Cyrus Levinthal

Cyrus Levinthal was a Professor of Biological Sciences at Columbia from 1968 until his death in 1990. During his 50 years in science he made many contributions of impact, contributions that spanned several different areas of biology, and whose sum reflects an outstanding career. In addition to his scholarship, Levinthal made a key contribution to the University in 1968 by bringing the revolution in molecular biology to the Morningside campus.

Prof. Levinthal came to Columbia in 1968 after having made important discoveries in molecular genetics at MIT. These included mechanisms of DNA replication, the relationship between genes and proteins, and the nature of messenger RNA. His work at Columbia from 1968 until his death in 1990 focused on the application of computers to 3-dimensional imaging of two types of biological structures. These structures were diverse: folded protein molecules on the one hand and cell connectivity in the developing nervous system on the other. He was a true pioneer in both areas; indeed, he could be considered the father of computer graphical display of protein structure that is commonplace today. His early efforts laid the groundwork for todayís continuing study of these two fundamental biological structures.

The wide scope of Cyrus Levinthalís interests can be seen in the summary of his research below:

1) Replication and recombination during the growth of bacterial viruses (1950ís). This first period of studies placed Prof. Levinthal within a group of physicists and physical-science oriented biologists that set up bacterial viruses as a model of the simplest living system, in order to get at the fundamental mechanism governing living things, their reproduction. During this period Prof. Levinthal collaborated with other key figures such as Luria, Thomas, and Visconti to describe the processes by which bacterial viruses replicate their DNA and how they exchange DNA molecules in the process of genetic recombination. In a key experiment, Prof. Levinthal used an elegant and ingenious new method to establish the size of the intact DNA molecule that constituted the genetic material of the virus, proving wrong the then current size estimates based on direct but flawed measurements. This wok was one of the first to measure the size of a genome in a a living system.

2) Colinearity of genes and proteins (early 1960ís).  During the early 1960ís Prof. Levinthal attacked a very basic question of how DNA codes fro proteins.. Prof. Levinthalís study of the bacterial gene for the enzyme alkaline phosphatase showed that there was a collinear relationship between a gene and the amino acid sequence of the protein it specifies. Mutations mapped top specific locations in the alkaline phosphatase gene showed up as amino acid changes at corresponding sites in the polypeptide structure. This kind of relationship represents one of the underpinnings of the molecular biological view of life that we know today.

3) Protein subunits interaction underlies genetic complementation (mid 1960ís). The work on alkaline phosphatase spawned another phenomenon: that two mutant alleles placed in the same cell could complement each otherís deficiency. To produce a normal enzyme as the gene product. Ina series of careful experiments, this process of intragenic complementation was clearly and completed documented for the first time.

4) RNA metabolism (mid and late 1960ís). The concept of messenger RNA had recently been established at this time. After devising rigorous quantitative measurement methods, Prof. Levinthal was the first to show that messenger RNA in bacteria was very unstable. The rapid turnover of this information provided an explanation for the ability of bacteria to respond quickly to to environmental changes by modulating the activity of their genes, giving physical supporting evidence to the key model of Jacob and Monod. In later experiments he extended this general work to explain the kinetics of synthesis of the specific messenger RNA of model inducible bacterial genes (the lac operon) and to the more stable ribosomal RNAs.

5) Bacterial virus-host interactions (late 1960ís) . The effects of bacterial virus infection on host functions were also examined during the late 1960ís. In particular, the ability of the virus to specifically stop bacterial protein synthesis while maintaining production of viral proteins was demonstrated.

6) Protein structure (late 1960's to 1980's). Soon before his arrival at Columbia, Prof. Levinthal pioneered the use of the computer to represent folded protein molecules in 3 dimensions, and to use s computational methods to predict the 3-dimensional structure of proteins. This approach blossomed in more recent years after the advent of the personal computer and continues to be a focus of intensive research both in theory and for drug design. Prof. Levinthalís ability to quantify the magnitude of the protein folding problem gave birth to the ďLevinthal paradox,Ē a calculation that predicts that proteins would never fold in a reasonable amount of time given the principles understood at the time and that remain elusive to this day. 

7) 3-dimensional reconstruction of nerve cell networks (1970ís and 1980ís). Prof. Levinthal extended the use of computers in another true pioneering direction: the production of a 3 dimensional view of cellular networks derived from images of serial sections of tissues. These methods were subsequently used to demonstrate the reproducible patterns of nerve cells grow in a highly reproducible manner during development and in the establishment of their final synaptic connectivity. These methods were also applied to the study of nerve cell regeneration after damage.

In the course of these years of research, a great number of graduate students and postdoctoral associates were mentored by Prof,. Levinthal. Most have gone on to productive and often distinguished careers in academic research. They include Alan Garen, and Frank Rothman (gene-protein co-linearity) , Milton Schlesinger and Ann-Marie Torriani (intragenic complementation), David Fan and David Schub (virus-host interactions), Milton Adesmik, Winston Salser, Robert Zimmerman and Grant Fairbanks (RNA metabolism), Marty Zwick, Barry Honig, Louis Katz, and Irwin Sobel (computing and protein structure) and Eduardo Macagno and Peter Sajovic (neurobiology).  He collaborated with his wife FranÁoise on the structure of bacterial pores.

