An Interview about a Nobel Prize Winner AND U.S. National Medal of Science

Sep 2, 2019 by

David Baltimore

Michael F. Shaughnessy –

1) Professor Varela, we have heard the term “Renaissance Man” many times, but I daresay that David Baltimore seems to be the closest thing to a Renaissance man living today. Let’s start at the beginning- where was he born and where did he go to school?

Dr. David Baltimore was born in the city of Manhattan, New York, U.S., on the 7th day in the month of March, in the year 1938, to parents Richard and Gertrude Lipschitz Baltimore. His father, a manufacturer, was Orthodox Jewish and raised David to practice the faith. Young David and his brother, Bob, were strongly encouraged by their mother to become physicians. She was a degreed psychologist and professor housed at Sarah Lawrence College, a private liberal arts institution located in Bronxville, Yonkers, New York. She is described as being a mother who was devoted to the education of her two progeny. In later years, Dr. Baltimore attributed his love of biology to his mother, who was among the first people to introduce the topic to him as a child.

The family lived in various suburbs of Queens such as Rego Park and Forest Hills. David was enrolled in elementary and high schools in Great Neck, NY, where he performed quite well in the topics of mathematics and science. In his junior year at high school, Baltimore enrolled in a summer research program at the Jackson Laboratory, in Bar Harbor, Maine, in the U.S. It is in this special program, in 1955, that David met a university senior named Howard Temin who was to serve as a peer advisor to the younger high school students and who would also become a co-Nobel Laureate with Baltimore in later years.

Temin’s influence upon Baltimore was profound. Because Temin had been a senior student at Swarthmore College, it was one of the key factors in Baltimore’s decision to enroll in the same institution upon his subsequent graduation from high school. Another key factor was Baltimore’s mother who was also keen in his decision to give Swarthmore a college try, as she had had longtime friends who were on the faculty, and they had provided a positive assessment of the college.

Thus, after high school graduation, Baltimore enrolled at Swarthmore, located in Philadelphia, Pennsylvania, in 1956, focusing his studies on the field of Biology and then later in Chemistry, so that he could perform a senior research thesis project. He graduated from Swarthmore College in 1960, having taken his undergraduate degree in Chemistry as his major while minoring in Biology, with the institution’s highest honors. While Baltimore derided his science education as second-rate, he nevertheless valued the liberal arts experience, developing a lifelong appreciation of music, art, literature, politics, and photography.

Upon gaining his undergraduate degree from Swarthmore, in 1960, Baltimore attended Massachusetts Institute of Technology (M.I.T.), but later moved to Rockefeller in order to study more closely animal viruses. The graduate work at Rockefeller was quite productive, dealing with viral replication, and Baltimore took his Ph.D. in 1964.

2) For college, he went to Swarthmore graduating with high honors in 1960. While some may not know it, Swarthmore is an exceptionally fine school, graduating many top notch scholars and researchers. Who did he study under there and who mentored him?

To put it succinctly, Baltimore’s undergraduate experience at Swarthmore was, in a word, adventurous. Baltimore had participated in several civil rights protests, as the college had had a low percentage of enrolled minority students at the time, and Baltimore and his fellow student protesters were demanding more progress on the integration process.

One of his adventures included the routine hiding of a forbidden car. Swarthmore college students were not allowed to have cars on campus. One of Baltimore’s college dorm buddies owned the contraband car, which was often concealed by being parked in neighboring streets and alleyways. The car-hiding system permitted them travel to Philadelphia’s pubs and Jazz clubs during weekends. The ruse worked for a while before the clandestine car was eventually discovered and banished.

Living in the Swarthmore dormitory, in Mary Lyons hall, Baltimore met new people about his age, many of whom became lifelong friends, such as Detmar Finke (the secret car owner), Lannie Rubin, Gil Harman and Peter Temin, who was Howard Temin’s younger sibling. You’ll recall it was Howard Temin’s influence that inspired the younger Baltimore to attend Swarthmore. The gifted and talented Howard Temin had already enjoyed a reputation as being of genius status while a college student. The college environment of Swarthmore during the time of Temin and of Baltimore has been described as relaxed and not terribly rigorous, academically-speaking. Thus it provided extra time for the pursuit of one’s intellectual interests.

During Baltimore’s first summer break from Swarthmore, after his freshman year, he had been invited to participate in a research laboratory at Mt. Sinai Hospital, where he studied under Bob Ledeen examining sea cucumbers. The purpose of the work had been to extract certain anti-tumor agents from the sea cucumbers. While his particular summer work was never published in a journal, the experience provided useful laboratory techniques which he would use in later years.

