Retrospective for ASBMB Today

The following was prepared for use in a Retrospective for ASBMB Today, the monthly magazine of the American Society for Biochemistry & Molecular Biology, and is reproduced here with the permission of Greg Petsko, the President of the ASBMB, and Nicole Kresge, Editor of ASBMB Today:

Retrospective:

Frederic M. Richards (1925-2009)

 

Frederic M. Richards, former President of the ASBMB (when it was the American Society of Biological Chemists) and of the Biophysical Society passed away at his home in Guilford, Connecticut on January 11^th.  He was 83.

Fred Richards was a towering figure in protein chemistry, having played a key role in moving the concept of proteins from amorphous colloids to discrete molecular structures.  His contributions to protein science ranged from his central role in founding what is now known as structural biology–both experimental and computational–to the design and application of new chemical reagents for probing protein structure and function.

Richards was born on August 19, 1925, in New York City, the youngest child of George H. Richards and Marianna Middlebrook Richards, both parents from old New England families.  After his graduation from Phillips Exeter Academy, he matriculated at MIT.  Military service toward the end of WWII intervened, but he returned to MIT after his discharge and received the B.S. degree in 1948.  For his graduate study, he moved to E.J. Cohn’s department at Harvard Medical School, where he worked with Barbara Low, receiving the Ph.D. in 1952.  He stayed at Harvard for a year as a Research Fellow with Cohn and then moved to the Carlsberg Laboratory in Denmark, where, with Kaj Linderstrøm-Lang and others, he began working with ribonuclease.  After a short stint at Cambridge as an NSF Postdoctoral Fellow, Richards joined the faculty of the Department of Biochemistry at Yale in 1955 as an Assistant Professor.  He rose rapidly through the ranks, becoming Professor in 1963.

In 1963, Richards was appointed Chairman of the Department of Molecular Biology and Biophysics at Yale, which entailed a move from the Medical School to the Yale College campus.  Following a sabbatical at Oxford in 1967-1968, for which Richards and his wife Sally sailed their own boat with a small crew across the Atlantic, Yale merged the Medical School Department of Biochemistry and the Yale College Department of Molecular Biology and Biophysics to form a new University-wide Department of Molecular Biophysics & Biochemistry (MB&B) with Richards as its founding chair (1969-1973).  There was considerable skepticism about the viability of a department with divided space on the two (Yale College and Medical School) campuses, not to mention faculty from the two distinct campus cultures.  However, due in good part to Richards’ strong leadership in the department’s early days, including a spectacular initial class of junior faculty hires that included at least two future chairs of the department (as well as a future chair of Chemistry), MB&B will celebrate its 40^th anniversary later this year.

Summarizing Richards’ contributions to protein science is difficult, because of the breadth that he covered.  A few examples will have to suffice.  Much of the early work in Richards’ laboratory focused on bovine pancreatic ribonuclease, and in particular a preparation that he discovered while in Linderstrøm-Lang’s laboratory, dubbed ribonuclease-S (RNaseS) that had been treated with subtilisin, to cleave the peptide bond between Ala20 and Ser21.  Richards and coworkers purified and characterized RNaseS, separated it into S-peptide (residues 1-20) and S-protein (residues 21-124), both enzymatically inactive, and showed that S-peptide did not retain an ordered structure in solution but could be reconstituted with S-protein into enzymatically active RNaseS.  They crystallized RNaseS and showed that RNaseS was enzymatically active in the crystal, putting to rest the widely held view at that time that protein crystal structures were irrelevant to the conformation and behavior of enzymes in solution.  In collaboration with the late H.W. Wyckoff, they solved the structure to atomic resolution (a tie for the third protein structure ever solved to atomic resolution) with and without bound nucleoside monophosphate.   While on sabbatical at Oxford, Richards designed and built the Richards Optical Comparator, better known in the field as Fred’s Folly, or simply the Folly, which remained the method of choice for converting electron density maps to models until it was supplanted by computer graphics.

The availability of high resolution structures led to the first computational studies (at a time when computational studies required a main frame computer).  First were calculations of the accessibility of solvent to the surface of proteins, followed shortly thereafter by calculations of the packing of amino acyl side chains in the interior.   These were followed by calculations of the packing of α-helices in myoglobin.  Calculations of the interior packing of proteins led much later to calculations of sequences compatible with a particular main chain conformation and in silico protein evolution.

