The Journal of Clinical Investigation | Volume 110 S5

This is the first time in its 77-year his-tory that the Kober medal has beengiven to two individuals. Sharing ofthe medal on this occasion is appro-priate because the partnership ofMichael S. Brown and Joseph L. Gold-stein has created a new paradigm forbiomedical research. In her book Cre-ative Collaboration, Vera John-Steinerpoints out that most successful scien-tific partnerships, such as that ofBrown and Goldstein, involve the com-plementarity of equals (1). This type ofcollaboration is effective because anyindividual, no matter how gifted, canrealize only a subset of human poten-tial, and partnerships broaden, refine,change, and expand individual possi-bilities. It is for this reason that greatideas emerge more commonly fromthe exchange of ideas than from soli-tary introspection. Scientific collabo-rations have common features thatinclude equal sharing of recognitionand rewards, joint authorship of allpublications, absolute trust, confi-dence in the other’s abilities, certaintythat disagreements can be resolved,and playing different roles in the part-nership (1). In addition, virtually allscientific collaborations since that ofPierre and Marie Curie involve one per-son John-Steiner terms a “thinker-dreamer” and another a “thinker-doer”(1). One should not overdo this analo-gy in the present instance (Mike andJoe sometimes switch roles), but in factall of these features characterize theremarkable and continuing partner-ship of Brown and Goldstein. Creationof a successful collaboration — requir-ing some transcending of individuali-ty — is itself a creative act, and conse-quently it is appropriate that we honorMike and Joe as individuals and at thesame time acclaim their remarkablethirty-year collaboration that began asa friendship in Boston and Bethesdaand came to fulfillment in Dallas.

The protagonistsJoe Goldstein grew up in Kingstree,South Carolina, which was namedafter a battle of the Revolutionary Warbut is now famous as his birthplace(Figure 1). His parents, Frances Alpertand Isadore E. Goldstein, were mer-chants. Joe began life as a gunslinger,but in high school his interest shiftedto journalism (Figure 1). He was editorof the school newspaper (The Boll Wee-vil) and the yearbook. He was presidentof his class and of the student bodyand class valedictorian. Joe attendedWashington and Lee University, wherehe majored in chemistry and biologyand was again class valedictorian. Hisdecision to become a physician wasinfluenced by a high school chemistryteacher and by a cousin who was aninternist, and in 1962 he came to theUniversity of Texas SouthwesternMedical School because fraternitybrothers from Dallas convinced himthat the school was up and coming.Joe hit the school like a cyclone andimpressed the faculty and the studentbody as an intellectual dynamo, unlikeany other student that most of us hadever encountered. To wit, he won theHo Din Award as outstanding mem-ber of the class of 1966 (Figure 1).

He was introduced to research as astudent fellow in the laboratory ofBurton Combes, where he developeda new spectrophotometric assay formeasuring conjugated forms ofbromsulfothalein (BSP) and used thistechnique to investigate the regula-tion of BSP metabolism in the liver(2–5). This first taste of discoveryproved fatal to his original plan to bea neurosurgeon, and by the time hewas a fourth-year student, he hadworked out a plan with Dr. DonaldSeldin to pursue a training programconsisting of a medical residency,research training, and a fellowship inmedical genetics in preparation for

returning to Southwestern to head adivision of medical genetics in theDepartment of Internal Medicine. Itwas common in those days to makesuch arrangements with house staffofficers but highly unusual to make afaculty commitment to a medical stu-dent. At any rate, when Joe left med-ical school he knew he had a job.

From 1966 to 1968 he was a medi-cine resident at the MassachusettsGeneral Hospital (Figure 2). ThisMGH house staff photograph from1968 contains an impressive numberof future academicians (including sixadditional future members of theAAP), and it was here that Joe becameacquainted with Mike Brown.

In 1968 Joe became a Clinical Asso-ciate in the National Heart Instituteand worked with Tom Caskey in Mar-shall Nirenberg’s laboratory, where, instudying the mechanism of proteinsynthesis, he characterized a new GTP-binding protein that stimulates release

Presentation of the Kober Medal

Presentation of the Kober Medal to Joseph L. Goldstein and Michael S. Brown

Daniel W. Foster and Jean D. Wilson

Figure 1Joe Goldstein, a native of Kingstree, South Car-olina, shown as a young gunslinger, as editor ofhis high school newspaper, The Boll Weevil, andreceiving the Ho Din Award as outstandingmember of the UT Southwestern MedicalSchool class of 1966.

