Tuesday, April 27, 2010

Remembering Fred's Folly (and more)

A couple of years ago, I began interviewing scientists who had done outstanding research in India. The first person I interviewed was Prof. C. Ramakrishnan (generally called CR), who is now professor emeritus at our institute (the Indian Institute of Science). He was a student of Prof. G. N. Ramachandran (popularly called GNR) in Madras University. As a student with GNR, CR had done the calculations that led to the famous Ramachandran Map – India’s most important contribution to modern Biology. For a long time GNR and CR got very little recognition for this work (that was deserving of a Nobel prize to say the least), which has now become a part of every text on protein structure. After some time, people even stopped thinking about how the map was conceived.

After talking to CR, I found myself thinking about another person I knew who had altered the face of protein chemistry in a very matter of fact yet striking way – Fred Richards. As time went by, my appreciation of Fred’s work grew stronger, more so each time I heard a good talk in Biophysics that reminded me of some aspect of his experiments (the last being the talk by Venkatraman Ramakrishnan (Venki) from the MRC Laboratory, a few months ago). Last year, Venki was a visiting professor here and we had an interesting and thought provoking conversation over lunch with him, exchanging notes on people we had known at Yale. All these experiences made me appreciate Fred’s work in a way that I never could as a student, when I was bound up in textbooks.

Fred died last year and though obituaries were published in several well known international journals, there was not a word about him in India. I was saddened by this and recently the urge to write something about Fred’s contributions overcame my reserve to write an uninvited article, and I sat down to write this:

Remembering Fred’s Folly (and more)

Fred Richards passed away quietly in his home in 2009 at the age of eighty three. His passing away was largely unnoticed in India, perhaps because he had won no Nobel prize and he generally didn’t bother with publishing in high profile journals (that Indian science tends to use as a scale of judgement). However, Fred’s work influenced many aspects of the protein science that we know today. Therefore I wished to write a little about Fred’s contributions – not a comprehensive biography, but my thoughts about Fred and his work.

As a graduate student I was a little in awe of Professor Frederic M. Richards (called Fred by one and all). I knew him as the founder chair of our department (Molecular Biophysics and Biochemistry, termed MB&B, which was founded in 1967) and a Sterling Professor Emeritus of the department. I read several of his papers as they were part of our core courses.

It was only much later, once I began to read and understand Biophysics and think about proteins – what made them stable and how they might function – that I realized how many aspects of this subject Fred’s work impinged upon. These days I often find myself sitting in Biophysics seminars thinking, “But Fred began that!” for his contributions are so fundamental in nature, so diverse in scope and so early in the evolution of the field that they are often no longer referred to.

It was only after I left MB&B and went on to study in other institutions and departments that I realized the uniqueness of this department. MB&B was a place that wove together not just different approaches to studying biological systems but also combined two physically separate buildings (in different parts of the campus) so they functioned as a cohesive whole. The MB&B graduate curriculum was remarkably flexible and unusually well designed in terms of training students; I feel this was largely due to Fred’s foresight, scientific clarity and administrative skill.

When I was a student Fred had already retired, but I would often see him- smiling as he nodded to someone, his head full of ideas and his hands full of equipment. He generally seemed to be enjoying himself immersed in his experiments – a sentiment that was reflected in his autobiographical article “Whatever Happened to the Fun? An autobiographical investigation”. (1) His group at the time was tiny but prolific, comprising very unusual and talented individuals. With great kindness they would periodically invite me to lunch in my early and friendless days at Yale, and regale me with snippets of gossip and stories of yore – my favourite being the lab’s sailing expedition on Sally’s (Fred’s wife’s) barge – where everyone was rolling about on the deck trying not to be sick – except Sally, who stood unaffected, perkily yelling out instructions that no one could put into effect.

Fred began his work on the enzyme bovine pancreatic ribonuclease A (RNAse A) when he was a postdoc with Linderstrøm-Lang at the Carlsberg Labs in Denmark. In 1953, he showed that RNAse A could be specifically cleaved by subtilisin to yield an enzymatically active intermediate, which he went on to purify (2). In 1955, he joined the Department of Biochemistry at Yale and continued these experiments. He showed that the cleavage products (termed RNAse S and S peptide) could not function individually but when mixed together could regain RNAse A-like activity, and suggested (with his customary foresight) that this is how peptide hormones might function in target organs (3). This work pierced through many fuzzy notions that existed about proteins at the time and raised intriguing questions about how proteins attained their final structure and function in solution. This experiment was done before Anfinsen’s classic experiment with ribonuclease. (Footnote A)

Different proteins are made of distinct combinations of twenty basic units (amino acids) and perform diverse functions in a cell. Each protein has a unique structure that is related to its function. Are all these different proteins guided by certain basic principles that dictate their shape and stability? Are experiments using protein crystals (vital for determining high resolution structures) relevant to our understanding of proteins in solutions (their normal milieu)? Fred addressed these questions with some path breaking experiments.

