING - 9

eel] anemia.
That isn't the whole of the story. A month or two later, Dr. Tunneau

brought in some blood from another patient who had a still more abnormal
hemoglobin, which was named Hemoglobin C, and then Hemoglobin D, Hemoglobin E,
Hemoglobin G, Hemoglobin H, Hemoglobin I -- some 30 or 40 of these. I haven't
kept track of them. Otu of these,abnormal hemoglobins have been found, many

of them associated with the disease, even with diseases wk that result in gort
of hybrid diseases that result from the inheritance of a Sickle cell amenia from
one parent and the inheritance of o C gene from the other. Zenamumpqens Neither
of these genes alone, in single dose, causes a disease that amounts to anytying,
but the patient who has inherited both the first abnormality and the second ab-
normality in single dose has a disease, a new kind of hybrid disease, hemolytic
anemia.

This example, I think, indicates what we can expect to find in schizo-
phrenia, not that there is a gene for schizophmenia, such that when the patient
inherits this gene in Souble dose he is schizophrenic, but rather that there are
many genes such that any one of them, when present in double dose, or perhaps one
single dose, and another one in single dose, or it may even be a combination of
several, of these genes, produces an abnormality, a quantitative abnormality to
make it difficult for the individual to accept reality, to think in the normal
state, or to retain his sanity under the normal stresses of living, or increasing
stresses of living in the modern world..

There may be factors involved in schizophrenia that come from the out-
side deficiency factors, some lack of some vitamins, or perhaps toxic chemical
substances that are present. Who knows?

The evidence that was presented to the symposium about the presence of

gome sort of a biochemical abnormality in the blood associated in some way with
PAULING _ 10
the globulin fraction of the serum of the blood seem to me to be very suggestively
convincing, because several groups of good investigators from different places
using different methods of investigation had obtained somewhat similar results
with the methods.

I feel this is a strong indication of an abnormality that is present
also in the brain and that is involved in the disease -- in some of the dis-
eases that we classify as schizophrenia. OF course, this muitiple character
of a disease will make it difficult to find a cure, a treatment. But for all
kinds of schizephrenia, I can't say that I have any hope that mental disease
can be brought completely under control. But I do believe that a tremendous
amount of progress can be made in controlling it, and in decreasing the amount
of humen suffering that is involved.

There are ways for treating diseases that can be envisaged that have
not yet been brought into practice and thet are worth serious effort. For ex-
ample, in an enzyme deficiency disease, galactocemia, or many of the other
enzyme deficiency diseases. With the progress in our knowledge about the nature
of enzymes, the structure of protein molecules, it will before long be possible
to synthesize artificial enzymes that will have enzymic activity to perhaps
implant a capsule containing some stable artificial enzyme as a substitution
therapy that permits the patient to get along well in the course of his life,
possibly with an occasional replacement.

New drugs will be discovered, some of them by the same mpx emptrical

pr ss, Dy means of which the Aborigines discovered the 2 efficacy of chewing
cea in the treatment of malaria.

But the time will come when we ahall have enough understanding of the
nature of mental disease to be able to synthesize drugs to order that will be
specific for a particular disease that will operate not in the rather generally

nonspecific monner of the present drugs that sre effective, that have changed
PAULING 12

the character of mental hospitals greatly, but that nevertheless will still
have to be described as representing a sort of shotgun attack on the problem
of the golution of disease.

In the case of diseases, congenital diseases involving gene abnormalities ,
we have now to recognize the possibility of the ft eplacenent -- replacement
introduction into the defective individual of Dia molecules that will serve the
purpose of the molecules that they did not inherit from their parents.

But, all of these are palliative measures. They are not the solution
of the problem. The pool of human germ plagma, you know, contimies to degenerate
day after day, as the natural mtagenic agents » hatural radioactivity, other
mitagenic substances, and those chemicals and artificial high energy radiation
that constitute a part of our modern life damage the Dass molecules constituting
the pool of plasma. It is a very precious one.

A person can inherit about 100,000 molecules of via, 50,000 from his
father, and 50,000 from his mother. I, all of these inherited by every one of
the 2 billion persons now living on earth were to be brought together -- could
be brought together -- they would constitute a mass of about 4 milligrams, the
size of 4 pinheads.

This is the pool of human germ plasma that I am concerned about. It
becomes damaged -- damaged day after day by mutagenic agents, and it isxpoorkftiot
purified. There is a natural process of purification that goes on. New genes
for yummmks phenyluria are caused by this mutation process. The probability
is something like one in a hundred births, or one in 50,000 children has a new
gene for this. For example, there is a dominant gene that causes dwarfism.

It is a dominant gene. The parents of a child who did not possess the abnormal
genes, but had two normal genes instead, would between the conception of the

parents and the conception of the child produce an abnormal gene that he inherited.
PAULING - l2

One child in 12,000 inherits this.

There is the disease cystic fibrosis. One child in SOO has inherited
from its parents two genes for cystic fibrosis which give him this very
serious disease -- and we don't know what these genes do. This is without
doubt a molecular disease, but the protein molecule that is abnormal has not
been identified.