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

S6 The Journal of Clinical Investigation | Volume 110

of polypeptide chains following termi-nation of synthesis (6). In keepingwith the Seldin plan, Joe spent1970–1972 as a fellow in medicalgenetics at the University of Washing-ton. With Arno Motulsky he describedthe syndrome of combined hyperlipi-demia, the most common monogeniccause of myocardial infarction (7), andhe learned the techniques of tissue cul-ture from Stanley Gartler (8). In 1972Joe returned to Dallas to set up a divi-sion of medical genetics in the Depart-ment of Internal Medicine. At thebeginning he had two grants — onefrom the NIH to study the hormonalregulation of phosphoprotein synthe-sis and one from the American HeartAssociation to study familial hyperc-holesterolemia.

No description of Joe would be com-plete without mentioning his love ofart. He knows an enormous amountabout the subject and attends artshows and exhibits all over the world.His personal collection is rich in DaleChihouly glass and Frank Stellagraphics (Figure 3).

Michael Brown was born in Brook-lyn, and the family moved toPhiladelphia when Mike was eleven.His father, Harvey Brown, was in thewholesale textile business, and hismother, Evelyn Katz Brown, workedat the Smith Kline research labora-tories. At age 13 Mike became fasci-nated with ham radio (and with theconstruction of radios) and withjournalism (Figure 4). At about thistime he met Alice Lapin, his first andcontinuing sweetheart (Figure 4). Hewon a prize in a high school sciencecompetition in Philadelphia, and,influenced by reading Sinclair Lewis’Arrowsmith, he wrote on his applica-tion to the University of Pennsylva-nia that he wanted to do medicalresearch. Like Joe, he is a prophet notwithout honor on his home turf,Cheltenham High School (Figure 4).At Penn, he obtained an undergrad-uate scholarship, became editor-in-chief of the Daily Pennsylvanian, andwas elected to Phi Beta Kappa. Hethen attended the University ofPennsylvania Medical School. Mikewas the top student in his medicalschool class and is shown in Figure 4making rounds at the University ofPennsylvania Hospital. Jim Wyngar-den came to Penn as Chairman ofMedicine in Mike’s senior year andwas an active backer of Mike’s appli-cation for a residency at the MGH.

As a student Mike spent three sum-mers working at Smith Kline on a proj-ect designed to develop agents for thetreatment of peptic ulcer. In the courseof this work he developed a novel tech-nique for the assessment of gastroin-testinal motility (9). His long-terminterest in gastroenterology can betraced to this experience. His commit-ment to science was solidified during arotation in Albert Winegrad’s laborato-ry, where he studied lipid biosynthesis.

Mike and Joe met on the first day ofinternship and immediately becamefriends. At first, most of their conver-sation had to do with their patientsand with medicine. Playing bridge andthen duplicate bridge together and

studying bidding systems allowedthem to develop confidence in eachother’s judgment.

Mike also went to the NIH in 1968,where he investigated the use of intes-tinal biopsies for diagnosis of inbornerrors of metabolism and then workedin the Stadtman laboratory, where hediscovered that the same enzyme thatactivates glutamine synthetase can alsoinactivate the enzyme, depending onwhether it is uridinylated (10).

Joe was a good proselytizer for UTSouthwestern (of which Mike was pre-viously unaware), and after soulsearching (and with some reserva-tions), Mike decided in 1971 to cometo Dallas for a fellowship in gastroen-terology. He spent most of the firstyear in clinical duties and learningendoscopy, but he also worked in thelaboratory. He initially studied intes-tinal lymph transport with JohnDietschy and then decided to studyHMG-CoA reductase, the rate-limitingenzyme in cholesterol biosynthesis.Mike discovered that the enzyme is

Figure 2The medical house staff at the MassachusettsGeneral Hospital in 1968. In addition to JoeGoldstein (white arrow), Mike Brown (blackarrow), Daniel Federman, and Alexander Leaf(the front row), the group includes six otherfuture members of the AAP (David W. Bil-heimer, David C. Dale, John D. Minna, SuzanneOparil, Thomas P. Stossel, and Richard M.Weinshilboum).

