Biophysical Chemistry 100(2003) 99–103

0301-4622/03/$ - see front matter� 2002 Elsevier Science B.V. All rights reserved.PII: S0301-4622Ž02.00267-3

Thinking about John T. Edsall

Alexander Rich*

Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, USA

Received 26 April 2002; accepted 27 May 2002

After entering Harvard College as a freshman inthe fall of 1942, I experienced the usual confusionof a young student without a clear goal in mind. Ittook me almost 2 years to decide that I wanted tostudy biochemical sciences after having flirtedwith philosophy and physics. My first contact withJohn Edsall was probably in the spring of 1944when I began taking a biochemistry course, andJohn was the head of the biochemical sciencestutorial program. Of course, this was in the middleof World War II, and I had already enlisted in theNavy V12 Program and remained at Harvard inthat program. Like many others, however, I leftcollege in mid-1944 to undertake a more activeform of military duty and remained away fromHarvard until the beginning of the Spring Term of1946. At that time, I returned to complete under-graduate training and do an undergraduate thesis inbiochemical sciences. John Edsall agreed to super-vise my thesis, and this led to my introduction toRaman and infrared spectroscopy with some focuson the amino acids that John had been studying formany years.

1. Research work with John Edsall

At that time John Edsall’s office was in HarvardMedical School in Edwin J. Cohn’s Department ofPhysical Chemistry on the top floor of Building C.

*Tel.: q1-617-253-4715; fax:q1-617-253-8699.E-mail address: cbeckman@mit.edu(A. Rich).

John had his office there, as well as laboratoryspace that contained the Raman spectrometer. Thisinstrument was a Hilger E439 glass spectrographand the measurements were made by isolating indi-vidual mercury lines with selective filters. Thework was carried out in a darkroom, and manyhours were spent accumulating spectral data.

John Edsall had initiated this study in the late1930s and had already discovered that amino acidsin solutions existed as zwitterions. Although thisfact seems obvious today, at the time it was a noveldiscovery. My work involved extending this studyinitially to a number of less common amino acids,such as cysteine and cystine. This made it possibleto identify the stretching frequency of the SH bondof cysteine. In addition, the S–S stretching bond ofcystine was identified.

The important innovation was the extension ofthe research to the dipeptide glycyl–glycine, whichwas studied both as a dipolar ion and as a cation.Formation of the peptide bond was associated withthe disappearance of the C_ O frequency of 1740cm and its replacement by a lower frequencyy1

vibration near 1400 cm w1x. Several vibrationsy1

were found in the range of 1000 cm which werey1

identified as stretching frequencies of the molecu-lar chain. It had already been shown in X-ray dif-fraction work that the C–N distance of the peptidelinkage is approximately 1.29 A, indicating a high˚degree of resonance and of double-bond characterin the peptide linkage. This work from CalTechprovided definitive proof of the planarity of the

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peptide bond. A stretching frequency near 1700cm was tentatively identified as related to they1

C–N peptide bond stretching frequency.This work served as a good introduction to

molecular spectroscopy, and it fired my enthusiasmfor learning more about the details of molecularconformation. This work was eventually publishedin the JACSw1x, where it was No. 7 in the seriesof Raman spectra of amino acids and related com-pounds that John Edsall had been pursuing.

My interactions with John Edsall were some-what formal at that stage. I was quite awed by hiscommand of a wide body of information in bio-physical chemistry, and I enjoyed discussing prob-lems of science with him. We often sat in his smalloffice and talked, and I was continually impressedby the large pile of letters that were neatly stackedon his desk, no doubt awaiting replies. At that timeit was difficult for me to envision having that muchcorrespondence. In later years, however, as similarpiles of that type accumulated on my desk, I beganto understand that it was an intrinsic part of thelife of a scientist. Of course, this was well beforethe days of email and fax or widespread use of thetelephone, especially for long-distance calls.

