The Journal of Clinical Investigation | Volume 110 S11

Let me begin by thanking Dan Fosterand Jean Wilson for their wonderfuland lively presentations. I assume thatyou all know that Dan and Jean areboth native-born Texans, which meansthat they are terrific tellers of tall tales.So don’t believe a word you’ve heard!

It is truly a great honor to join thedistinguished company of previousKober medalists. And it’s also a greathonor to share this award with mylong-term partner in crime, MichaelBrown, about whom I’ll have more tosay in a moment.

Growing up in a small town in theOld South, I was relatively insulatedfrom the world of ideas and intellectu-als. Kingstree High School was a farcry from the Bronx High School of Sci-ence. But nonetheless, I aspired to anindividuality, yearned for achievement,and longed to succeed in some realmof otherness that I could not define atthe time.

I did not discover that mysteriousotherness until I became a medical stu-dent at UT Southwestern in 1962 andexperienced the thrill of medicalresearch. As you have just heard, atSouthwestern I fell under the spell ofDonald Seldin, a man of toweringintellect, immense erudition, keen zestfor life, irrepressible curiosity, anddeep respect for clinical scholarship.As a teacher, Dr. Seldin was a truemaestro in the way he taught clinicalmedicine to third-year medical stu-dents. His discussions of pathophysi-ology were enriched and enlivenedwith stories of the virtuoso perform-ances of famous clinical investigators.Seldin was the Toscanini of the stu-dent CPC. If a patient with perniciousanemia were presented to Dr. Seldin,he would tell the remarkable story ofhow William Castle discovered intrin-sic factor. If the patient was a youngwoman with amenorrhea and hir-sutism, we learned about theadrenogenital syndrome and howFuller Albright, in a tour de force ofclinical reasoning, figured out itspathophysiology and predicted itstreatment with suppressive cortisone.

If the patient had hemophilia, Dr.Seldin told us how Oscar Ratnoff wasunraveling the complexities of theclotting cascade by studying the bloodof his famous patient Mr. Hageman.

What a wonderful way for a studentto be introduced to the beauty andexcitement of clinical research. Givenrecent changes in medical education, Iwould be pleasantly surprised if anymedical students have ever heard ofCastle, Albright, or Ratnoff. It saddensme to realize that the future leaders ofclinical medicine will have no appreci-ation of their rich academic heritage.

To paraphrase the Seldin dictum ofthe 1960s and put it into a contempo-rary context, each sick patient has asick molecule and the route to medicalprogress is to investigate sick patientsand their sick molecules. Seldin’s tuto-rials made me a true believer in thechurch of biomedical research.

In 1966 I left Dallas and moved toBoston to begin a medical internshipat the MGH. About three months intothe internship, I was on duty in theemergency room with a fellow intern,Mike Brown, when a patient with par-tial lipodystropy presented with acutemeningiococcal meningitis. This fasci-nating patient triggered a lively dis-cussion between Mike and me on whatmight be the metabolic defect in

lipodystropy. Little did we realize thatthe two of us would produce a mousemodel of lipodystrophy 33 years later.It was clear from this first discussionthat Mike and I shared an enthusiasmfor sick patients and sick molecules, asubject on which we have had innu-merable and interminable discussionsduring the last 36 years.

And let me remind you that 36 years isa really long time. It is seven years longerthan the entire time it took Mozart tocompose 41 symphonies, 27 piano con-certos, 25 string quartets, 17 operas, and516 other pieces of music. This is asobering fact when you consider thatMozart accomplished all of this by him-self — he didn’t need the likes of aBrown-Goldstein collaboration.

But not all musicians are as clever asMozart, and some of the most originaland popular music of the 20th centu-ry resulted from legendary partner-ships, such as those of Rodgers andHammerstein, who worked togetherfor 19 years, and Lerner and Loewe,who worked together for 17 years andwrote the most popular Broadwaymusical of all time, My Fair Lady.

The secret to the success of Rodgersand Hammerstein and Lerner andLoewe is the same that has worked forBrown and Goldstein. The secret is tohave lots of ideas, whether they are

Acceptance of the Kober Medal

Figure 1Le Mouvement perpetual (Perpetual Motion) by René Magritte. 1935. Reprinted with permission ofthe Artists Rights Society.

This article is adapted from a presentation at the ASCI/AAP Joint Meeting, April 26–28, 2002, in Chicago, Illinois, USA.