Figure 3Joe Goldstein’s collection of art is rich in glassand graphics.

Figure 4Mike Brown, a Philadelphia ham radio enthus-iast, met his future wife, Alice Lapin, at an earlyage. He was a hero of Cheltenham High Schooland is shown making rounds as a student (thirdfrom the right) at the University of Pennsylvania,where he was number one in the class of 1966.

Figure 5Mike Brown, the sailor at the helm, as his pas-senger, Joe Goldstein, looks into the future.

cold-labile, and he solubilized and par-tially purified the liver enzyme (11) (atthe same time helping run theendoscopy service at Parkland Hospi-tal). By the time Joe Goldstein cameback to Dallas in 1972 to set up a med-ical genetics division, Mike was animportant member of the department.

Mike is a fisherman and sailor (Fig-ure 5) and is devoted to his family (Fig-ure 6). He is shown here with Alice andhis daughters Elizabeth and Sara onthe occasion of the graduation of Dr.Elizabeth Brown from the Universityof Pennsylvania Medical School.

The collaboration beginsInitially, Mike and Joe had separatelaboratories in the department, Mikein the Division of Gastroenterologyand Joe in the Division of MedicalGenetics. However, their interestsoverlapped, and they decided to col-laborate in studying familial hyperc-holesterolemia. At NIH they had seena girl with profound hypercholes-terolemia who had had a myocardialinfarction at age 6, and they werefamiliar with evidence suggestingthat the severe form of the disease

might be due to homozygosity of themutant gene. At the time almostnothing was known about the patho-physiology of autosomal dominantdisorders, and since HMG CoAreductase is the site of cholesterolnegative feedback regulation ofhepatic cholesterol synthesis, theydecided to combine Mike’s experiencein assaying this key enzyme with Joe’sexpertise in the culture of skin fibrob-lasts. They initially demonstratedthat HMG CoA reductase activity incontrol fibroblasts is regulated bylipoproteins in the culture medium(12), and then a telephone call cameto Marvin Siperstein (who was inSwitzerland) from Thomas Starzl,who was about to operate in Denveron a child with severe hypercholes-terolemia (subsequently shown to bedue to the receptor-negative form ofhomozygous familial hypercholes-terolemia) (13). The secretary referredthe call to Mike, who flew to Denverand returned with a skin biopsy forthe growth of fibroblasts, and the restis history.

PaydirtIt is a daunting task to summarize themore than 400 research papers thathave come from the Brown and Gold-stein laboratory since 1973, a produc-tivity that continues at a remarkablyconstant level (Figure 7). The criticalexperiment done in fibroblasts grownfrom Starzl’s patient with homozygousFH is shown in Figure 8 (13). In panel8a, the activity of HMG CoA reductase,the rate-limiting enzyme in cholesterolsynthesis, was measured after incuba-tion of fibroblasts in medium devoid oflipoproteins. No change was seen in thetop curve, the patient fibroblasts, whichhad basal activity some 200´ greaterthan control cells. In contrast, cellsfrom controls, bottom curve, showedbrisk increase in HMG CoA activityafter incubation in the absence ofinhibiting lipoproteins. In Figure 8b isshown the effect of addition of low-density lipoproteins at concentrationsof 2 and 20 mg/ml. Normal fibroblastsshowed the expected feedback inhibi-tion, while there was no inhibition inthe FH fibroblasts.

The findings from the first phase ofthe studies are summarized in Figure 9(reviewed in refs. 14 and 15). Low-densi-ty lipoprotein (LDL) containing choles-terol ester and protein binds to a cell sur-

face receptor — the LDL receptor — locat-ed in a coated pit. This area then pinchesoff to form a coated vesicle which carriesthe LDL to the lysosome where it isdegraded with the release of amino acidsand cholesterol. The released cholesterolserves as a “second messenger” and has atleast three effects: decreased HMG CoAreductase activity (the consequence ofdecreased synthesis and increased degra-dation of the enzyme), increased esterifi-cation of cholesterol due to enhancedactivity of acyl CoA: cholesterol acyl-transferase (ACAT), and decreased syn-thesis of the LDL receptor.

