An Interview with Dr. Manuel Varela: The Immune System

Sep 15, 2019 by

Michael F. Shaughnessy –

1) Professor Varela, we have all heard about the immune system, which apparently protects us. Someone closely associated with it is Dr. Gerald Edelman, who like a lot of other scholars we have studied, was interestingly enough born in New York City, probably at the height of the stock market crash in 1929.  What do we know about his early life?

Gerald (Gerry) Maurice Edelman was an American biomedical scientist who specialized in the structural protein biochemistry of antibodies, developmental biology, and neurobiology. Dr. Edelman shared the 1972 Nobel Prize in Physiology or Medicine with Dr. Rodney Robert Porter for having determined the structural nature of the antibody molecule.

Edelman was, as you pointed out, born in New York City, in the Queens borough, Ozone Park, in the U.S., to parents Anna Freedman and Edward Edelman on the first day of the month of July, in 1929, just prior to the crash of the stock market and the ensuing Great Depression of the 1930s. Edelman’s father was a physician, and his mother was an insurance agent. The Edelman family was known to partake in intellectual pursuits, such as art, literature, and music.

The child Edelman had wanted to become a concert violinist as one of his earliest interests. He was particularly interested in the music composed by Wolfgang Mozart. Young Edelman attended the New York public school system, from kindergarten through to high school, attending John Adams High School, in Queens. His interest in music was serious, having studied under a famous music teacher Albert Meiff. During this time, however, while in high school, Edelman, perhaps influenced by his father, decided to pursue medicine as a career. Another account holds that Edelman discovered that performing was not necessarily of interest to him, after having performed a sonata in front of an audience. Thus, he tried composing music and learned fairly quickly that he felt he had no talent for music composition. The decision to become a scientist instead emerged soon after this early realization.

He graduated from high school in 1946. After high school graduation Edelman attended Ursinus College, a private liberal arts institution which was located in the small town called Collegeville, in the state of Pennsylvania, in the U.S. Choosing to focus his major studies in the field of chemistry, Edelman took his undergraduate degree with honors (magna cum laude) in 1950.

During the same year, Edelman married Maxine M. Morrison, and the couple remained married until his death on the 17th day of May, in 2014, at 84 years of age. Together, the Edelman’s had three children.

After graduation from college, in 1950, Edelman was accepted into medical school and enrolled in the School of Medicine at the University of Pennsylvania, receiving his M.D. degree in 1954. Newly minted Dr. Edelman became an intern at the Johnson Foundation for Medical Physics, at the University of Pennsylvania, for approximately one year, until 1955. Next, Dr. Edelman moved to Boston, Massachusetts, for further internship training at the famous Massachusetts General Hospital. His official title at Mass General was medical house officer.

2)  Again, like many other Nobel Prize winners, he spent time in the military. What do we know about his work during that time frame?  

Dr. Edelman’s military service commenced during the same time frame as his medical internship years, in 1955. After a year interning at Mass General, he joined the U.S. Army Medical Corps in which he spent the next two to three years stationed in Paris, France, serving at the officer rank of Captain at a military hospital and spending time in a nearby hospital attending to civilian patients, as well.

During this military service, Dr. Edelman practiced general medicine. He was known to have visited with thousands of patients and delivered countless infants. Interestingly, and fortunately for the rest of us, it is also the same time frame in which he acquired an interest in immunology and, in particular, the antibodies. The new interest stemmed partly from his observations with the then cutting-edge modern molecular biological research being conducted at the nearby Sorbonne.

Another source has posited that his interest in antibodies arose because he had read a book on the subject of immunology. He read that exposure to antigens, i.e., foreign agents such as microbes or non-self-substances, in the body provoked the production of the antibodies, which then presumably neutralized the potentially pathogenic effects of the invading foreign antigens. He had further noticed that while a great deal of information was known about the antigens, very little, however, was known at the time about the nature of the antibody itself. This unknown aspect of immunology piqued his interest in antibodies and immunology.