Enrolling in Biology courses, Baltimore found them lacking in their treatments of experimental and molecular biology. He had learned about these new fields as a member and later as president of the Swarthmore Biology Club. Worse, he found that no textbooks on the topic of molecular biology had been available at the time. This is likely due to the fact that molecular biology was a fledging field. Nevertheless, Baltimore went to the scientific journals, attempting to read primary papers on the topic, but found them teeming with unclear jargon. Therefore, Baltimore spent his spare time poring over review articles, which he found more understandable. The problem with this approach, however, was that the Swarthmore library contained few of the molecular biology-based journals. Thus, he spent lots of his time at the Bryn Mawr and Haverford college libraries, reading review articles on molecular biology, his primary interest.

He read about the works of famous scientists of the time, such as Drs. Joshua Lederberg, George Beadle, Edward Tatum, Frederick Griffith, Salvador Luria, Max Delbrück, Martha Chase, Alfred Hershey, Oswald Avery, James Watson, and Francis Crick, all early pioneers of molecular biology. Molecular biology became a lifelong passion for Baltimore.

One of Baltimore’s favorite courses was a Microbiology seminar, where papers dealing with molecular biology were examined closely. During these discussions Baltimore learned that he could get his hands on bacteriophages! The place to go was Cold Spring Harbor Laboratory, in New York. Thus, while back home on Easter vacation during his junior year of college, Baltimore borrowed his parent’s car and drove to Cold Spring Harbor Laboratory. There he became acquainted with investigators Drs. Helen Gay and George Streisinger. Impressed with Baltimore’s interest, Dr. Streisinger was glad to teach him the techniques used in working with bacteriophages, such as culturing Escherichia coli bacteria, the hosts of the widely used T4 phages, and the famous plaque assay, for culturing the phages.

Upon Dr. Streisinger’s suggestion, Baltimore, in 1959, took a summer research course later that same year in a program known as URPP (Undergraduate Research Participation Program), at Cold Spring Harbor Laboratory, and he was mentored by Streisinger himself. The URPP had been funded by the National Science Foundation. Not only did Baltimore benefit from the newfound technical knowledge of phage biology, he also had the opportunity to meet the authors of the review articles he had voraciously read: Drs. Watson, Delbruck, Luria, Hershey, etc. Additionally, Baltimore had the chance to attend the latest research seminars of many young and established investigators of molecular biology. These connections permitted Baltimore to be recruited to attend M.I.T. as a graduate student after graduation from Swarthmore.

During his last year at Swarthmore, working under the tutelage of Dr. Philip George, professor of chemistry, Baltimore conducted his senior research thesis project which entailed studying ATP chemistry and protein purification. While the work was not published, it nevertheless provided Baltimore with a biochemistry methods toolkit which he would later put to good use on the road to the Nobel.

3) Apparently he entered MIT and was known as somewhat of an innovative, brash, but brilliant student who perhaps approached the study of biology quite energetically and enthusiastically. What do we know about his early interests in phage genetics? (Then animal viruses.)

Indeed, Baltimore a newly minted graduate student at M.I.T., quick acquired his brash, but brilliant and innovative reputation. In 1960, Baltimore moved to Cambridge, Massachusetts, to enter graduate school at the prestigious Massachusetts Institute of Technology (M.I.T.), focusing his studies on the topic of Biology. Having met Dr. Cyrus Levinthal, from M.I.T., while participating as an undergraduate in a summer program at Cold Spring Harbor Laboratory, in New York, Baltimore chose to work in Levinthal’s research laboratory. At first, he studied phage genetics, joining a project devoted to assessing whether a certain phage had one or more chromosomes and examining the amount of genetic information contained within the phage genome.

For his Ph.D. thesis project, Baltimore had instead decided to focus on animal viruses, that is, viruses that infect higher organisms. A major problem at the time, however, was that no faculty at M.I.T. had an expertise in the field of animal virology. Thus, Baltimore spent a summer at the Albert Einstein School of Medicine, studying the animal virology field in the laboratory of Dr. Philip Marcus and in a summer course at the Cold Spring Harbor Laboratory. Having been seemingly rejected by a brand new faculty member, Jim Darnell, at M.I.T. to study animal viruses, Baltimore thus transferred to Rockefeller University and entered the research laboratory of Dr. Richard Franklin, who had a laboratory devoted to the study of viruses that infect animals at the institution.

4) He moved to Rockefeller Institute in New York City- another quiet place of study, but one that produced many great discoveries and soaring staggering intellects. What did he study there? What is an RNA replicase and what did he do his Ph.D. on?

