ARTHUR KORNBERG, M.D.

BASIC MOTIVES OF A

I WENT TO MEDICAL SCHOOL and then served as a
house officer. I enjoyed clinical medicine and
fully intended to go into practice. Then the events
of 1941 forced me into unexpected circumstances.
As a commissioned officer, during a tour of duty,
I was ordered to do full-time research. I found I
liked it and stayed with it. Yet I have always re-
mained close to medical schools and medical
problems. I have wondered many times to myself
and with my students about the opportunities and
responsibilities of a physician's life.  I want to
share some of these thoughts.

An earlier American president admonished us :
"Ask not what your country can do for you but
what you can do for your country." This is very
fine sounding and also very misleading. Because
most of the time we should and do occupy our-
selves with personal interests, and we pursue na-
tional interests only when our personal and na-
tional interests happen to coincide.
I have met people in scientific research and in
other professional activities who state that the
prime mission in their professional lives is to help
humanity. It has seemed to me that these people
are either deluded or dishonest. I have worried
over the years that my attitudes might be too
harsh and off the mark but I was encouraged re-
cently to find similar ideas charmingly expressed
in some autobiographical notes of G. H. Hardy,
the late and gifted English mathematician.

I would like to indicate what Hardy believed
and what I believe to be the basic motives of a
professional life, be it in mathematics, biochem-
istry or medicine. There are essentially three mo-
tives. These are:

First, pleasure in solving problems that provoke
intellectual curiosity;
Second, pride in solving these problems with
professional skill; and
Third, ambition to be creative and thereby to
be an artist instead of a practitioner.
The burden of this paper will be to explain why
I regard these three motivations to be the prime

I dedicate this paper to Dr. William S. McCann, Pro-
fessor of Medicine, Emeritus, of the University of
Rochester, on the occasion of his 80th birthday. I was a
student and house officer in his department during the
years 1939-1942. I recall with deep gratitude his gen-
erous personal concern for me and his courageous fight
against bigotry, intolerance and chauvinism.     AK

PROFESSIONAL LIFE

components of a true professional life. But first I
must consider the more usual attitude that the es-
sence of a physician's profession is to dedicate
himself to service. 1 assume that the physician
when he performs such service for patients is pri-
marily serving himself. He serves patients because
he derives deep personal satisfaction from being
of service or because he gains private wealth or
most probably for both reasons. Obviously, re-
gardless of motive, the patient's comfort or his
very life depend on the services of a good physi-
cian. Sometimes physicians engage in teaching or
administrative work, part time or even full time.
But these are usually additional forms of com-
munity service. My appeal to students is that they
consider the opportunities that training in medi-

Dr. Kornberg (AaA, Rochester, 1941) has
just completed ten years as Professor and
Chairman of the Department of Biochemistry
at Stanford. During this period, his Depart-
ment has achieved an enviable reputation,
both for its investigative productivity as well
as for its stimulating teaching program for
medical students and graduate students.
Dr. Kornberg, who received a Nobel Prize
in 1959, based this paper on an address de-
livered at the Commencement exercises of
the University of Utah College of Medicine
in June, 1969.

cine offers for a professional life with even larger
dimensions, a professional life that includes more
artistic and intellectual activity. This fuller profes-
sional life, I believe, will best serve both personal
as well as community interest.
What I am describing is in some sense an ideal
standard, and ideal standards are shrugged off in
medicine as often as they are in politics. But this
does not justify one's seeking anything less. Wal-
ter Lippman said many years ago that it is "bad
to shrug off ideal standards in politics . . . because
it defeats us and frustrates our lives. If we do not
harden ourselves by stretching ourselves to reach
upward to these not wholly attainable ideals, we
slump down and settle into flabbiness and foot-
lessness and boredom."