In coming to Columbia in 1968, Cyrus Levinthal completely reorganized the study of biology on the Morningside campus, merging the Departments of Zoology and Botany into a new Department of Biological Sciences. His years of chairmanship during the late 19060ís and 1970ís forged a new modern department that reacquired much of the distinction that Columbia enjoyed during the early part of the 20th century. He also led a reformation in the teaching of introductory biology, putting emphasis on the description of hierarchical biological structures and processes starting from a firm understanding of their molecular nature.

In addition to his outstanding research and teaching accomplishments, Prof. Levinthal stood out in his involvement as a scientific and social citizen. An active member of the National Academy of Sciences and of the Institute of Medicine, he chaired many committees devoted to national scientific problems. He served on editorial boards and biotechnology advisory boards. He was active in the anti-war movement and especially in organizations devoted to the non-proliferation of nuclear weapons. Within the University, his was an active voice representing biology, science and scholarship in the Senate and as Chair.

There is no doubt that Cyrus Levinthal was one of the outstanding scientists in Columbiaís history.


An obituary:

The Scientist 4[24]:0, Dec. 10, 1990

News - Obituary

Cyrus Levinthal, 68, a Columbia University biologist who made fundamental contributions to molecular biology and molecular modeling, died of lung cancer on November 4 at his home in New York City. Levinthal earned his Ph.D. in physics in 1951 at the University of California, Berkeley, but later in the decade turned his attention to the rapidly emerging field of molecular biology. After teaching physics at the University of Michigan, Ann Arbor, for seven years, he went to the Massachusetts Institute of Technology, Cambridge, in 1957 to help build a biology department based on using the tools of physics to solve biological problems. In 1968 he joined Columbia University in New York as the chairman of the newly established department of biological sciences, and a year later was named the university's first William R. Kenan, Jr., Professor of Biophysics, a chair he held until the time of his death.

In the early 1960s, Levinthal demonstrated the direct relationship between genes and the proteins they encode, a cornerstone of modern molecular genetics. He also proved that messenger RNA is highly unstable, which led to an understanding of how genetic messages could be changed quickly to help organisms adapt to their environments.

Levinthal began using computers to represent and predict the three-dimensional structure of proteins at MIT in 1964, and pioneered molecular computer graphics. In the 1970s at Columbia, he developed a computer system for tracing three-dimensional images of brain cells that allowed the visualization of a nerve cell's growth during development, among other functions. In his most recent project, completed within the last year, Levinthal designed FASTRUN, a molecular mechanics computing system at Brookhaven National Laboratory in Upton, N.Y., that allows three-dimensional analysis of proteins to be carried out at supercomputer speeds.

Levinthal was a member of the National Academy of Sciences and was an NAS representative to the United Nations Educational, Scientific, and Cultural Organization.



[NOTE: This is the text of a manuscript that Cyrus Levinthal wrote and circulated shortly before his death in 1990. We are grateful to Francoise Levinthal for making this text available to us]

In the Fall of 1964, the research in my laboratory at MIT was directed towards understanding intra-cistronic complementation. We had studied pairs of mutant strains of E. coli, each of which produced alkaline phosphatase protein which had no enzymatic activity and each of the proteins was electrophoretically different from the wild type and different from each other. Phosphatase dimers were dissociated and the separated monomers reassociated to produce some hybrid molecules which could be identified and separated electrophoretically. Several of these hybrid molecules were enzymatically active. Various attempts were being made in the lab to make physical models in an attempt to understand the specifics of the molecular interactions involved.

A few days before Christmas, in 1964, I talked to Bob Fano, who was the director of MIT's Project MAC, to ask whether we could get computer time to handle scintillation counter data since we had recently acquired a multichannel counter and at that time the calculations involved were tedious. During our conversation, Fano told me about the "kludge" which had recently been developed at Project MAC, by Tom Stotz and John Ward, with which one could produce, on a video screen, an image which gave the illusion of a three dimensional object in rotation. In thinking about this over Christmas day, I became enthused at the idea of making protein models which I thought could be used for our complementation work and a variety of other macromolecular modeling problems. The following day I spoke further with Fano, got a password for the system, and immediately began learning programming from Richard Mills, who was the associate director of MAC and from Tom Stockman, who was then one of the junior faculty members in electrical engineering. A few days after this, I called Bob Langridge, who had started using computers in 1956 in connection with x-ray diffraction studies of DNA, to ask whether he knew of anyone who was already using interactive computer graphics to model proteins or other molecular structures. He told me he did not know of anyone but he became as enthused as I at the notion of being able to do this. Within about three weeks, I had learned enough programming in the language then used at Project MAC, called MAD (Michigan Algorithm Decoder), to generate the coordinates of a polypeptide chain which could be put into the form of an alphahelix or other sub structures.

