Published in Volume
110, Issue 12 (December 15, 2002)
J Clin Invest. 2002;110(12):S11–S13.
doi:10.1172/JCI120038.
Copyright © 2002, American Society for Clinical
Investigation
Supplement
Acceptance of the Kober Medal
Joseph L. Goldstein
Published December 15, 2002
Let me begin by thanking Dan Foster and Jean Wilson for their wonderful and lively
presentations. I assume that you all know that Dan and Jean are both native-born Texans,
which means that they are terrific tellers of tall tales. So don’t believe a
word you’ve heard!
It is truly a great honor to join the distinguished company of previous Kober medalists.
And it’s also a great honor to share this award with my long-term partner in
crime, Michael Brown, about whom I’ll have more to say in a moment.
Growing up in a small town in the Old South, I was relatively insulated from the world
of ideas and intellectuals. Kingstree High School was a far cry from the Bronx High
School of Science. But nonetheless, I aspired to an individuality, yearned for
achievement, and longed to succeed in some realm of otherness that I could not define at
the time.
I did not discover that mysterious otherness until I became a medical student at UT
Southwestern in 1962 and experienced the thrill of medical research. As you have just
heard, at Southwestern I fell under the spell of Donald Seldin, a man of towering
intellect, immense erudition, keen zest for life, irrepressible curiosity, and deep
respect for clinical scholarship. As a teacher, Dr. Seldin was a true maestro in the way
he taught clinical medicine to third-year medical students. His discussions of
pathophysiology were enriched and enlivened with stories of the virtuoso performances of
famous clinical investigators. Seldin was the Toscanini of the student CPC. If a patient
with pernicious anemia were presented to Dr. Seldin, he would tell the remarkable story
of how William Castle discovered intrinsic factor. If the patient was a young woman with
amenorrhea and hirsutism, we learned about the adrenogenital syndrome and how Fuller
Albright, in a tour de force of clinical reasoning, figured out its pathophysiology and
predicted its treatment with suppressive cortisone. If the patient had hemophilia, Dr.
Seldin told us how Oscar Ratnoff was unraveling the complexities of the clotting cascade
by studying the blood of his famous patient Mr. Hageman.
What a wonderful way for a student to be introduced to the beauty and excitement of
clinical research. Given recent changes in medical education, I would be pleasantly
surprised if any medical students have ever heard of Castle, Albright, or Ratnoff. It
saddens me to realize that the future leaders of clinical medicine will have no
appreciation of their rich academic heritage.
To paraphrase the Seldin dictum of the 1960s and put it into a contemporary context,
each sick patient has a sick molecule and the route to medical progress is to
investigate sick patients and their sick molecules. Seldin’s tutorials made
me a true believer in the church of biomedical research.
In 1966 I left Dallas and moved to Boston to begin a medical internship at the MGH.
About three months into the internship, I was on duty in the emergency room with a
fellow intern, Mike Brown, when a patient with partial lipodystropy presented with acute
meningiococcal meningitis. This fascinating patient triggered a lively discussion
between Mike and me on what might be the metabolic defect in lipodystropy. Little did we
realize that the two of us would produce a mouse model of lipodystrophy 33 years later.
It was clear from this first discussion that Mike and I shared an enthusiasm for sick
patients and sick molecules, a subject on which we have had innumerable and interminable
discussions during the last 36 years.
And let me remind you that 36 years is a really long time. It is seven years longer than
the entire time it took Mozart to compose 41 symphonies, 27 piano concertos, 25 string
quartets, 17 operas, and 516 other pieces of music. This is a sobering fact when you
consider that Mozart accomplished all of this by himself — he
didn’t need the likes of a Brown-Goldstein collaboration.
But not all musicians are as clever as Mozart, and some of the most original and popular
music of the 20th century resulted from legendary partnerships, such as those of Rodgers
and Hammerstein, who worked together for 19 years, and Lerner and Loewe, who worked
together for 17 years and wrote the most popular Broadway musical of all time, My Fair
Lady.