Now let me be specific about these three moti-
vations in a physician's professional life that are
so often lost sight of.
The first, as I have said, is the pleasure in
solving problems that provoke intellectual curiosi-
ty. Hippocrates is my best example. He is cited
for his Oath, which contains some highly ques-
tionable guides for modern medical etiquette. He
deserves to be celebrated, rather, for being the
first to reject the priestly aspects of the physi-
cian's profession and for applying his intellect in-
stead. He urged the use of inductive reasoning in
place of tradition and superstition, he made astute
clinical observations, which incidentally included
the use of auscultation, he carefully recorded case
histories and he argued that the physician, rather
than the gods, has the responsibility to interpose
treatments in order to influence the course of a
disease.
Clinical practice abounds in difficult and
thought-provoking problems. If the physician has
failed to ask himself penetrating questions about
a disease, its basic pathogenesis and treatment,
he will find that the medical literature is full of
such questions and even some answers. But the
busy physician doesn't have the time to think, to
read, to indulge in this academic exercise. He is
too busy delivering urgent service. I have a spe-
cific suggestion. The physician should find ways
of being more efficient in disposing of routine
service work in order to earn the leisure to use
his brains. Let me cite an example.
An interesting study is in progress of the habits
of pediatricians in private practice. In a rather
extensive and careful survey, it was found that
the pediatrician sees an equal number of sick and
well children in his office. But whereas the av-
erage visit with a sick child takes about five min-
utes, the visit with a well child takes almost twice
as long. Most of the time spent with the well baby
and child is taken up with routine measurements
and shots. Therefore two-thirds of the physician's
time is consumed with this simple routine work,
work that a trained assistant should be able to do.
On the basis of these findings, each of several
pediatricians engaged a nurse,  and within two
months trained her to take over most of the rou-
tine office functions. It has turned out that during
the past year their patients have not only acceptzd
the nurse's services but even prefer them to the
doctor's, which tend to be more hurried. The pa-
tients still pay the same fees. Now that the doctor
has been relieved of time-consuming, boring ef-
fort he can use these extra hours thinking and
reading about and probing the intellectually pro-
vocative problems presented by his very sick pa-
tients.

If the first motivation of the truly professional
physician is pleasure in solving intellectual prob-

lems, then the second motivation is pride in solv-
ing these problems with skill and style. The fine
physician can justly take pride when he uses in-
tuition and wisdom to solve an especially difficult
diagnostic or therapeutic problem. But such fa-
vorable instances are not common or predictable
enough. In the work-a-day practice of medicine,
physicians could do far better by exploiting im-
proved operational approaches. Some ideas occur
to me from my experience in trying to solve re-
search problems.
I want to consider first the collection and re-
cording of data.
Despite what one hears, the successful research
worker usually tackles difficult problems with a
brute force approach. He makes many measure-
ments. Important observations don't come usual-
ly from inspired ideas but rather from thorough
and systematic analyses. A problem takes on en-
tirely new directions and proportions as out-
growths from what may have seemed to be rou-
tine measurements. I think physicians would do
well to collect more data. Collecting data takes
time and money. I am certain we can devise more
economical and efficient ways to get these analy-
ses done. As we collect more data, we must learn
how to record them so that we can use and recall
them.
The keeping of clinical records has been my
pet peeve since medical student days. The worst,
of course, is the absence of records entirely. But
nearly as bad are the usual chicken tracks of a
chronicle that is scattered, incomplete and inco-
herent. No research student or laboratory assist-
ant in my experience has ever kept daily records
on problems of bacteria or of enzymes as undis-
ciplined as those that fill the charts of patients in
our university hospitals. It seems to me incredible
that our schools and teaching hospitals have failed
to demand disciplined and standardized records.
Such records are crucial not only to the immedi-
ate and long-term welfare of the individual pa-
tient but are also essential to the progress of med-
icine as a whole. Good records will generate new
insights and subtle deviations that now go un-
noticed will become more explicit.
Energetic collection of data and their intelli-
gent tabulation will solve part of the problem.
But the full solution of a clinical problem includes
its proper treatment. Which drug or procedure to
choose and how to use it?
The problem of therapy is too large and diffi-
cult a subject for me, but I am struck by two
things. On the one hand, there is extraordinary
commercial and advertising promotion of drugs,
and on the other hand there is a ready acceptance
of these claims by the physician because he does
not have the means to judge and appraise them.
New drugs and clinical procedures are accepted

by the physician and used until they are proven
to be toxic or without redeeming value. By con-
trast, the research worker regards a new tech-
nique, a new compound or a new idea as suspect
until proven valid.
The story of chloramphenicol is an interesting
case in point. A hematologist colleague of mine
was called upon several years ago to treat a wom-
an with aplastic anemia that arose from the use
of this drug. He was later involved as a witness in
litigation because the use of chloramphenicol in
this case had been ill-advised. I learned from him
that chloramphenicol was widely promoted and
used in this country long after its potential for
producing fatal anemia was well known. There
were, in 1963, in California alone, 10 deaths di-
rectly attributable to the use of chloramphenicol,
an incidence 13 times the general population risk
of aplastic anemia. It seemed clear even then
that the use of chloramphenicol was rarely war-
ranted. It is even more clear today and still
chloramphenicol is prescribed far more than it
should be.