In 1967, Hal Wykoff and Fred solved the structure of RNAse S – this was the second crystal structure of an enzyme to be solved (4, Footnote B).

After determining the crystal structure of RNAse S, Fred went to Oxford on sabbatical. Sally and Fred, along with a crew of two, sailed out from the US to the shores of England in their own boat. In the following period, while Sally explored unexpected English ways, Fred worked in David Phillip’s lab. At this time, he built the optical comparator (called Fred’s Folly or Richard’s box) – a device that helped translate X-ray diffraction data to a physical model of a molecule (5). This device began to be used in all labs studying crystal structures till it was eventually replaced by computer programmes.

Fred then went on to develop new tools to look at protein structure and packing. He described proteins as having an outer, solvent-accessible surface and a well-packed inner core and developed ways to quantify these (6,7). This work shed light on some factors that contribute to protein structure, folding and stability – which ultimately determine how a protein will function in a cell (8). This continues to be an important and little understood area in Biology.

These were just some of Fred’s contributions to science. Equally importantly, he had a tremendous impact on guiding not just graduate students, but the field itself in issues relating to ethics and principles of research. He pushed for complete accessibility to protein structural data that was collected by all scientists in the field – and the Protein Data Base that was established as a result of this continues to be an essential information source world wide.

Fred’s style of functioning was frank, forthright and rock solid. He was large hearted in an understated way. His distinctive (and original) style of speech and tendency to drop off during seminars (due to a medical condition) sometimes made people underestimate his astuteness and keen intelligence. Often times, the audience and speaker would be startled when Fred abruptly awoke from his nap and asked a question that probed the core of the subject being discussed, sometimes bringing forth aspects that no one had thought of before.

I am fortunate to have witnessed Fred in action, if only briefly and peripherally. I realize that his no-nonsense approach had a touch of the visionary, and I appreciate the depth of his work all the more as time goes by. I saw him in 2007, a year and a half before he passed away. He showed us the lab he had set up in the basement of his house (which Sally and he built at the edge of the water in Long Island sound). He was still talking with tremendous enthusiasm about experiments that he was planning to do. This is always how I shall remember him.

Fred liked to work with his hands. (Photograph taken from http://www.flickr.com/photos/19739417@N02/3277130016/in/set-72157613746233949/)

Fred (extreme right), Thelma and Johnnie (second and third from the right) were the unchanging components of the Richards lab. (Photograph taken in Guilford, 1998).


A. Anfinsen showed that for small globular proteins, amino acid sequence was sufficient to drive attainment of the native protein structure.

B. To put this in some perspective, the first atomic structure of a protein (myoglobin) was determined using X-ray crystallography at the MRC Laboratory in 1957 and the second (hemoglobin) in 1959. For this work, John Kendrew and Max Perutz were awarded the Nobel prize in Chemistry in 1962.

The first protein enzyme crystal structure (lysozyme) was determined by David Phillip in 1965. This was followed by Hal and Fred’s work on RNAse S.

Recently, Venkatraman Ramakrishnan, Thomas Steitz and Ada Yonath were awarded the 2009 Nobel prize in Chemistry for solving the ribosome structure. Interestingly, Tom is faculty at MB&B and Venki (now at the MRC Laboratory) embarked on his first experiments on ribosomes in the lab of Peter Moore, who is professor emeritus at MB&B.


1. Whatever happened to the fun? An autobiographical investigation. Richards FM. Annu Rev Biophys Biomol Struct. 1997; 26:1-25

2. Degradation of ribonuclease by subtilisin. Kalman SM, Linderstrøm-Lang K, Ottesen M, Richards FM. Biochim Biophys Acta. 1955 Feb; 16 (2): 297-9

3. On the enzymatic activity of subtilisin-modified ribonuclease. Richards FM, Proc Natl Acad Sci USA. 1958 Feb; 44 (2): 162-6

4. The structure of ribonuclease-S at 3.5 A resolution. Wykoff HW, Hardman KD, Allewell NM, Inagami T, Johnson LN, Richards FM. J Biol Chem. 1967 Sep 10; 242 (17): 3984-8

5. The matching of physical models to three-dimensional electron-density maps: a simple optical device. Richards FM. J Mol Biol. 1968 Oct 14; 37 (1): 225-30

6. The interpretation of protein structures: estimation of static accessibility. Lee B, Richards FM. J Mol Biol. 1971 Feb 14; 55 (3): 379-400

7. Tertiary templates for proteins. Use of packing criteria in the enumeration of allowed sequence for different structural classes. Ponder JW, Richards FM. J Mol Biol. 1987 Feb 20; 193 (4): 775-91

8. Areas, volumes, packing and protein structure. Richards FM. Annu Rev Biophys Bioeng. 1977; 6: 151-76

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