3) Apparently, he earned both the M.D. and the Ph.D.  Any ideas as to how this came about?

As a medical military officer serving in post-World War II France, Dr. Edelman, with an M.D. in hand, was a practicing physician, seeing both military and civilian patients, between 1955 and 1958, when he was honorably discharged from the Army. His interest in the field of immunology had been sparked during this stretch, and it is at this point during his career that he decided to pursue additional formal education.

He chose to acquire another doctorate, this time the Ph.D. Consequently, Dr. Edelman, the M.D., applied to the Ph.D. graduate program at the Rockefeller Institute for Medical Research, concentrating on immunology. He entered the research laboratory of Prof. Henry G. Kunkel, a prominent immunologist in his own right. In Prof. Kunkel’s lab, Dr. Edelman focused his attention on separating apart the various immunoglobulin chains that constituted the antibody molecule.

In 1960, he took his second doctoral degree, becoming Gerald M. Edelman, M.D., Ph.D. The graduate thesis work he conducted for this second doctoral-level degree would start the pathway to the Nobel Prize.

4) His name is linked to the Rockefeller Institute, again in New York City- what kind of work did he do there?

At the time, Dr. Edelman, an M.D., undertook graduate-level studies and conducted a thesis project for his Ph.D. at the Rockefeller Institute, known today as Rockefeller University. He successfully defended the thesis project and took his Ph.D., in 1960. That same year he accepted a new position as assistant dean of graduate studies, until about 1963, when he became associate dean. Then, in 1966, he was promoted to full professor, until 1992, when he retired from the university and moved to the Scripps Research Institute, in La Jolla, California, in the U.S.

Starting with his graduate thesis studies, Dr. Edelman focused his attention on the antibody molecule, wanting to study its structure from a chemical standpoint, using chemical-based tools to do so. Towards this, he first elected to treat the antibodies with chemical agents that broke apart certain bonds known as disulfide bridges that kept the antibody molecule together. One of these chemical agents is called beta (β)-mercaptoethanol. These disulfide bonds consist of two sulfur atoms that are connected to each other.

When the disulfide bonds are broken, the sulfur atoms come apart, releasing the rest of the larger molecules that are connected to them along with the sulfur atoms. The chemical process of breaking disulfide bonds with reducing chemicals, such as the β-mercaptoethanol, is called reduction. Next, he treated the broken up antibody molecule parts with an alkylating agent, such as dithiothreitol (DTT), in order to keep the individual broken-up parts from re-associating back together. He had to keep the individual antibody parts separated from each other. Next, he isolated the individual antibody parts from each other by using a biochemical technique called gel filtration. The technique permitted Dr. Edelman to determine the molecular sizes of the antibody parts.

He discovered that the original intact antibody molecule consisted of two large (i.e., heavy) peptide chains and two small (i.e., light) peptide chains. Thus, the graduate student Dr. Edelman found that the antibody molecule consisted of 4 peptide molecules: two heavy chains and two light chains. He further discovered that each of the heavy chains had massive molecular weights of about 50,000 Daltons, and the light chains were each about 22,000 Daltons. It is this work that was to start the process on the road to the Nobel Prize.

Later on, throughout the 1960s, still at Rockefeller, he was able to determine the so-called primary structure of the antibody chains. The primary structure consists of the sequence of amino acids along a protein chain. At the time that he had learned the amino acid sequences of the heavy and light chains of the antibody, it had been the biggest molecule ever to have been sequenced in such a manner. It was a monumental effort.

By combining the results of his studies with those of Dr. Rodney Robert Porter, then at Oxford University, a molecular model of the antibody was proposed, in 1969. Professor Porter would shortly become Dr. Edelman’s 1972 co-Nobel Laureate in the Physiology or Medicine category, for having correctly deduced the proper antibody structure. The achievement was of enormous importance, not only to immunologists but also to biochemists, cell biologists, microbiologists, and molecular biologists. The rapidity of the Nobel bestowment to Drs. Porter and Edelman so soon after the structural discovery of the antibody became known is a testament to the immense importance of the work.