At Rockefeller, Baltimore concentrated on viruses that contained RNA as their genomes, such as influenza virus, Newcastle virus, and in particular the mengovirus, which infects mice. The synthesis of RNA had been detected in the cytoplasm of mice cells in culture but was lacking in the nuclei of the cell; it had been an observation made in the laboratory by a student intern, Jon Rosner. Following up on this observation, Baltimore reasoned that the viral RNA was synthesized by machinery that functioned in the cytoplasm, circumventing normal RNA synthesis machinery contained within the cell’s nucleus.

In late 1962, Baltimore decided the best approach was to purify the viral RNA polymerase, also called RNA replicase. It had been laborious, painstaking work. It was work that was also fraught with microbial or chemical contamination, either of which could easily confound any one of the many steps involved in the protein purification process.

During the course of his Ph.D. thesis work at Rockefeller, Baltimore managed, however, to make a startling discovery. He accumulated evidence for an RNA polymerase that needed RNA as a starting substrate, strongly implicating the presence of a protein that was an RNA-dependent RNA polymerase! Normally, according to the central dogma, RNA synthesis depended on DNA as a starting substrate. Baltimore was proposing that RNA could be made with RNA as a starting substrate. The notion in a sense had violated the central dogma! Nevertheless, Baltimore and Dr. Franklin published the work together, in 1962. In the end, however, he was not successful in completely purifying the elusive RNA replicase.

Satisfied with having discovered the presence of the mengovirus RNA replicase activity, although the purification of the actual protein would not happen for another 15 years, Baltimore nevertheless, moved on to another project while a Ph.D. student at Rockefeller. He turned his attention to another RNA-based virus, namely that of poliovirus, the causative agent of the potentially harmful poliomyelitis in humans. At the time, polio, as it was colloquially referred to, was wreaking havoc worldwide, causing severe outbreaks, with devastating consequences. Very quickly Baltimore was able to discover another RNA replicase enzyme activity in the poliovirus.

Following up on his poliovirus RNA replicase discovery, Rockefeller graduate student Baltimore and postdoctoral colleagues Drs. Igor Tamm and H.J. Eggers, next examined the effect of the poliovirus on the host cells, in this case the famous HeLa cells, with respect to the protein synthesis machinery. They found that poliovirus shut down HeLa cell translation and replaced it with a completely different poliovirus-directed mode of translation. The trio of investigators published three articles in scientific journals. It was ground-breaking work.

At about this time, an event occurred that was to change the direction of Baltimore’s education.

His graduate advisor, Dr. Franklin, had decided to leave Rockefeller, heading for a new post at Colorado. This constituted a unique and unprecedented problem for Baltimore. The choice was to either follow Dr. Franklin to his new location or graduate somehow with his Ph.D. thesis as it stood. Because of Baltimore’s work ethic, he had already accumulated 4 papers worth of data, certainly enough for a Ph.D. The problem, however, was that Baltimore had been at Rockefeller for only 18 months, which was considered by the university insufficient time for a proper Ph.D.

Rather than choosing to “write slowly” his thesis for a few additional years and bide his time, he simply left Rockefeller, in 1963, and headed for a postdoctoral position at M.I.T. to work under Dr. Jim Darnell. It is recorded that Dr. Baltimore was granted the Ph.D. from Rockefeller in 1964, which was a couple of years after he had already left the institution for postdoctoral training.

5) He later studied with Jerard Hurwitz at the Albert Einstein College of Medicine- delving into virus replication and studied enzymology- for the uninitiated, could you first tell us exactly what enzymology is?

Briefly, enzymology is the study of enzymes, which are proteins that catalyze biochemical reactions in living beings. Enzymes work by binding to a dedicated substrate to conduct a chemical reaction upon the substrate, producing a product at the end of the biochemical process. The enzymes will conduct their particular biochemical reactions repeatedly, performing the same reaction over and over, a result of their catalytic activities. Thus, the enzymes can function efficiently over time, producing a high concentration of product from their substrates.

The enzymes in biological systems also permit chemical reactions to proceed without the requirement for the extremely high temperatures that are typically needed for conventional chemical reactions in a scientific laboratory. The enzymes can function at relatively lower temperatures, like 37°C, normal body temperatures, such as those seen in humans and other animals. Thus, the enzyme activities allow living beings to conduct their needed biochemistry reactions without being also burnt to death in the process!