During that period the Cohn Laboratory had aweekly seminar which was held in Edwin J.Cohn’s rather spacious office, with an invitedspeaker frequently coming from out of town. I viv-idly remember the talks delivered by Lars Onsagerof Yale University. He spoke with such a heavyNorwegian accent that it was often difficult to fol-low the line of his presentation. Those meetingswere especially interesting because of the widevariety of people who assembled. The laboratorywas a particularly active one with permanent mem-bers including Larry Oncley and John Ferry. It wasjust recovering from its wartime operations inwhich it played a heroic part in fractionating bloodand making blood products available for the armedservices. It was a magnet for many post-doctoralfellows, especially from abroad. Visitors flowedthrough the laboratory in large numbers. I wasespecially impressed when John Edsall introducedme to J.D. Bernal, who was visiting from London.I came to know Bernal rather well in the mid-1950s when I spent over half a year in Cambridge,

England. But the memory of his first visit to theCohn Laboratory is vivid in my mind even today.

One thing bothered me at the time. It was thefact that Edwin Cohn had a very lavish office,while John Edsall was relegated to rather crampedquarters, both in his office and in space for hisexperimental work. I only gradually realized thatthere was a complex relationship between thesetwo men. It was clear to me that John Edsall wasthe better scientist although Edwin Cohn seemedto be brilliant in publicizing his work and also washelpful in bringing out the best work from hisassociates.

In John Edsall’s post-doctorate years, he workedwith Alexander von Muralt, and they publishedpapers in the early 1930s dealing with the physicalchemistry of muscle proteins. One of the methodsthey employed was double-refraction of flow. Thiswas a method widely used in the 1930s and 1940sto study the rotary diffusion constants of elongatedmolecules. When long molecules are exposed to ashear gradient, they align themselves, and thisalignment can be measured quantitatively througha study of birefringence. It was necessary to lookat the birefringence established by the gradient.Limitations in the field were often related to theinstruments that were available. One of the projectsthat John embarked on in which I also participatedwas in the design and construction of an instrumentfor measuring double-refraction of flow, using aconcentric cylinder apparatus in which the annulusbetween an inner and outer cylinder was filled withliquid. The outer cylinder rotated, but the inner cyl-inder did not. Relatively large velocity gradientscan be obtained using this instrumentw2x. A zir-conium arc lamp was used as a light source, togeth-er with an interference filter, and sheets of selectedpolaroid were used as polarizer and analyzer. Whenthe liquid is at rest and the field is observedbetween crossed polaroids, it is dark. However, onrotating the outer cylinder, the velocity gradientmakes the elongated molecules line up. When thegradient is established, there are four points in theannulus where the light is occluded. The planepolarized light entering the liquid is generally con-verted into elliptically polarized light which is notextinguished by the analyzer. The birefringent liq-uid acts like a cylindrically symmetric uniaxial

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crystal. At the four points 908 apart, where theoptic axis is parallel or perpendicular to the inci-dent plane of vibration, the liquid transmits plainpolarized light which is then extinguished by theanalyzer. The four darkened segments in the annu-lus are called the Cross of Isocline. A descriptionof this instrument was published in theReview ofScientific_Instruments w2x. The machine was verycompact and could be put on a stand with rollingwheels. It became somewhat popular and was man-ufactured and sold by an instrument maker inBrooklyn, New York. The experience of workingwith this instrument and helping to design it wasone that I found very instructive, and it clearlyshowed me that John Edsall’s analytic abilitiesextended into the practical realm of machinedesign.

In this paper we described the unusual motionof the Cross of Isocline, as seen on rotating theanalyzer. The darkened areas move together witha scissors-like motion. This was a property of theSenarmont compensator which was used to meas-´ure double-refraction of flow. At a later time I ana-lyzed the movement in a paper published in 1955w3x. In doing this work in 1950–1951, I castaround for a molecule that was elongated anddecided to use DNA in order to measure its prop-erties. This work was carried out before DNAgained its subsequent popularity as a carrier ofgenetic information.