The Journal of Clinical Investigation | Volume 110 S7

Figure 6Mike Brown, together with his daughters, Saraand Elizabeth, and his wife, Alice Lapin Brown,on the occasion of the graduation of Dr. Eliza-beth Brown from the University of PennsylvaniaMedical School in 2000.

Figure 7Peer reviewed publications by Mike Brown andJoe Goldstein, 1973–2001.

Figure 8Regulation of HMG CoA reductase activity infibroblasts from a normal subject (open sym-bols) and from a FH homozygote (closed sym-bols). (a) Fibroblast monolayers were grown in10% fetal calf serum, and on day 6 after plating(day 0) the medium was replaced with mediumcontaining 5% human serum from whichlipoproteins had been removed. At the timesindicated, extracts were prepared, and HMGCoA reductase activity was measured. (b) 24hours after changing to medium containinglipoprotein-deficient serum, human LDL wasadded to give the indicated cholesterol concen-trations, and HMG CoA reductase activity wasmeasured in cell-free extracts at the indicatedtimes (Reprinted from ref. 13).

Figure 9Sequential steps in the LDL receptor pathway ofmammalian cells. LDL, low density lipopro-teins; HMG CoA reductase, 3-hydroxy-3-methylglutaryl coenzyme A reductase; ACAT,acyl-CoA: cholesterol acyltransferase. (Reprint-ed from ref. 15.)

Familial hypercholesterolemia isdue to mutations in the gene thatencodes the LDL receptor, the het-erozygous state being less severe thanthe homozygous state. The overallmechanism by which LDL cholesterolis internalized and processed wasnamed receptor-mediated endocyto-sis, a process subsequently shown tobe responsible for the internalizationof many different molecules fromplasma. Discovery of receptor-mediat-ed endocytosis was a monumentalaccomplishment.

The initial studies had establishedthat cholesterol essentially functionsas a “second messenger” in control ofcholesterol synthesis. Brown andGoldstein have now worked out thesignaling system by which cholesteroltransmits its messages, a system

termed the sterol regulatory-elementbinding protein (SREBP) pathway(Figure 10) (reviewed in ref. 16). Crit-ical components of the systeminclude SREBP cleavage-activatingprotein (SCAP) and Site 1 and Site 2proteases (S1P and S2P). The startsite is the endoplasmic reticulumwhere SCAP is a sensing element forcholesterol and is bound to the regu-latory domain of SREBP. When thecell is replete with cholesterol, theSREBP/SCAP complex remains in theendoplasmic reticulum, and SREBP isnot activated by proteolysis. Adecrease in the intracellular level ofcholesterol is sensed by SCAP, and theSCAP/SREBP complex moves to theGolgi apparatus. There the S1P pro-tease clips the hydrophilic hairpinloop, allowing the basic-helix-loop-helix (bHLH) transcription factordomain to migrate to the S2P, whichcleaves it within the transmembranehelix. The bHLH domain then movesinto the nucleus, where it binds to thesterol regulatory element and initi-ates transcription of cholesterolresponsive genes that encode the LDLreceptor, HMG CoA reductase, andother enzymes of lipid synthesis. As inthe case of receptor-mediated endo-cytosis, the SCAP/SREBP systemexpanded far beyond cholesterol andis now known to control the regula-tion of at least 30 genes involved inlipid metabolism.

In 1985 Brown and Goldstein wereawarded the Nobel Prize for Medicineor Physiology for their discovery ofreceptor-mediated endocytosis. Theyare the eighth and ninth members ofthe AAP who have won both theNobel Prize and the Kober Medal(Table 1). In an article in Sciencedescribing their Nobel Prize, ArnoMotulsky made a prophetic com-ment: “Considering their past record,the scientific community is eagerlyawaiting their future work” (17). Notonly has their subsequent work beenas exciting as the early studies, but,more importantly, we still eagerlyawait their future work.