In 1964, at the Albert Einstein College of Medicine, in the Bronx neighborhood of New York City, Dr. Baltimore took on a postdoctoral position working under the supervision of Prof. Jerard (Jerry) Hurwitz. Interestingly, it was at about this time that Baltimore’s Ph.D. degree arrived in the mail, after having been a postdoctoral fellow for several years at M.I.T. in Cambridge, MA. Dr. Baltimore’s interest in learning enzymology had been based on his earlier work with the RNA replicase enzyme, which he had not yet purified. He had nevertheless already determined the conditions for RNA synthesis, in Dr. Darnell’s M.I.T. laboratory.

At the Einstein College of Medicine, Dr. Baltimore in particular had had an interest in the enzyme responsible for making DNA, a protein called DNA polymerase. After several months of work, his efforts to determine for the first time in history the necessary conditions for the initiation of DNA synthesis had failed. In an effort to make the starting conditions known, Dr. Baltimore played with various temperatures, with various concentrations of substrates, the nucleotides that were supposed to come together to make DNA, with various pH levels, etc. He could not get his experiments to start making DNA. All of these laboratory efforts had led nowhere.

During these difficult times, Dr. Baltimore had taken sanctuary in Dr. Darnell’s laboratory, now housed at the Albert Einstein College of Medicine, having moved there from M.I.T., studying the poliovirus, an effort that ultimately led to the publishing of a small number of papers in journals. Thus, Dr. Baltimore was able to establish a certain level of productivity even in uncertain times with his other failed DNA experiments.

Thus, Dr. Baltimore turned his attention to the synthesis of RNA, likewise, focusing on the initiation of the synthetic process. Dr. Baltimore was able to add some purified RNA polymerase enzyme that he had borrowed from one of his colleagues in his boss’s laboratory, plus some borrowed substrates, which consisted of radioactively labeled ribonucleotides. The new effort proved successful. With a brief row about who deserved the most credit for the discovery occurring between the three investigators, they agreed to share authorship of the publication.

Though Dr. Baltimore had failed to learn the secret to initiating DNA synthesis, the mystery was indeed solved in later years by others. The problem had been that during the reaction mixture, Dr. Baltimore had been unaware (as had every other scientist up to that time) of the reaction’s requirement for RNA! During DNA synthesis, RNA was found to be needed as primer. RNA was another requirement, and, in fact, the term is now referred to as an RNA primer. RNA as a primer was needed in order to make DNA. It was, perhaps, evolution’s way of maintaining the biological relevance for RNA once the ancient RNA world gave way to the new DNA world of life.

Interestingly, it was at about this time that Dr. Baltimore learned of a new opportunity to work with the great scientist Dr. Renato Dulbecco, who was soon to move to the newly constructed Salk Institute, housed in the city of La Jolla, in California. The new institute was established in honor of the famous Jonas Salk, who had developed the extremely useful polio vaccine.

Thus, in 1965, Dr. Baltimore cut short his enzymatic misadventures at Albert Einstein College of Medicine and moved to southern California, taking his brand new wife, Sandra Woodward, with him. Unfortunately, the marriage to Woodward was short-lived.

6) Another career move followed to the Salk Institute for Biological Sciences in La Jolla California- what happened there?

Dr. Baltimore and his wife Sandra moved to La Jolla, CA, in order to purse a research associate position under Prof. Renato Dulbecco, who in 10 years’ time, would win the Nobel along with Drs. Baltimore and Temin. The new post would provide some freedom for the first time to pursue his own independent line of biomedical research.

Dr. Marc Girard, whom Dr. Baltimore had recruited as his very first postdoctoral fellow to come to the Salk Institute, had studied the process involved in the synthesis of RNA in the poliovirus. Soon Dr. Baltimore hired his first graduate student, Michael Jacobson, to advise directly while starting out at the Salk Institute. Dr. Baltimore hired another postdoctoral fellow, Dr. Alice Huang, originally from China, but fresh from earning her doctorate at the prestigious Johns Hopkins University, having studied the vesicular stomatitis virus. Jacobson was charged with examining the synthesis of protein in poliovirus, and Dr. Huang was charged with studying the interplay between the poliovirus itself and its host cells.

In 1965, an interesting episode occurred at the Salk. It had to do with the overabundant production of live poliovirus necessary to study its protein synthesis and cellular infection. Other investigators at the Salk grew nervous at the thought of live and potentially infectious poliovirus being produced in great quantities in the Baltimore lab. Even though all of the personnel at the Salk Institute had been dutifully vaccinated against the dreaded polio, many at the Salk nevertheless personally knew of someone who had previously contracted the serious paralytic form of the disease, and they were somewhat jittery of the poliovirus work coming out of the Baltimore lab. Furthermore, they regularly made their concerns known. To make matters worse, these concerns were present in light of an outbreak that had occurred, in 1962, involving a poorly produced batch of the polio vaccine. Dr. Baltimore had lamented that his Salk colleagues, most of whom studied phage biology and who knew little of animal virus biology were unnecessarily nervous.