The secret to the success of Rodgers and Hammerstein and Lerner and Loewe is the same
that has worked for Brown and Goldstein. The secret is to have lots of ideas, whether
they are good or bad. In order to be creative, you have to have lots of bad ideas
because it is only by sorting through the bad ideas that you hit upon the rare good
idea. And this is where a good partner comes in. In the beginning of any new adventure,
whether it be conceiving the personalities of Eliza Doolittle and Professor Higgins or
conceiving the idea of an LDL receptor, the landscape is always blurry, and there are
multiple possibilities for advancing different theories and taking different
directions.
Choosing among the multitude of theories and directions for experiments is greatly
facilitated by the constant dialogue that ensues between two different minds that are
accustomed to batting ideas back and forth and that are comfortable with criticizing
each other’s way of looking at the world. It’s also much more
fun to play with ideas and theories and test them in the laboratory when you are working
closely with someone who understands all the subtleties of the problem. The constant
dialogue between two close partners allows you to get rid of the bad ideas rapidly so
that you can discover the good ones.
The biggest challenge to establishing a long-term collaboration is to get into the habit
of thinking aloud. When you think alone, you have the luxury of coming up with lousy
ideas and secretly rejecting them. But with a collaborator, you have to overcome the
embarrassment of sharing each other’s lunacy. Once two collaborators become
accustomed to thinking aloud, the constant dialogue creates a remarkable energy and
synergy of the minds, often propelling the research into unforeseen directions. The type
of perpetual motion that can be generated from the meeting of two minds is illustrated
in the painting in Figure 1)by the surrealist artist René Magritte. I will
leave it to each of you to decide whether it’s Brown or Goldstein who pulls
his weight!
Long-term collaborations of the type that Mike and I have enjoyed are rare in both the
musical world and the scientific world. But, remarkably, 11 of the last 20 Nobel Prizes
in physiology or medicine have been awarded to two scientists who did their
prize-winning work together in the same laboratory. Mike and I hold the record for the
longest collaboration among these 11 pairs, having worked together for 30 years.
Gertrude Ellion and George Hitching worked together for 23 years, David Hubel and
Torsten Wiesel for 20 years, and Mike Bishop and Harold Varmus for 19 years. The only
scientific partnerships longer than ours is that of Cori and Cori, who worked together
for 33 years on glycogen metabolism, for which they received the Nobel Prize in
1947.
Although successful partnerships have many advantages, Francis Crick complains of one
annoying problem — people are always getting him mixed up with Jim Watson.
Mike and I have the same problem. People are always calling me Joe [sic].
This turns out to be a trivial problem compared to what The New York Times did to Lerner
and Loewe, the legendary partnership that produced My Fair Lady. Figure 2a shows a
picture of Alan Jay Lerner (left) and Frederick Loewe (right). When Alan Lerner died in
1986, The New York Times featured his obituary on the front page together with a picture
of him wearing his characteristic dark glasses (Figure 2b). Two years later Frederick
Loewe died, and he too received a front page obituary in The New York Times. But The
Times got Lerner and Loewe mixed up and published Lerner’s picture alongside
Loewe’s obituary (Figure 2c). My only hope for obitual fame is to make sure
that Mike lives forever.
The take-home lesson from the long-term partnerships of Broadway and Dallas is clear:
Don’t be afraid to enter into a long-term collaboration, provided the
chemistry is right and you choose a partner who is smarter than you.
Michael S. Brown
I want to thank Dan Foster and Jean Wilson for doing so much homework. Three years ago I
helped Joe write the Kober Medal Presentation for Jean, and I know how much work it is.
For us it was a labor of love, and I hope that Dan and Jean feel the same way.
Joe’s presentation to Jean featured several Magritte paintings, and
you’ve seen more today. There’s a Magritte for every purpose.