Joseph L. Goldstein

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good or bad. In order to be creative,you have to have lots of bad ideasbecause it is only by sorting throughthe bad ideas that you hit upon therare good idea. And this is where agood partner comes in. In the begin-ning of any new adventure, whether itbe conceiving the personalities of ElizaDoolittle and Professor Higgins orconceiving the idea of an LDL recep-tor, the landscape is always blurry, andthere are multiple possibilities foradvancing different theories and tak-ing different directions.

Choosing among the multitude oftheories and directions for experi-ments is greatly facilitated by the con-stant dialogue that ensues betweentwo different minds that are accus-tomed to batting ideas back and forthand that are comfortable with criticiz-ing each other’s way of looking at theworld. It’s also much more fun to playwith ideas and theories and test themin the laboratory when you are work-ing closely with someone who under-stands all the subtleties of the prob-lem. The constant dialogue betweentwo close partners allows you to get ridof the bad ideas rapidly so that you candiscover the good ones.

The biggest challenge to establish-ing a long-term collaboration is to getinto the habit of thinking aloud.When you think alone, you have theluxury of coming up with lousy ideasand secretly rejecting them. But witha collaborator, you have to overcome

the embarrassment of sharing eachother’s lunacy. Once two collabora-tors become accustomed to thinkingaloud, the constant dialogue creates aremarkable energy and synergy of theminds, often propelling the researchinto unforeseen directions. The typeof perpetual motion that can be gen-erated from the meeting of twominds is illustrated in the painting inFigure 1 by the surrealist artist RenéMagritte. I will leave it to each of youto decide whether it’s Brown or Gold-stein who pulls his weight!

Long-term collaborations of thetype that Mike and I have enjoyed arerare in both the musical world and thescientific world. But, remarkably, 11of the last 20 Nobel Prizes in physiol-ogy or medicine have been awarded totwo scientists who did their prize-win-ning work together in the same labo-ratory. Mike and I hold the record forthe longest collaboration amongthese 11 pairs, having worked togeth-er for 30 years. Gertrude Ellion andGeorge Hitching worked together for23 years, David Hubel and TorstenWiesel for 20 years, and Mike Bishopand Harold Varmus for 19 years. Theonly scientific partnerships longerthan ours is that of Cori and Cori,who worked together for 33 years onglycogen metabolism, for which theyreceived the Nobel Prize in 1947.

Although successful partnershipshave many advantages, Francis Crickcomplains of one annoying problem— people are always getting himmixed up with Jim Watson. Mike andI have the same problem. People arealways calling me Joe [sic].

This turns out to be a trivial prob-lem compared to what The New YorkTimes did to Lerner and Loewe, thelegendary partnership that producedMy Fair Lady. Figure 2a shows a pic-ture of Alan Jay Lerner (left) and Fred-erick Loewe (right). When Alan Lern-er died in 1986, The New York Timesfeatured his obituary on the front

page together with a picture of himwearing his characteristic dark glasses(Figure 2b). Two years later FrederickLoewe died, and he too received a frontpage obituary in The New York Times.But The Times got Lerner and Loewemixed up and published Lerner’s pic-ture alongside Loewe’s obituary (Fig-ure 2c). My only hope for obitual fameis to make sure that Mike lives forever.

The take-home lesson from the long-term partnerships of Broadway andDallas is clear: Don’t be afraid to enterinto a long-term collaboration, provid-ed the chemistry is right and you choosea partner who is smarter than you.

Michael S. Brown

I want to thank Dan Foster and JeanWilson for doing so much homework.Three years ago I helped Joe write theKober Medal Presentation for Jean,and I know how much work it is. Forus it was a labor of love, and I hopethat Dan and Jean feel the same way.

Joe’s presentation to Jean featuredseveral Magritte paintings, and you’veseen more today. There’s a Magritte forevery purpose. Some of you mayremember Jean’s response — anotherMagritte — shown in Figure 3. It showshow a Kober medallist feels. This year,it’s different (Figure 4). This provesthat two swelled heads are bigger thanone. Now we’ve started a new tradition— dueling Magrittes.

Figure 2The Deathblow to a long-term partnership. (a)Alan Jay Lerner, left, and Frederick Loewe, right,the legendary partnership of 17 years that pro-duced My Fair Lady and many other hit musicalson Broadway. (b) Obituary of Alan Lerner pub-lished on the front page of The New York Times onJune 15, 1986. (c) Obituary of Frederick Loewepublished on the front page of The New York Timeson February 15, 1988.