The studies conducted in the Baltimore lab nevertheless were fruitful. First, they discovered that during protein synthesis in poliovirus-infected cells, the viral protein was produced as one giant polypeptide, with all of the inherent viral proteins attached to each other in tandem. The giant polypeptide, once it was complete, would then be broken up into various smaller pieces, each piece constituting a functional viral protein, making as many as 10 new fully functional poliovirus proteins. It had been an amazing discovery of a quite remarkable mechanism for protein synthesis. No one else in the world had ever seen such a similar ground-breaking discovery.

With Dr. Baltimore’s scientific life producing wonderful results with a terrible virus, his personal life was becoming a shambles. He had become involved in more political and anti-Vietnam War protests, and his wife’s art show had been unceremoniously shut down due to an offensive display involving the U.S. flag; his marriage to Woodward was at an end. To make matters worse, a job interview at Harvard had been a disaster, having failed to get along with the departmental chair, and as a consequence, no professorship offer would be forthcoming from Harvard.

In despair, Dr. Baltimore made a phone call to his longtime friend Dr. Salvador Luria, who then made arrangements for Dr. Irwin Sizer from M.I.T. to readily make a job offer to Dr. Baltimore. In 1968, Dr. Baltimore moved to M.I.T. to become a new associate professor of Microbiology.

7) Way above my head- he studied proteolytic processing in the synthesis of eukaryotic proteins- why is this important to understand?

The process you speak of is of tremendous interest to protein biochemists, molecular biologists, and virologists alike. The so-called proteolytic processing during eukaryotic protein synthesis has to do with the discovery that Dr. Baltimore made while he had been at the Salk Institute. It involved a newly discovered protein synthesis mechanism that no other scientist in the world had ever known about.

In short, the process involves the making of one large protein, called a polypeptide, which is made during the translation of poliovirus. The large protein is then cleaved into pieces, i.e., proteolytically processed. It is called as such because various other proteins are involved in breaking down of the large protein into several smaller proteins, each of which in turn can function.

As you may have deduced, the poliovirus harbors an RNA-based genome. But what may not be known is that the RNA genome is covered by a gigantic protein, called a protein coat or a capsid. The viral capsid is a macromolecule, and it is made up of a large number of small proteins. The poliovirus virion (i.e., intact mature virus) is also made up of a number of other proteins in its viral structure, and it has other functional proteins that are needed for other purposes, such as infection of host cells, especially cells that constitute brain neurons.

The virus has solved the problem of having to make one massively huge protein supra-molecule to cover its RNA genome, which, by the way, is way too small to accommodate a giant sized gene that would be needed encode such a supra-protein anyhow. The solution to the problem (not enough genomic RNA from which to make a supra-sized capsid molecule), as invented by the poliovirus, and as discovered by Dr. Baltimore, is to simply make as big a protein as it can, and then cut it into smaller proteins. The smaller proteins can be used inside the host neuron to assemble into the larger viral capsid, like stacking small bricks to construct a large wall—only the protein wall covers an RNA genome in the poliovirus. Other smaller proteins can help perform other needed duties for the complete virion to manifest itself in large numbers.

The process invented by poliovirus and discovered by Dr. Baltimore and colleagues is as follows. Viral RNA is used as a template from which to produce the giant protein using host neuronal eukaryotic translation machinery. The result is the production of an unprecedented large macro-sized protein, called a polyprotein precursor, consisting of three domains called P1, P2, and P3. Then, the proteolytic processing takes place. This involves the cutting of the polyprotein precursor by protease enzymes into two smaller pieces, called P1 and P2-P3, the latter of which has the two domains, P2 and P3 still attached, but with the P1 piece becoming a separate entity. The breaking up of the large proteins into smaller sections is referred to as the proteolytic processing.

Next, P1 peptide is in turn broken down by protease enzymes into three smaller pieces called VP0 (for viral protein 0), VP1, and VP3. Then VP0 is further cut into pieces called VP2 and VP4.

Then, the still connected P2-P3 domain polypeptide is cut up by protease enzymes. The P2 domain is broken down into smaller portions called 2A, 2B, and 2C. On the other hand, the P3 domain is cut into two smaller parts, called 3AB, and 3CDpro. The 3AB protein is also called VPg, and it binds to the front end of the RNA genome, possibly serving a role in the initiation of RNA synthesis. The 3CDpro is further cut into 3Cpro and 3Dpol.