The academic citizensMike and Joe are exemplary academiccitizens. Their record of mentorshipincludes the training of 10 Ph.D. and11 M.D./Ph.D. students and 87 post-doctoral fellows. Nineteen of theirtrainees are full professors: 3 in

departments of medicine; 16 in basicscience departments or research insti-tutes. Two, Helen Hobbs and SandraHofmann, are members of AAP.Three are Howard Hughes MedicalInstitute investigators. Four are sci-entific directors at biotechnologycompanies. Two, Thomas Sudhoffand Xiaodong Wang, have receivedmajor awards for their work in thefields of neuroscience and pro-grammed cell death, respectively. Atthe same time, Brown and Goldsteinare dedicated members of the faculty— helping to recruit to many depart-ments, raising funds for the school,serving on committees for the benefitof the institution, and directing themedical scientist–training program.Their loyalty to Southwestern neverwavers, and everyone who knowsthem profits from their wise counsel.At the national level their impact issimilarly important — including serv-ice on boards of regents, prize com-mittees, and granting agencies.

It is also appropriate to commendsome of the non-academic sides ofBrown and Goldstein. They have anenormous zest for life. They enjoytheir status as celebrities and therewards that go with such status

S8 The Journal of Clinical Investigation | Volume 110

Figure 11Mike and Joe enjoy their celebrity status,including the opportunity of meeting PresidentReagan in the White House, Prime MinisterShamir of Israel in his office, and Prime Minis-ter Margaret Thatcher of the United Kingdomin their office.

Figure 12Joe and Mike “hamming it up” at a laboratory party.

Table 1Winners of both the Nobel Prize and theGeorge M. Kober Medal

Winner Nobel prize Kober medalGeorge M. Minot 1934 1929George H. Whipple 1934 1939Edward C. Kendall 1950 1952Peyton Rous 1966 1953Herbert S. Gasser 1944 1954Dickinson W. Richards 1956 1970E. Donnall Thomas 1990 1992Michael S. Brown 1985 2002Joseph L. Goldstein 1985 2002

Figure 10Model for the cholesterol-mediated proteolyt-ic release and processing of sterol regulatory-element binding proteins (SREBPs) from mem-branes. ER, endoplasmic reticulum; SCAP,SREBP clevage-activating protein contains reg-ulatory (reg) and basic helix-loop-heliz (bHLH)domains; S1P and S2P, site 1 and site 2 pro-teases (modified from reference 16).

(Figure 11). They are both dedicatedparty animals and party givers, asindicated by the elaborate skits theyperform (Figure 12). They approachevery endeavor with the same enthu-siasm they apply to science, theyenjoy themselves, and they are thebest of company.

ConclusionMike Brown and Joe Goldstein havewon many prizes, honorary degrees,recognitions, and fame, but theirreceipt of the Kober Medal is uniquelyappropriate because of the impact thatthey have had on the Association andon the American Society for ClinicalInvestigation. Beginning in 1974,when they presented to the plenarysessions of both organizations, Mikeand Joe (and their trainees) have made

14 plenary session and state-of-the-artlectures at these meetings (not count-ing presidential and after-dinneraddresses). This record is unequalledin modern times.

Joe Goldstein’s favorite painter is theBelgian surrealist René Magritte, andthe 1959 Magritte painting entitled“The Castle in the Pyrenees” is appropriateto commemorate this occasion (Figure13). The title is a word play on theFrench version of “Castles in the Sky,” andthe painting is believed to derive from astory by Edgar Allen Poe in which asemi-Gothic structure appeared to besuspended in mid air (18). Mike and Joebuilt a phenomenal castle in the sky,and they built it on the solid foundationof a remarkable collaboration. In sodoing, they revolutionized biomedicalscience and developed a new paradigmfor the conduct of research. It is a pleas-ure and an honor to present, on behalfof the Council of the AAP, the 2002Kober medals to Michael S. Brown andJoseph L. Goldstein (Figure 14).

1. John-Steiner, V. 2000. Creative Collaboration.Oxford University Press. New York, New York,USA. 259 pp.

2. Schenker, S., Goldstein, J., and Combes, B. 1965.Sulfobromophthalein sodium (BSP) excretion infetal guinea pigs. Am. J. Physiol. 208:562–572.