Figure 3L’art de vivre (The Art of Living) by René Magritte.1967. Reprinted with permission from theArtists Rights Society.

The four of us — Dan, Jean, Joe, andI — have something in common. Weare all sons of Donald Seldin. But I dif-fer from the other three. They are legit-imate. They were created by Seldin andborn into medicine. I was adoptedlater in life. Joe, Jean, and Dan wereraised in small Southern towns:Kingstree, South Carolina; Wellington,Texas; and El Paso. They went toSouthern colleges. Donald Seldin wasthe first Eastern intellectual that theyever knew. They met him when theyentered medical school fresh out ofcollege. I was born in Brooklyn and gotmy education at Penn, the oldestAmerican university. I didn’t meetDonald Seldin until after my residen-cy when I came to Dallas as a GI fellow.

What bait did Seldin use to seducefour bright young men and scores ofothers like us? I can tell you what it wasfor me. As you have heard, I had donemy residency at the MassachusettsGeneral Hospital which was then, andmay still be, the most famous and suc-cessful clinical training program in theworld. Every year the top student atPenn applied to the MGH, and everyyear that student was rejected. The lastPenn student accepted at the MGHwas John Potts, and that was thirteenyears earlier. For some reason, I wasaccepted. Of course I was thrilled —

until they sent the list of my fellowinterns. There was Joseph Goldsteinfrom Southwestern Medical School inDallas, Texas. The year was 1966, onlythree years after the Kennedy assassi-nation. Dallas didn’t have a very goodimage, and I had never heard of South-western Medical School. I thought itwas a Bible College. Why would theMGH accept Joseph Goldstein? Maybeno one had applied that year, and sothey were desperate. That wouldexplain my acceptance as well. Thesedoubts were dispelled on the first dayof internship when I met Joe and real-ized that somehow he seemed to knowmore than anybody else. He thoughtdeeply about his patients, and he wasinterested in the mechanism of theirdiseases. He didn’t want to know onlywhat the patient had, but he wanted toknow why the patient had it and how itcame about. These were the questionsthat turned me on as well. This com-mon interest in mechanisms ignitedour friendship.

But where had Joe acquired thismechanistic curiosity? I was deter-mined to find out, and so I visitedDallas, and there I found a dozen JoeGoldsteins running around Seldin’sDepartment. The whole departmentfocused on disease mechanisms.Everyone had a laboratory. You could

have called it the Department ofApplied Physiology except that theytook very good care of the patients atParkland Hospital.

I quickly decided to move to Dallas,but my hardest job was convincingAlice. She was a New Yorker like me,and Dallas was the Deep South. ButAlice put aside her doubts, and shemade a wonderful life for herself andour daughters in Dallas. If I didn’t havea wife like Alice, Joe would have had tolook much harder for a partner — so heand I both owe everything to Alice.

When I arrived in Dallas, I wasthrilled by the departmental confer-ences that Seldin dominated like agreat oracle. These conferences werepeppered with fiery arguments andsalted by Seldin’s demand for evidenceto support every assertion. There aretwo kinds of evidence that one can useto win arguments in medicine. Thefirst is inductive and observational.You go to the library, find the largestseries of patients, and list their symp-toms. The other evidence is deductive.You can reason from physiologic prin-ciples. At MGH you won argumentsby induction. The person with thebiggest series or the longest clinicalexperience won. This is natural. Clini-cal observations are the alpha andomega of medicine. All of our knowl-edge begins and ends with clinicalobservation. But for me, personally,this was not enough. I wanted toknow the mechanisms of disease. Iwanted to do science and medicine.MGH had great scientists, includingAlex Leaf, the Chief of Medicine, butthey were generally not the peoplewho ran the wards. At Southwestern,scientists ran the place. You won argu-ments by deduction. Clinical observa-tions were essential, of course, butthey weren’t complete unless youcould explain the observation by arational mechanism.

Now Seldin’s children have grown,and we all have scientific children andgrandchildren. I fervently hope thatthese young scientists have the sameopportunity for mechanistic under-standing that we had in the last third ofthe twentieth century in Dallas, Texas.

The Journal of Clinical Investigation | Volume 110 S13

Figure 4Updated version of L’art de vivre by Rene Magritte — adapted for two Kober medal recipients.