The Richards Lab always included a “wet” component, focused on the properties of proteins in solution and on the design and application of new chemical reagents for modifying proteins in ways that reported on the proteins’ structure and/or function.  Types of reagents pioneered in the Richards laboratory included hydrophilic and hydrophobic photoactive reagents for studying membrane protein topology, cleavable cross-linking reagents for studying protein quaternary structure, and reagents that exploited the remarkably strong binding between ferritin and avidin for use in localizing target proteins within cellular structures.

Richards received many honors for his scientific achievements, including the Pfizer-Paul Lewis Award in Enzyme Chemistry (1965), a Guggenheim Fellowship (1967-1968), election as Fellow of the American Academy of Arts and Sciences (1968), election to the National Academy of Sciences (1971), the Kai Linderstrøm-Lang Prize in Protein Chemistry (1978), ASBMB Merck Award (1988), the Stein and Moore Award of the Protein Society (1988), and the State of Connecticut Medal of Science (1995).

What should not be overlooked in reviewing Richards’ science is that the Richards Lab was a wonderful place to develop as a scientist, whether one’s experience there was as an undergraduate student, graduate student, postdoctoral fellow, or sabbatical visitor.

 

 

Quotes for use with the Retrospective on Frederic M. Richards

 

James V. Staros, who had been a graduate student with Fred Richards in the early 1970’s, and who is currently Professor of Biochemistry and Dean of the College of Arts & Sciences at the State University of New York at Stony Brook, remarked, “One of Fred’s outstanding characteristics was his penetrating, almost prescient vision, his ability to see far beyond the experiment at hand.  One example:  In a paper published in the JBC half a century ago (Richards & Vithayathil [1959] JBC 234: 1459-1465), in which were described the separation of ribonuclease S into enzymatically inactive S-protein and S-peptide and the reconstitution of enzyme activity by the re-association of S-protein and S-peptide, he observed ‘The strength of the interaction in this enzyme system appears to be of the order of magnitude that might be required to explain the initial effects of peptide hormones in the target organs.’  As someone who has spent much of his scientific career working on receptors for one class of polypeptide hormones, I find this remarkably visionary—and typical of Fred.”

 

Louise Johnson, who spent a postdoctoral year with Fred Richard in 1966 and was a member of the crystallographic team that solved the structure of RNaseS, and who is currently the Sir David Phillips Professor of Molecular Biophysics at Oxford University, offered the following remembrance: 

“Fred’s lab was a marvellous place to be. I had also come to learn some biochemistry. Fred was enormously encouraging and was prepared to support some way-out experiments. One such was our attempt to determine the binding site for the platinum heavy atom derivative, platinum diaminodichloride with RNAse, using neutron activation.  We travelled by a small plane to Brookhaven where our electrophoresis samples were irradiated. The samples came back red-hot from the sodium in the chromatography paper. Fortunately the activated sodium isotope decayed before the gold isotope of the activated platinum.

We all had tremendous admiration for Fred both for his scientific wisdom, expertise and creativity and also for his extra-science pursuits in ice-hockey and in sailing.

In the following year 1967, Fred and Sally came to Oxford for a Sabbatical year with David Phillips.  They made the unusual travel arrangements in sailing their own boat across the Atlantic. They also took the precaution of having an admiral’s son on board.  The Sabbatical in Oxford was a great success.  In those days the manual interpretation of electron density maps in protein crystallography was a time-consuming and inaccurate process. In Oxford Fred constructed with his own hands and with the help of the workshop staff the device that became known formerly as the Richards Box (or less formally in the lab as Fred’s Folly).  Using a half-silvered mirror it allowed a projection of the model onto the electron density map and greatly aided interpretation before the days of computer graphics.  I also recall in Oxford Fred was interested in chitinases and would cycle over to Wytham Woods (a University reservation about 5 miles from Oxford) to collect mushrooms as a source of enzyme.

I recall Fred with great affection.  He was a marvellous mentor (although I was always a little in awe of him), and great scientist with whom one could discuss a whole range of phenomena (for example diffusion of ligands into proteins and protein crystals), and most of all a person who made science and the life of science great fun.”