The problem of drug-induced disease has been
and will always remain with us. It is a problem in
which society has a collective responsibility but in
which the intellectual effort of the skillful physi-
cian will always have a large and decisive role.
I have discussed two motivations, the pleasure
a physician can derive from coping with intellec-
tually demanding problems and the pride he can
take in tackling such problems with professional
vigor and method. Now I come finally to the third
motivation of a professional life, the ambition to
be creative and thereby to be more of an artist
than a practitioner. This could be the most impor-
tant aspect of a physician's life and is the most
rarely realized. I would like to dwell on this sub-
ject.
Do we select students for medical school for
their creative capacities? I think rather we select
for general intelligence and motivation. In fact,
the pressure of medical school courses and the
patterns of clinical training tend to suppress cre-
ativity in the student. The redeeming and sorne-
times saving feature of a medical education is ex-
posure to the magnificence of nature as it is dis-
played in the form and function of the human
body. Who can lack the sensitivity to be awed
and inspired by the fantastic intricacy and in-
genuity in the operation of a cell membrane, a
muscle, a reflex response? Who can be unaffected
by what we know of the chemistry, physiology
and anatomy of vision and how much remains to
be discovered about the entire visual process that
lies between the retina and the brain?
Most of us as we passed through our courses in
pathology and physical diagnosis became the cer-
tain victims of some fatal disease. In my case I

succumbed to carcinoma of the bowel, an aortic
aneurysm and amyotrophic lateral sclerosis, all in
one semester. And as we recovered from these
successive afflictions, we realized what a miracle
it is to be and remain alive. Since it takes so little
to upset this exquisite balance,  there must be
mechanisms, beyond our appreciation, that keep
us in a steady state of health.

The physician has the opportunity in his daily
concern with the human organism to contribute
original observations about the function of the
body in health and disease. Imagine the great
leap forward in medicine, if each of the 300,000
physicians in the U.S. contributed one new fact
in his lifetime. Some may argue that few of our
300,000 physicians have the intellect or imagina-
tion to make an original contribution, but I would
emphatically deny it.
How smart does a creative scientist have to
be? I recall a story told by Professor Rabi, the
physicist, about a scientist who lent $10 to a
friend and after a while began to hound him for
the money. The friend in irritation gave the sci-
entist a bag full of pennies. The scientist being
suspicious began counting the pennies. When he
reached 500, 501, 502, he tired and said, "It's
been right so far; they must all be here."
How creative are physicians? I could cite phy-
sicians who currently excel as poets, playwrights,
artists, musicians, craftsmen and financiers. Yet I
am not implying that physicians do creative things
in everything but medicine and science. The his-
tory of medicine is studded with names of physi-
cians who made major scientific contributions.
But Jenner, Koch and Ehrlich belonged to an-
other century and it might seem that that phase
of medical history would not repeat itself. While
it is true that much of modern science and medi-
cine is highly specialized, it is also true that there
are incalculable opportunities for a thoughtful,
curious and determined physician to add a fact
or more in his lifetime.

I met such a physician a few weeks ago. He is
a 40-year-old ophthalmologist who practices in a
small town in northern Minnesota. He flies his
own plane to see patients within a radius of over
100 miles. He has a large practice, a large family
and a large number of outdoor hobbies. He is also
making an important contribution to the treat-
ment of glaucoma. He was disturbed by the awk-
ward and inadequate way in which his glaucoma
patients had to take the required doses of pilo-
carpine. His patients' annoyance is shared by over
2 million people in the U.S. with glaucoma who
take eye drops two to six times a day. Added to
the discomfort of eye drops is the immediate
miotic reaction which interferes with vision and
the frequent conjunctival irritations and infec-
tions.

This physician is a thoughtful and curious man.
He had heard about a new plastic which permits
slow diffusion of small molecules. He obtained
some of this plastic and began experimenting in
his office with small drug containers, fashioned
from this plastic, which could be easily placed
and comfortably retained beneath the lower eye-
lid. He later incorporated a tiny magnetic ele-
ment in the plastic container, so that a metal
probe could be used to install and remove the
container. He was successful in obtaining a patent
and the collaboration of an outstanding pharma-
ceutical company. As a result there is now active
research on the optimal shape, size and pilocar-
pine content of the container. There is a strong
prospect that with proper design, the container
need be replaced only once every 24 hours, that
a very much lower dose of pilocarpine need be
used, and that this dose will achieve a sustained
and optimal drug level that will keep the intra-
ocular pressure in the physiological range.  Of
course, success in this work will encourage the
use of such devices for other ophthalmic drugs
and beyond that the application of similar de-
vices to therapeutic problems in other parts of
the body.