Each of these small end-point proteins harbors specialized functional viral proteins that help poliovirus infect a brain cell. For instance, the VP1, VP2, and VP3 proteins assemble together like toy Legos to make the capsid outer covering, to protect the poliovirus RNA genome on the inside. Interestingly, some of the proteases that cut up the viral proteins into their smaller fragments are themselves a part of these protein pieces. These latter proteases are 2Apro and 3Cpro. This amazing viral process for infection is regularly included in textbooks of molecular biology and virology.

8) His wife Alice S. Huang worked with him at MIT and a grad student at the time, Martha Stampfer uncovered that VSV involved an RNA polymerase in the virus. Why is this important and what is it all about?

Dr. Baltimore’s second wife, Dr. Alice Huang, was the second postdoctoral fellow to be hired to work in the Baltimore laboratory at the Salk Institute. She was born in Nanchang in Kiangshi, China. For her graduate work at Johns Hopkins, Dr. Huang had studied the mode of cellular infection by the so-called vesicular stomatitis virus (VSV). The VSV was a causative agent of a notorious disease in cattle. When Dr. Baltimore accepted a new post at the M.I.T., in 1968, Dr. Huang accompanied him. As a newly minted associate professor at M.I.T., Dr. Baltimore hired his first graduate student, Ms. Martha Stampfer, in 1969. Together, the Baltimore-Huang-Stampfer research team decided to examine a so-called “interesting property” of the VSV, an endeavor that would ultimately lead to the Nobel Prize.

The property of interest was that the VSV microbe had an RNA genome that was negative- or anti-sense. That is, the RNA strand that made up the VSV genome was of the complementary sense to a normal positive- or sense-strand that was typical of the poliovirus genome or of the RNA found in humans and other animals. It posed a problem if one was interested in knowing how the VSV genome replicated itself when infecting host cells.

One could argue that the RNA polymerases found in human and animal cells are all of the so-called DNA-dependent kind, that is, that they needed a DNA template as a starting substrate. Thus, the VSV obviously required an RNA-dependent RNA polymerase in order to produce a positive-sense RNA product from the negative-sense RNA template strand. It then stood to reason that the VSV virion must harbor just such a bizarre enzyme. That is to say, the VSV must carry inside its capsid a so-called RNA replicase, which could make a positive-stranded RNA product by reading the negative stranded RNA viral genome. This notion made sense because no animal cell known to mankind had hitherto (or since) been found with an RNA-based RNA replicase. Thus, the virus itself must carry it!

The trio of investigators had heard about a new theory that had been proposed by Dr. Howard Temin, Dr. Baltimore’s good friend from the Cold Spring Harbor days. He had proposed that such viruses, with their positive sense RNA genomes, integrated into the DNA-based genomes of their hosts, thus, implicating a DNA intermediate nature for viral RNA genomic replication, thus contributing to the host cancer causing result. In order to make this hypothesis tenable, Dr. Temin had thus proposed the idea of a so-called RNA-dependent DNA polymerase, which was believed to require RNA as a starting point for the production of viral DNA. He was proposing the reverse of transcription, i.e., RNA being converted to DNA! He even had provided some preliminary experimental evidence to support the idea.

The implications were enormous; it suggested that RNA viruses, in making more RNA, would go first through a DNA intermediate, strongly implicating the notion that there must also be a reverse of transcription, i.e., a reverse transcriptase! Needless to say, Dr. Temin’s idea was widely and quite vigorously criticized, especially if reverse transcription by viruses somehow also involved carcinogenesis.

The idea for viral genomic integration into host genomic DNA was not entirely farfetched. Dr. Allan Campbell had hypothesized just such a phenomenon for a bacteriophage called lambda (λ) and its viral genomic DNA insertion into the genome of its dedicated host Escherichia coli. In fact, Dr. Renato Dulbecco, future co-Nobel Laureate, was eventually to provide evidence demonstrating integration of oncogenic viral DNA into host genomic DNA.

Nevertheless, Dr. Baltimore decided to test the idea that had been hypothesized by the brilliant Dr. Temin. The Baltimore laboratory at M.I.T. examined the insides of the VSV and of the Rous sarcoma virus (RSV), another RNA-based virus with an RNA genome, and they found a DNA polymerase enzyme in both viruses! They quickly wrote a manuscript describing the historic discovery and sent it to Nature. Next, Dr. Baltimore called Dr. Temin on the phone and told him of the shocking news: a tumor-causing RNA virus harbors a DNA polymerase inside of it! What Dr. Baltimore didn’t know at the time of the phone call was that Dr. Temin had already discovered the same sort of thing, telling all who would listen at a scientific conference only days prior to the call—he had yet to write the paper on his discovery. Another phone call was made, this time to the editor of Nature, so that each of the investigators could publish their respective works in the same issue of the journal.