5) His name is linked with the following fields: biophysics, protein chemistry, immunology, cell biology, and neurobiology. Could you perhaps link his most important investigations with each one of these areas?

Dr. Edelman’s research experiences did indeed touch upon several seemingly disparate fields of study. I shall briefly summarize his connections to each of these areas.

His involvement with the field of biophysics started in 1954, when he focused on medical biophysics at the University of Pennsylvania, working in the research laboratory of Prof. Britton Chance, a biophysical and medical biochemist. It turned out to be the very first research experience that Dr. Edelman had gained in his scientific career. Working under Dr. Chance, Dr. Edelman participated in the spectrophotometric analysis of an important protein called cytochrome C peroxidase in mutant yeast microbes. The enzyme is involved in the oxidative phosphorylation process of the respiratory chain, a system for generating biological energy in the form of ATP. The work was of tremendous importance because it confirmed the enzyme-substrate association as originally predicted by another great biochemist Dr. Leonor Michaelis.

Dr. Edelman’s protein chemistry work involved his studies, during the 1960s, on the antibody structure, using chemical means to split apart the various peptide chains by exploiting reducing compounds that would disrupt disulfide bridges that held the chains together and then using alkylating agents that would block the broken bonds in order to prevent the chains from coming together again. This type of protein chemistry work was a main staple in the toolbox of techniques used by biochemists and protein chemists. Working with such a gigantic molecule as the antibody, it required an enormous amount of work. Furthermore, the determination of the primary amino acid sequence of the protein chains required a firm knowledge of the protocols necessary for peptide sequencing. Sequencing the amino acids along a protein chain was a laborious process.

The protein chemistry work of Dr. Edelman comes hand-in-hand with that of immunology. The antibody molecule is one of the most important proteins ever known, especially when one considers that they confer the acquisition of immunity against pathogens, cancer, and against any foreign agent that invades the body. Incidentally, antibodies are also referred to by protein chemists and immunologists alike as immunoglobulins because, at the molecular structural level, the chains have globular configurations to them. That is, the antibodies consist of a set of globs!

Hence, antibodies are also frequently called immunoglobulins, or Ig, for short. The antibodies are the prime fighters of cancer and microbial pathogens, and exposure to these types of antigens represents the onset of potentially serious diseases. The antibodies, induced after antigenic exposure, thus provide protection and immunity to these antigens. Therefore, Dr. Edelman’s discovery of the antibody (immunoglobulin) structure will no doubt continue to be of great importance. Consequently, Dr. Edelman’s name will forever be connected to immunology.

During the 1970s, Dr. Edelman started a new line of research. This effort involved the study of the cellular and molecular mechanisms that controlled the growth of biological cells. He also studied cellular developmental biology of multicellular organisms.

He concentrated on those embryonic systems which connected cells to each other, a phenomenon known as cell-cell interactions. The type of cells he focused on consisted of developing neurons, which function in the brain. Thus, as he became a cell biologist he also became a neurobiologist.

This cell biological and neurobiological work of Dr. Edelman ultimately led to his discovery of a new type of cellular glue, i.e., molecules that held cells together. These molecules are known as cell adhesion molecules. The discovery of these cellular glue-like molecules has been regularly included in textbooks involving both the fields of cell biology and neurobiology alike.

Expanding upon the neurobiological work he later paid attention to the functioning of the brain, proposing a new idea to explain how the brain develops and organizes its neurons. The mechanism is known as neuronal group selection. He became well known for his contributions to the field of neuroscience as a result, even shedding new light on the biological mechanisms of consciousness.

6) The Nobel Prize- was apparently shared with a Rodney Porter- what exactly did they win the Nobel Prize for?