The physician I have told you about is unusual
but not unique. When I examine the experiences
of a number of physicians like him who have
made significant original contributions, I am im-
pressed by two things. They have concentrated
on a single subject or better still on a single facet
of a single subject. Secondly, this sharp focus on a
subject has not limited but rather enlarged their
general stature as a physician. The same can be
said for a laboratory research worker. He con-
centrates on a single question and probes it from
many angles. Invariably, clarification of any facet
of a problem opens new fields to his vision, of-
fers him fresh alternatives for his further studies
and thus enlarges his horizons of science.
My own research experience has included both
clinical and chemical work. It started as a medi-
cal student, when I developed jaundice and tried
to figure out why. Incidentally, that diagnosis in-
volved a chemical measurement of my bilirubin
level and it was real. Thereafter, for three years,
I made as many measurements of bilirubin levels
and bilirubin clearances as time and access to
people's veins would allow me. From this work
we learned something about the incidence and
significance of a not uncommon dysfunction of
bilirubin excretion.
As for chemical or laboratory research, I had
no special interest in it in medical school. En-
zymes were hardly mentioned in my biochemistry
course in 1937. My fascination with enzymes in
general began ten years later and with one en-
zyme, in particular, DNA polymerase, in 1955.

This enzyme is remarkable because it can copy
long stretches of DNA, the genetic material, with-
out error. It can synthesize viral DNA which is
fully infective. From this we infer that the genes
in the chromosome of a virus are replicated faith-

But how does this remarkable enzyme do its
job? We were in the doldrums regarding this
question for many years. The problem was not
advanced by inspiration but by time-consuming
and back-breaking work. We learned how to
streamline the preparation of the enzyme from
Escherichia coli so that we could work up 200
pounds of bacterial cell paste and thereby obtain
half a gram of pure enzyme. Previously we had
had only a few milligrams at any one time.

Having these large amounts of pure enzyme in
hand radically changed our approach. We could
afford for the first time to make routine but nec-
essary measurements of the size and composition
of the enzyme and to determine its capacity to
bind DNA and the nucleoside triphosphates that
serve as building blocks in synthesis. These were
not novel experiments but they yielded new data
and raised novel questions. For the first time we
began to develop a comprehensive picture of the
working center of this enzyme molecule.
From this picture we came to realize that the
enzyme can work not only as a sewing machine to
make DNA, but under certain circumstances can
also cut out sections of DNA. It occurred to us
that this ability of the enzyme to cut out sections
of DNA might enable it to excise distorted re-
gions of DNA such as lesions produced by ultra-
violet light (UV)  irradiation. Such a lesion in
DNA prevents it from being copied and can
therefore be lethal. However, we know that all
cells, bacterial and animal, possess the capacity
to excise such a UV lesion and patch the area
from which the section is removed, thus restoring
the DNA to its original state. In fact, very re-
cently investigators at the University of California
Medical School in San Francisco have shown that
patients suffering from Xeroderma pigmentosa, a
disease in which there is extraordinary sensitivity
to sunlight and a disposition to skin cancer, lack
the ability to excise UV-induced lesions from
DNA. When we tested DNA polymerase in the
test tube, it proved to have a great facility for
excising UV-induced lesions and for patching the
section of DNA from which the lesion was ex-
cised.

At this point we don't really know whether
DNA polymerase repairs UV-induced lesions in
the cell as it does in the test tube. If it does, then
the cellular operations may be as follows: First,
there is a special enzyme which patrols the
chromosome and upon finding a distortion in the
double helix introduces a cut next to or near the

fully.

lesion. Thereupon, DNA polymerase excises this
section of DNA at the same time replacing it with
new DNA. Finally another enzyme, called DNA
ligase, whose function it is to seal cuts in DNA,
then restores the chromosome to a fully intact
double helix.
I have cited these recent experiences of a Min-
nesota physician and some current work from my
laboratory to illustrate the opportunities in biolo-
gy for inquiries which, if sustained, inevitably
lead to new information. Medicine is full of these
opportunities. What medicine can do for each
physician in his lifetime is to let him use his mind
as well as his heart. In addition, medicine offers
him the splendid opportunity to use that artistic

combination of mind and heart which leads to cre-
ative effort.
There is a statement attributed to Aristotle,
who was the son of a physician, was trained by
his father and influenced by Hippocrates,  and
who is said to have practiced medicine early in
his career. This is a statement which means a
great deal to me and with which I shall close. He
said: "The search for Truth is in one way hard
and in another easy. For it is evident that no one
can master it fully nor miss it wholly. But each
adds a little to our knowledge of Nature,  and
from all the facts assembled there arises a certain
grandeur."