They would share the discovery of the famous reverse transcriptase! It was a discovery that altered the course of history for all concerned molecular biologists.

9) Please tell us about Rous sarcoma virus- and its importance and his involvement with this….

The Rous sarcoma virus has its scientific roots embedded in 1911 the studies of Dr. Peyton Rous, who had provided evidence that the virus was associated with causing solid tumors of the cancerous type within laboratory chickens. This finding, a viral causation for cancer, led to an ultimate understanding of the cellular and molecular bases of cancer in modern times. The biology of cancer is now a large, complex, ongoing field of contemporary study. Dr. Baltimore’s contributions to this field consist of three fundamental principles.

First, he discovered a DNA polymerase enzyme packaged inside of the intact virion of the Rous sarcoma virus, which had an RNA genome. Second, his virology work led to the development of a virus classification scheme based on their modes of transcription and genomic nucleic acid replication. In fact, the scheme is called the Baltimore classification of viruses, and it is gathering widespread acceptance amongst the virologists.

Third, Dr. Baltimore’s studies led to the use of Rous sarcoma virus as a molecular tool for other studies. One prime example of this type of study involved the so-called insertional activation mechanism for generating new tumors. In this system, the Rous sarcoma virus was used to insert its genome into the genomes of host cells, thus breaking the genes encoding cellular “off-switches” for cell growing functions. The Rous sarcoma virus genome would insert itself into the middle of these checkpoint genes, keeping them from preventing cell growth when they were supposed to and, thus, allowing unchecked cellular growth, i.e., tumorigenesis. Such an insertional activation mechanism has been thought to have played a role in an unwanted induction of leukemia after gene therapy had been used to treat a certain genetic disease. It had been a terribly unfortunate incident, and it set back the progress towards genetic disease treatment. The incident meant that biomedical scientists and clinicians had to go back to the drawing board and learn more immunology and virology.

The Rous sarcoma virus was used to test the notion that during tumorigenic transformation of normal cells into potential cancer cells that such tumors and cancers lose an important property called contact inhibition. That is, when normal cells grow, they then later stop growing when they have made physical contact with neighboring cells in culture. On the other hand, cells that are transformed by Rous sarcoma virus continue growing despite making contact with their cellular neighbors. Such tumors simply pileup into large masses of clumped cells, having lost their contact inhibition property.

Later studies by 1989 Nobel Laureates Drs. Harold Varmus and J. Michael Bishop showed that the loss of contact inhibition is due to a Rous sarcoma virus gene called src, which is a rather famous gene amongst molecular biologists, virologists, biochemists, cancer biologists and biomedical scientists. The name “src” was derived from the sarcoma name of the virus. The src gene is known to encode a protein tyrosine kinase enzyme, which in normal cells is referred as c-src. It was also a good proto-oncogene in the sense that its gene product, a protein called c-Src, dependably halted cell growth, when it was supposed to. The “c” in the c-src gene and the c-Src protein stands for normal cellular functions. The growth of normal cells was regulated by the c-Src protein. On the other hand, the oncogenic version of the src gene, a mutated variant, called v-src did not regulate cell growth. The “v” in v-src and v-Src stand for virus, having been discovered residing within the genome of the famous Rous sarcoma virus.

10) What was the big idea or central dogma of genetic theory that Baltimore overturned?

The central dogma, the big idea, known now in modern times as the flow of genetic information, refers to the direction of the genetic information stored in genomes of all organisms. The central dogma term is an historical expression meant to denote that fact that early molecular biologists brazenly believed in its basic tenets despite an obvious lack of evidence to support the notion, i.e., a dogma. The expression “central” takes its meaning from the idea that the genome made up of DNA is central to life, the blueprint for conferring life and in maintaining it through the generations.

In the central dogma scheme, the genetic information is stored in DNA, and it is replicated into another DNA copy, which is then sent to the next generation of individuals. Furthermore, the genetic information in DNA is also transcribed into an RNA form, making RNA as an intermediate. The genetic information now in the form of RNA is then translated into protein, which in turn direct the cellular and molecular functions of living beings. In this scheme, direction of information flow was clear: DNA → RNA. This was the very basis of transcription, RNA synthesis.

Drs. Temin and Baltimore were now asserting that genetic information was flowing in the opposite direction, i.e., RNA → DNA! It was the REVERSE of transcription! Their very notion of a reverse transcription had violated the direction of information flow inherent within the central dogma itself. It deeply upset virtually all of the molecular and cellular biologists. Drs. Temin and Baltimore had committed a scientific heresy of sorts.