Together, Drs. Edelman and Porter shared the 1972 Nobel Prize for their work involving the structural elucidation of the antibody molecule. We discussed the antibody work of Dr. Edelman above, which encompassed breaking up the four various peptide chains, two heavy and two light protein chains, that make up the antibody, in determining the molecular sizes of these chains, and in determining the amino acid sequences along the antibody chains.

Dr. Porter’s work with the antibody structure determination took a different track than that of Dr. Edelman. In the Porter laboratory, they added an enzyme called papain to an antibody molecule and broke it into three separate fragments. Two of the three antibody fragments were identical in size and correctly presumed to be identical in nature. These two fragments were discovered to bind to the antigens. Even when broken up into their pieces, the fragments could specifically and tightly bind to their dedicated antigens. Thus, these two fragments were referred to as Fab, for antibody fragments that perform antigen binding. It was the first time it became known that an intact antibody could bind to two molecules of antigen. It was also found that the Fab fragments contained the entire complement of light chains but only part of the overall heavy peptide chains.

The third fragment was distinct from the two identical Fab fragments, and it was shown that this third distinctive part could readily precipitate into a crystallized form. Hence, this third antibody fragment was called Fc, meaning a fragment that crystallizes easily. The Fc fragment consists of the rest of the heavy chains, but without any of the light chains. Later work showed that the Fc part of an antibody participates in performing other functions associated with humoral immunity and in communicating with certain components of innate immunity.

7) I lifted a phrase from his bio- perhaps you can help me understand it. “In his most recent work, he and his co-workers have been investigating the “fundamental cellular processes of transcription and translation in eukaryotic cells.”  First, what are eukaryotic cells? And what exactly is meant by these terms?

Strictly speaking, a eukaryotic cell harbors a nuclear membrane that surrounds an internal nucleus. The nucleus resides inside the cell of the eukaryote, surrounded by the cell’s cytoplasm. The term eukaryotic means the true nucleus. The nucleus, in turn, harbors the cell’s chromosomal DNA contents of a cell’s genome, plus associated proteins involved in, for instance, nucleic acid synthesis, regulation of gene expression, and in chromosomal DNA packing, among other constituents. In general, organisms that are eukaryotic in nature are considered to be higher organisms, i.e., higher than, let’s say, prokaryotes, which do not harbor such cellular nuclei. Such prokaryotes include the bacteria and the archaea.

Dr. Edelman’s contributions to this eukaryotic field include his findings related to transcription, i.e., RNA synthesis, and to translation, i.e., protein synthesis. The Edelman laboratory was key to making new DNA promoters that helped to enhance gene expression, i.e., turning on transcription and translation of DNA-based genes. The DNA promoter elements encoded so-called ribosome binding sites that when transcribed into RNA, the ribosome binds this RNA site in order to facilitate greater translational efficiency.

This work has become of major importance within the newer bioinformatics-based discipline of proteomics, which deals with the entirety of the protein collections within a cell, or a tissue type, or of an entire living being. Dr. Edelman’s work with eukaryotic molecular biology is also of fundamental importance to genomics. The research study of genomics is concerned primarily with genomes and their relationships to their evolution, function, and structure, including the physical mapping of the genes harbored with the genomes.

8) Why study antibody structure?

The short answer to your question is if one knows the structure of a molecule, then one may also understand its function. While this tenet may not be applicable to all molecules of known structure, it is most certainly true in the case of the antibody structure. The antibody is a central player in the overall immune system. The antibody forms the basis of the so-called humoral immunity. One of the four humors, originating from ancient medicine, is blood, and antibodies are made by plasma cells which can reside in the blood. Later on, these humoral factors, the antibodies, were known also as Bence-Jones proteins, then later as antitoxins, and more recently as immunoglobulins.

In the natural world, antibodies confer immunity, i.e., protection from a second exposure to a possibly pathogenic antigen, after having been exposed to the antigen the first time. Knowledge of antibody structure and its mechanisms of production can be used also to produce certain antibodies with highly precise binding sites for certain antigens of interest. Such highly specific antibodies can, in turn, be used to detect and purify these interesting antigens for further study.