2. John Edsall as a role model

After receiving my undergraduate bachelor’sdegree in June of 1947, I stayed on at HarvardMedical School to complete the last 2 years of myM.D. and therefore maintained contact with JohnEdsall during this period. The third and fourth clin-ical years of medical school were quite stimulating,but it was clear to me that my bent was towardcontinuing basic research, rather than medicalpractice. I spoke several times with John Edsallabout the relative merits of going on to do a post-doctoral fellowship immediately after finishingmedical school, vs. taking an internship and thengoing on to do research. John told me that he hadfaced a similar dilemma as he was finishing med-ical training at Harvard. However, in his case, the

situation was made somewhat more difficult sincehis father was then the Dean of the MedicalSchool. John’s commitment to carrying outresearch work made him decide to go on directlyinto research, rather than carrying out an intern-ship. For me, this was an important issue becauseit showed me that it was possible to do sciencedirectly, without having the ‘insurance’ associatedwith an internship. Thus, I decided to follow thesame course of action. This was not a decisionwidely shared among any of the other members ofmy medical school class, and many considered thisan unsound career decision.

Late in 1948 at the beginning of my senior year,John and I discussed various laboratories where Imight apply to do post-doctoral work. He suggest-ed a number of outstanding scientists: Linus Pau-ling, Melvin Calvin, Henry Eyring, WalterKauzmann were among them. I wrote letters to allof these individuals, and they accepted me as apost-doctoral fellow, if I could come with my ownfellowship. Here, again, John Edsall played a keyrole. He urged me to apply for a National ResearchCouncil fellowship which was, at the time, virtu-ally the only type of post-doctoral fellowship avail-able. NIH had not started a post-doctoralfellowship program, and the NSF had not beenestablished. I believe it was John Edsall’s support-ing letter that made it possible for me to receivethis fellowship. I wrote to Linus Pauling, sayingthat I was pleased to accept his invitation andwould arrive there in the fall of 1949.

In retrospect, this was perhaps the most crucialdecision in the development of my research career.John Edsall had spent a year(1940–1941) in Pas-adena, California, as a visiting scientist at the Gatesand Crellin laboratory where Linus Pauling wasChairman of the Chemistry Department. He toldme how strongly he was impressed by Linus’ com-mand of chemistry and the great contributions hehad made in understanding the three-dimensionalstructure of proteins. In retrospect, I recognize thatthis was a most fortunate decision in helping meto develop as a structurally oriented biochemist.

I felt a warm sense of friendship in dealing withJohn Edsall. He had the ability to speak to a stu-dent in a way that boosted the student’s sense ofself-worth. He was always considerate and recep-

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tive to new ideas. Although he was friendly, he stillmaintained the formality of a New England gen-tleman, a combination that I found both stimulatingand somewhat awe-inspiring. I always referred tohim as ‘Dr Edsall’. That changed only after morethan 10 years of our association, being replacedlater by the less formal ‘John’.

3. Caltech and NIH

After leaving Harvard Medical School, Iimmersed myself in the totally different experienceof southern California living at CalTech. As I cameto know more about Linus Pauling, I realized thathe held John Edsall in very high regard and thatprobably it was John’s letter to him that initiallyopened the way for his accepting me as a post-doctoral fellow. Linus had recently described sicklecell anemia as a molecular disease, and I joined inthe search for other molecular defects in hemoglo-bin. I learned something about the role of fetalhemoglobin in various anemiasw4x.

My contact with John was intermittent for sometime, but intensified considerably in 1953 whenLinus Pauling organized a conference on the struc-ture of proteins and nucleic acids at CalTech in thefall. John Edsall came to this meeting, and wespent many hours walking around Pasadena, talk-ing about what was happening at the laboratory atHarvard Medical School. I clearly remember theconcern he expressed over the fact that EdwinCohn was experiencing some episodes of transientconfusion that I suspected were associated withsmall hemorrhagic events in the brain. Sadly, thisturned out to be true, since Edwin Cohn died of astroke not long afterward.