Now when these defective children are born and die without progeny,
they remove from the pool of human germ plasma 2 of the defective genes, and
so there hes been a steady state, such that some 4 per cent of the children who
are born have some degree of mental defect; some 7 per cent are congenitally
defective & either physically or chemically.

I believe that it 1s possible for us now to begin to carry out the
process of purifying the pool of human germ plasma at a rate to keep up with
this continued contamination, without the suffering that is involved in the
birth and death, x without progeny of the defective children. If two parents
have a phenylalanine, then it is known that they are carriers of the gene for
yuyephenylketonuria for each successive child; the chances are 25 per cent
that the child, this chidd, too, will be defective. If two parents have a
ehild with cystic fibrosis, or with many other diseases, nadacks disease,
ninintax disease, we developed a test, a rather difficult one, for detecting
the heterozygous for phenylketonuria. One of the parents involved came to see
us later. His wife had died. He knew that he and his first wife, if they
had had further children, there would have been the 25 per cent chance. He
came with a young woman that he wanted to marry, and he said he wanted to know
whether she carried the gene for phenylketonuria. After the test was made,
he was told she was not a carrier for phenylketonuria; that they could get
married, and that none of their children would have the disease phenylketonuria;
PAULING - 13

of course they would have some other defects, because everyone inherits some
econgenitel defects, mainly minor ones. The minor ones are not to be laughed

at. They are a cause of a tremendous amount of human suffering, because they
are not enough to prevent procreation, and the genes are passed on for geners-
tion after generation causing continuous adding to the amount of humon suffering
in the world.

But it is possible in many cases now to say that a&ipamionog’ offspring
in this marriage would have a 25 per cent, each child being grossly defective.
This is « great amount of human suffering, and I would say that it is too great
a chance to be taken; that a chance as great as 25 per cent of giving birth to
a defective child, increasing the amount of buman suffering is so great that
this matter should not be left to s combination of ignorance combined with free
enterprise in life as is customary at the present time.

People need knowledge. People need to know what their situation is,
and then of course to decide for themselves in these personal matters. I do not
ag@vocate legal action. I do not advocate eugenics as a means of improving the
race. We don't know enough about how to improve the race; but we do know some-
thing about how to decrease the amonht of human suffering, and if 2 heterozyal
were to marry a normal individual as this man, the father did, then half of
those children would inherit his gene. If the only thing that was done as a
resht of xtax increase in knowledge was to get people who possessed defective,
serlously defective genes of a certain sort to marry other people who do not
possess these genes, then there would be no elimination of the defective genes
from the pool of human germ plasma, and pretty soon everyone would have a
greater chance of being defective than he has at the present time.

I think that in the case of people who know that they are carrying a
gene, a recessive gene for a serious disease, should marry normal individuals,

and then have a somewhat smaller number of children then normal,
PAULING - 14
one or two children, rather than three or four. In this way these defective
genes would be removed from the pool of human germ plusms slowly, perhaps at «
rate thet they are now being removed by the death and suffering of the defective
ehildren, but without the death snd suffering of these children. This, I believe,
4s a humane and rational wy of attacking the problem of disease, congenit.1
disease coused by minted genes, 2 wey thet does not invelve the birth snd
suffering of defective children, ond aa the years go by, we shell be xble to
obtain for mental disesses, toc, more and more knowledge ebout the disesses cnd
methods of predicting whether one union has 2 » high probability of leading to
these defective births.

But, oe course, we must also consider the question of pullistive treat-
pment. I wish scmxpet the support for investigators who ore studying the bio-
chemice1 abnormalities of schizophrenic individuclsa could be doubled, tripled,
quodrupled. You know there «re plenty of scientists, very able people in the
world, who would like to be working on problems lie this, but who are instead
working on other problems the nature of which I haven't time to go intc. But
we have no need to hove technologicel scientific unemployment resulting from
disarmament. There is plenty of room for the scientist to do for the benefit
of humen beings in the United Stetes and cll over the world.

I believe thet we are going to have = better and o better world in the
future, and that the scientists are going to do their part in contributing to
it -- ond of course with the help cf the psychistrists, people who work in the
field of mental disease. We couldn't get onywhere without the help of the
peyehiatrists.

I want to say again thet es I have become acquointed with more and
more psychiatriste-- ond our eldest son is a psychictrist now, 37 yeors old, ond
I think miking « success in this profession, he seems to me to be «2 very good

men, one of the soundest, most well-balenced men that I anow. I think that
PAULING - 1°

he is good for bis patients; no doubt does the best that he can for his
patients. I hope that my ossocictes snd I out in Pasademe will, as we con-
tinue with our work, which is on a small scole, carried out not with the hope
that we can make any aymk epoch-m:iking discoveries, but with the firm con-
fiction thet we can do someting thet will be of sid to him in his future
work, and to all of the fine medical men in the world who are devoting them-
selves to the trentuent of the mentally ill.

Thank you.

TAT SE AHAB