Interestingly, the number of antigens, these so-called non-self-entities, is vast. They can number into the billions, and yet our genetic programming, with only a mere approximately 33,000 human genes, has the capability to produce precisely specific antibodies that, on the whole, can recognize and bind to virtually any or all of these countless antigens! Thus, one type of molecule, the antibody, has this astonishing heterogeneity.

As mentioned above, the Fab portions of an antibody, whether intact or in fragments, can bind to antigens in a precise manner. The antigen-binding sites of the Fab are made up of both light and heavy chains, and each Fab section is thus variable in their structures in order to accommodate their binding specificity to the vast array of available antigens. In theory, every antibody molecule is unique for a given antigen, and one basis for this astounding heterogeneity is the variable sections inherent in the Fab segments of the antibody.

Such antigen binding by the Fab sections of an antibody serves to neutralize the potentially pathological effects of the antigens. Some Fab parts of the antibody can participate in actually oxidizing bound antigen, resulting in their destruction. The Fab part can undergo an agglutination process, which can, in turn, be exploited experimentally to determine, for instance, one’s blood type, or to diagnose an infection, or even to detect tumors. Yet, with such extreme variability in their mode of antigen binding, the same molecule has retained a remarkable consistency with its other parts!

The Fc part of the antibody structure is amazingly conserved—it is considered constant. Furthermore, the Fc has its own set of functions associated with it. For example, the Fc directly participates in inducing inflammation, enhancing phagocytosis, turning on the complement cascade, recruiting natural killer cells against cancer or virus-infected cells, and helping an antibody from a pregnant mom cross her placenta in order to confer passive immunity to her baby in utero.

In summary, the antibodies will continue to be of remarkable importance to the worlds of immunology, protein biochemistry, and biomedical science. The relevance of the antibody will most definitely be a long-lasting one. It is my opinion that biomedical scientists are only beginning to tap the marvelous potential of these antibodies.

9) The study and control of cell growth- why is this important in the big scheme of things?  

All living cells grow to various extents. Some cells can become specialized in their functions, perhaps to produce certain biomolecules for immunity, or to produce necessary hormones and other communication-based molecules, etc. Even single-celled organisms will grow, producing more numbers of cells. Cell growth is a basic life process. Certain cells with desirable functions, such as synthesizing needed molecules can be encouraged to grow extremely efficiently in order to maximize production of important products. Such growth processes are important for biotechnology and in the cellular-based industries.

Normal cells will grow when it is necessary. Further, such normal cells will stop growing when required to do so. Living systems have developed sophisticated molecular mechanisms for controlling when to start and stop such cellular growth. This area is of great importance in the field of developmental biology, such as in producing an intact living organism from a fertilized egg.

On the other hand, certain cells, the tumorigenic type come to mind, may not permit themselves to be subjected to these normal growth control mechanisms. The tumors may consequently grow in an uncontrollable manner. Such uncontrolled tumor growth can lead to a potentially more serious type of cell growth, namely, that of the malignant kind. Malignancy involves the movement of parts of the overall tumor mass within the body to other parts of the same body and resulting in abnormal cellular functioning. Interruption of normal cellular functioning by malignant tumor masses can not only be detrimental, causing morbidity but can also be deadly. Therefore, circumventing malignancy, by studying cell growth control systems, is a crucial goal of cancer biology research, an important field within the biomedical sciences.

10) What have I neglected to ask about this great scientist, investigator and Nobel Prize winner?

Dr. Edelman’s body of scientific literature is immense, having published over 500 articles in the technical journals. He also penned numerous popular books, many of which dealt with the functioning and evolution of the nervous system.

In an interview, released as a series of the so-called Web of Stories, Dr. Edelman relates many aspects of his life, complete with many delightful anecdotes that are not covered here. I highly recommend that our readers spend the time to watch these enjoyable, if not humorous, stories!

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