The conference was exciting since many atten-dees were scientists from England as well as fromthe United States. Max Perutz gave a paperdescribing his discovery of the phasing power of amercury derivative, the key event leading to theultimate solution of the structure of hemoglobin.Both Watson and Crick were at the meeting andspoke about their newly proposed structure ofDNA. My contribution was to present results ofmodeling studies of ways in which DNA and pro-teins might interact, most of which subsequentlyturned out to be incorrect.

I moved to NIH in the following year, where Iset up a section on physical chemistry and beganfocusing my research on RNA structure. John vis-ited Washington frequently and several times cameto our house in Bethesda near NIH. John’s appear-ance then at age 65 was somewhat unchanged fromhis appearance 10 years earlier when we had firstmet, and he did not change appreciably since then.Thus, John appeared older than his years in hisearly life, but in his later life he appeared youngerthan his years. This always struck me as a remark-able paradox.

We carried on a long-term dialogue on the natureof proteins and the manner in which their proper-ties were a consequence of both the structure andcomposition of each protein. John assumed the edi-torship of theJournal of Biological Chemistry, andit kept him very much abreast of what was hap-pening in this broad field. I have always marveledat his comprehensive grasp of many different fac-ets of protein research.

At one point John Edsall arranged a lecture forme at Harvard College, where he had now movedhis office and laboratory. This visit gave me a goodchance to learn more about his current work andalso to tell him about my own research on RNAstructure.

4. Back to Cambridge, Massachusetts

In 1958, I accepted a position in the BiologyDepartment at MIT and, from that point on, mycontact with John Edsall was more continuous. Wefrequently saw each other at seminars and inter-acted both socially and professionally. In morerecent years, we had made a point of having lunchtogether every 2–3 months. These lunches offereda very pleasant vehicle for exchanging opinions onscientific, political and social events. I have a vividrecollection of having an extended lunch discus-sion with John about the voting habits of his fatherDavid. As Dean of Harvard Medical School, heinteracted with many of the prominent members ofthe Boston business community, and they generallyassumed that he voted as a Republican. However,he was a staunch Democrat, and John explained tome in some detail the position that he took in theelection of 1896. I was struck by the fact that thedate of this lunch was 1996, and the topic of our

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conversation concerned voting patterns a hundredyears earlier.

From my perspective the contacts with JohnEdsall were stimulating and often inspiring. Heshowed steadfast devotion to scientific issues,while at the same time maintaining a moral recti-tude about what is appropriate in science. In par-ticular, I have always been greatly impressed bythe principled stand he took in declaring that hewould turn down an NIH budget if support for Lin-us Pauling’s research was withheld on politicalgrounds. This occurred at the height of the hysteriaof the McCarthy era. His willingness to stand upfor proper and just behavior provided a model ofhow a scientist should act in a democratic society.

I feel privileged to have had continuing contactwith John Edsall over a 60-year period and am

very grateful that he had such an impact on myscientific development.

References

w1x J.T. Edsall, J.W. Otvos, A. Rich, Raman spectra of ami-no acids and related compounds. VII. Glycylglycine,cysteine, cystine and other amino acids, J. Am. Chem.Soc. 72(1950) 474–477.

w2x J.T. Edsall, A. Rich, M. Goldstein, An instrument forthe study of double refraction of flow at low and inter-mediate velocity gradients, Rev. Sci. Instr. 23(1952)695–701.

w3x A. Rich, Use of the Senarmont compensator for meas-´uring double refraction of flow, J. Opt. Soc. Am. 45(1955) 393–395.

w4x A. Rich, Studies on the Hemoglobin of Cooley’s Ane-mia and Cooley’s Trait, Proc. Natl. Acad. Sci. 38(1952)187–196.