3. Goldstein, J., Schenker, S., and Combes, B. 1965.Sulfobromophthalein sodium (BSP) conjugationand excretion in neonatal guinea pigs. Am. J. Phys-iol. 208:573–577.

4. Goldstein, J., and Combes, B. 1966. Spectopho-tometric assay of the liver enzyme that catalyzessulfobromophthalein-glutathione conjugation.J. Lab. Clin. Med. 67:863–873.

5. Goldstein, J., and Combes, B. 1966. The effect ofsteroids on the activity of the enzyme that cat-alyzes sulfobromophthalein-glutathione conju-gation. J. Lab. Clin. Med. 67:830–835.

6. Goldstein, J., Milman, G., Scolnick, E., andCaskey, T. 1970. Peptide chain termination: VI.Purification and site of action of S. Proc. Natl.Acad. Sci. USA. 67:99–106.

7. Goldstein, J.L., Schrott, H.G., Hazzard, W.R.,Bierman, E.L., and Motulsky, A.G. 1973. Hyper-lipidemia in coronary heart disease. II. Geneticanalysis of lipid levels in 176 families and delin-eation of a new inherited disorder, combinedhyperlipidemia. J. Clin. Invest. 52:1544–1568.

8. Goldstein, J.L., Campbell, B.K., and Gartler, S.

1971. Cystathionine synthase activity in humanlymphocytes: induction by phytohemagglutinin.J. Clin. Invest. 51:1034–1037.

9. Brown, M.S., and Groves, W.G. 1966. Intestinalpropulsion in restrained and unrestrained rats.Proc. Soc. Exp. Biol. Med. 121:989–992.

10. Brown, M.S., Segal, A., and Stadtman, E.R. 1971.Modulation of glutamine synthetase: Adenyla-tion and deadenylation is mediated by metabolictransformation of the PII-regulatory protein.Proc. Natl. Acad. Sci. USA. 68:2949–2953.

11. Brown, M.S., Dana, S.E., Dietschy, J.M., and Siper-stein, M.D. 1973. 3-Hydroxy-3-methylglutarylcoenzyme A reductase: Solubilization and purifi-cation of a cold-sensitive microsomal enzyme. J. Biol. Chem. 248:4731–4738.

12. Brown, M.S., Dana, S.E., and Goldstein, J.L. 1973.Regulation of 3-hydroxy-3-methylglutaryl coenzymeA reductase activity in human fibroblasts by lipopro-teins. Proc. Natl. Acad. Sci. USA. 70:2162–2166.

13. Goldstein, J.L., and Brown, M.S. 1973. Familialhypercholesteroleia: Identification of a defect inthe regulation of 3-hydroxy-3-methylglutarylcoenzyme A reductase activity associated withoverproduction of cholesterol. Proc. Natl. Acad. Sci.USA. 70:2804–2808.

14. Goldstein, J.L., and Brown, M.S. 2002. Discovery ofthe LDL receptor: Clues to receptor-mediatedendocytosis. Ergito Great Experiment Essays,2001. http://www.ergito.com/index.jsp.

15. Brown, M.S., and Goldstein J.L. 1986. A receptor-mediated pathway for cholesterol homeostasis.Science 232:34–47.

16. Goldstein, J.L., Rawson, R.B., and Brown, M.S.2001. Mutant mammalian cells as tools to delin-eate the sterol regulatory element-binding pro-tein partway for feedback regulation of lipid syn-thesis. Arch. Biochem. Biophys. 397:139–148.

17. Motulsky, A.G. 1986. The 1985 Nobel prize inphysiology or medicine. Science. 231:126–129.

18. Hammacher, A. M. 1995. René Magritte. Harry N.Abrams, Inc. New York, New York, USA. 162.

The Journal of Clinical Investigation | Volume 110 S9

Figure 13Le Chateau des Pyrenees (The Castle in the Pyre-nees) by Rene Magritte. 1959. Reprinted withthe permission of the Artists Rights Society.

Figure 14Joseph L. Goldstein and Michael S. Brown inStockholm at the time of their receiving the1985 Nobel Prize for Medicine or Physiology.