As programs were being developed for the generation of protein coordinates so that displays were possible it became clear that one of the major uses of computer graphics in this work was the ease with which one could use the graphics as a way of debugging programs. The first example of this was one in which a particular bond in the peptide chain changed as the chain grew, indicating that one of the rotation matrices which I had written was not orthogonal. As soon as this was clear, it was simple to find the problem and correct it.

Observing the display was extremely exciting at that time and it generated a great deal of enthusiasm on my part and on the part of one of my graduate students, Martin Zwick. Zwick then joined me in the project. He also learned to program quickly and together we went on to study proteins, protein crystals and whatever structural data we could get our hands on. At that time, it was difficult to obtain crystallographic coordinates although the results of the structural analysis had been published. To a considerable extent we deduced the general nature of the structure from published stereo-pair photographs of Kendrew brass models, and combined this information with the model building of alpha-helices.

About this time, I spoke further with Langridge and asked him to join me at Project MAC so that he could pursue his work on the x-ray structures and the mechanics of nucleic acids while I continued working on proteins. Langridge and Andy MacEwan, Martin Zwick and I then continued working on the problems of computer graphics; Zwick and I on proteins, and Langridge and MacEwan on nucleic acids. Except as an attempt to be funny in making movies, we made no effort to think about the interaction of proteins and nucleic acids.

I started the protein work with considerable hope that the use of the graphics would allow us to guide computer programs in a search for a minimum energy structure and thus aid in understanding the problem of protein folding. It quickly became clear that this was grossly over-optimistic, but trying to analyze the problem lead to the notion that the folding of a protein has to be thought of at least as much in terms of the selection of potentially stable structures during biological evolution as a simple problem in physical chemistry. In order to speed the calculations for determining the energy of a protein conformation, I developed a procedure for "cubing" a protein in space with the help of a set of "list-processing" programs of Joe Weizenbaum, also at Project MAC. "Cubing" was one of the first examples of the use of a divide-and-conquer algorithm to simplify the process of determining relevant interactions in a protein. With it each atom was located within a cube in space and its interaction distance was tested with respect to atoms in the same cube and the 26 surrounding ones. With the storage limitations of the IBM 7094 then being used, this procedure saved considerable time although with present generation computers it is not clear that it is very useful.

Some time after we were well along on the modeling work I was approached by William Raub and Bruce Waxman who were at NIH to consider developing programs for small molecules which could be used by pharmacologists in attempting to design drugs which might interact with proteins. I became interested in this proposal as a useful application of what we had already done, so we initiated a contract with NIH when I decided to move to Columbia University in the Spring of 1967. Much of the work that we did on this small molecule project was done with Lou Katz and others at Columbia but it was ultimately taken over in a more serious way by the Prophet system set up by NIH.

My own involvement in the work on protein structures waned somewhat at about the time I moved to Columbia because it seemed to me that most of the activities which were directed at predicting structure from sequence data were, at that time, more game playing than serious science. Writing a computer program to predict what is already known from crystallographic data has been too dangerous. However, in our laboratory, and even more in that of Langridge, the use of much improved interactive computer graphics programs for the docking of proteins, and the interaction of small molecules with proteins has played a major role. In my laboratory we continued to improve the computational and interactive aspects of programs so that we have had a steadily improved version of an interactive modelling package of programs called the PKG, which uses rotatable bonds as the variables with energy minimization in torsional space. The interactive torsional minimizer is now running on a STAR-100 array processor with code written by Mr. Huajun Wang at our facility so it is fast enough to be effectively interactive, and it can be used to feed coordinates to a conventional cartesian program like Amber, Charmm, or Discover which also run on the STAR by virtue of the microcode written by Dr. Bernard Brooks at NIH. However, for interactive purposes where one wants to move parts of a protein through a substantial distance, the torsional program is much faster than a cartesian program although the latter are much more efficient for local minimization and dynamics. My attitude on the usefulness of calculational predictions changed significantly when it became clear that techniques in recombinant DNA research made it possible to modify proteins or generate new proteins and thus, provide a way of evaluating models which were generated computationally. In addition the use of computational methods to predict the structure of proteins which are homologous to others which have been solved crystallographically becomes more important as more amino acid sequences are deduced from DNA sequencing.

It seems likely that deducing the conformations of homologous proteins will require extensive calculations on high-speed computers as well as effective interactive graphics. The availability of time on super-computers, as well as the increased use of mini-supers, array processors and attached processors has increased the computer power available for the biophysical chemistry calculations. However, it is obvious that greater computational speed have also increases the demands on graphics systems. Homologies in conformation are most readily noted by human observation of 3-D structures and frequently ambiguities in computational results can only be understood by studying the graphical outputs. Our initial hope that our "chemical insight" could be used to guide the programs has been superseded by a much more realistic hope that although we may not have "chemical insight" there are more and more 3-D structures determined experimentally to aid in understanding which conformational results are reasonable and which are not; as long as we can look at them.