Some of you may remember Jean’s response — another Magritte
— shown in Figure 3. It shows how a Kober medallist feels. This year,
it’s different (Figure 4). This proves that two swelled heads are bigger
than one. Now we’ve started a new tradition — dueling
Magrittes.
The four of us — Dan, Jean, Joe, and I — have something in
common. We are all sons of Donald Seldin. But I differ from the other three. They are
legitimate. They were created by Seldin and born into medicine. I was adopted later in
life. Joe, Jean, and Dan were raised in small Southern towns: Kingstree, South Carolina;
Wellington, Texas; and El Paso. They went to Southern colleges. Donald Seldin was the
first Eastern intellectual that they ever knew. They met him when they entered medical
school fresh out of college. I was born in Brooklyn and got my education at Penn, the
oldest American university. I didn’t meet Donald Seldin until after my
residency when I came to Dallas as a GI fellow.
What bait did Seldin use to seduce four bright young men and scores of others like us? I
can tell you what it was for me. As you have heard, I had done my residency at the
Massachusetts General Hospital which was then, and may still be, the most famous and
successful clinical training program in the world. Every year the top student at Penn
applied to the MGH, and every year that student was rejected. The last Penn student
accepted at the MGH was John Potts, and that was thirteen years earlier. For some
reason, I was accepted. Of course I was thrilled — until they sent the list
of my fellow interns. There was Joseph Goldstein from Southwestern Medical School in
Dallas, Texas. The year was 1966, only three years after the Kennedy assassination.
Dallas didn’t have a very good image, and I had never heard of Southwestern
Medical School. I thought it was a Bible College. Why would the MGH accept Joseph
Goldstein? Maybe no one had applied that year, and so they were desperate. That would
explain my acceptance as well. These doubts were dispelled on the first day of
internship when I met Joe and realized that somehow he seemed to know more than anybody
else. He thought deeply about his patients, and he was interested in the mechanism of
their diseases. He didn’t want to know only what the patient had, but he
wanted to know why the patient had it and how it came about. These were the questions
that turned me on as well. This common interest in mechanisms ignited our
friendship.
But where had Joe acquired this mechanistic curiosity? I was determined to find out, and
so I visited Dallas, and there I found a dozen Joe Goldsteins running around
Seldin’s Department. The whole department focused on disease mechanisms.
Everyone had a laboratory. You could have called it the Department of Applied Physiology
except that they took very good care of the patients at Parkland Hospital.
I quickly decided to move to Dallas, but my hardest job was convincing Alice. She was a
New Yorker like me, and Dallas was the Deep South. But Alice put aside her doubts, and
she made a wonderful life for herself and our daughters in Dallas. If I
didn’t have a wife like Alice, Joe would have had to look much harder for a
partner — so he and I both owe everything to Alice.
When I arrived in Dallas, I was thrilled by the departmental conferences that Seldin
dominated like a great oracle. These conferences were peppered with fiery arguments and
salted by Seldin’s demand for evidence to support every assertion. There are
two kinds of evidence that one can use to win arguments in medicine. The first is
inductive and observational. You go to the library, find the largest series of patients,
and list their symptoms. The other evidence is deductive. You can reason from
physiologic principles. At MGH you won arguments by induction. The person with the
biggest series or the longest clinical experience won. This is natural. Clinical
observations are the alpha and omega of medicine. All of our knowledge begins and ends
with clinical observation. But for me, personally, this was not enough. I wanted to know
the mechanisms of disease. I wanted to do science and medicine. MGH had great
scientists, including Alex Leaf, the Chief of Medicine, but they were generally not the
people who ran the wards. At Southwestern, scientists ran the place. You won arguments
by deduction. Clinical observations were essential, of course, but they
weren’t complete unless you could explain the observation by a rational
mechanism.
Now Seldin’s children have grown, and we all have scientific children and
grandchildren. I fervently hope that these young scientists have the same opportunity
for mechanistic understanding that we had in the last third of the twentieth century in
Dallas, Texas.