In the end, we know now, of course, that the experimental evidence in favor of reverse transcription is overwhelming. But at the time, when it was published in 1970, it was heresy. Converts emerged, albeit slowly. The universal acceptance of reverse transcription was complete with the 1975 Nobel award to Profs. Baltimore, Temin and Renato Dulbecco.

11) Baltimore’s Nobel Prize (with Howard Temin and Renato Dulbecco) was for and I quote “for their discoveries concerning the interaction between tumor viruses and the genetic material of the cell.”  Why is this important?

The implications are huge. On the face of it, the connection between viruses, especially those causing tumors, and the biological elements of a regular cell, speak to their tremendous potential effects on all living beings on Earth. In this case, the Nobel is most certainly warranted. The discoveries by Drs. Baltimore, Temin, and Dulbecco have ramifications across all living beings.

First, the interactions between tumorigenic viruses and host cell genomes speak to the fundamental processes that occur in living systems. It speaks to life itself. The viral-host interaction is at the forefront between the life and non-life. Many scientists are actually uncertain whether viruses can be considered living microbes or non-living aggregates of complex molecules consisting mainly of nucleic acids and proteins. In any case, viruses are at the cusp of what constitutes life. A fundamental question that has moved many generations of scientists is “what is life?” In a sense, many biomedical scientists are just as fundamentally affected by such curiosities.

Second, viruses can cause cancers. Therefore, we need to know how they do so. Importantly, we must know how to stop these viruses and to prevent them from causing cancers in the first place. Such interests lead to serious effort in conducting biomedical investigations by scientists, trying to find anti-cancer treatments, such as chemotherapy, or immunology and vaccines, in an attempt to thwart the oncogenic onset before they take hold upon an individual.

Another ramification involves the use of the molecular biological information gleaned from studies involving the effects of viruses upon host cells. For example, the reverse transcription phenomenon now widely accepted by biomedical scientists, is actually routinely used in scientific laboratories worldwide as a fundamental molecular-based method. The reverse transcription is used to discern new genes that perform desired cellular functions, such as making products we need, e.g., medicines, vitamins, gasoline, plastics, bioremediation, etc.

The procedure of using reverse transcription, i.e., making DNA from RNA, to find new genes that conduct useful processes can be invoked as follows. First, cells that are performing the useful process, e.g., insulin making, can be grown, and their RNA harvested. Presumably, the cellular RNA represents the transcribed genes from DNA that encode the useful process, e.g., insulin making. Next, reverse transcriptase is used to convert the cellular RNA into a double-stranded version of DNA. The newly made DNA is often called copy DNA (cDNA). The cDNA is then cloned, sequenced, expressed into proteins, and the gene products purified. The products are then studied biochemically and examined functionally. The proteins can be tweaked by mutagenesis to perform the processes more efficiently. However the method is used, the new products can be produced readily and used clinically (insulin), or industrially, or biotechnologically, etc. The possibilities can be endless.

12) Along the way, Baltimore held a host of other administrative positions, leaving one to wonder how the heck he could have accomplished as much as he did- your final thoughts?

That is a most interesting question. I think that if we all knew the answer to your inquiry, biomedical scientists, and scientists all over the world, would be invoking these solutions straight away, attempting to make great discoveries and perhaps even garnering a Nobel for themselves. It is widely considered amongst scientists in general that a Nobel cannot be planned from the outset. As a college student, Baltimore and his fellow classmates, living in the Mary Lyons dormitory, at Swarthmore, spent many an evening and night discussing this very possibility. They reckoned that a Nobel could be garnered if one played their cards correctly. They played their cards, and it worked for Baltimore.

The young Swarthmore students deduced that it if one were to win the Nobel, it would require creativity that was spent at a very early stage in their research careers. This particular avenue was so important, in Baltimore’s mind, that in one of his premiere autobiographical reviews he specifically mentioned how. He wrote that when he received the Nobel, he was only 37 years of age. He had already been conducting research for approximately 14 years at the time. He was already a full professor, and he received his first NIH grant when he was only 28 years old. Today Dr. Baltimore has lamented that many of these hallmark’s in a scientist’s career come along many years later during one’s lifetime. The average first-time recipient of a grant from the NIH is approximately 42 years of age. Many principal investigators do not garner a tenure-track assistant professorship until they are well into their thirties. Dr. Baltimore specifically states that if more independence were given to biomedical scientists and at a much younger age, they might, too, benefit from their own creativeness and make great discoveries, just as well.

Another notion, noticed by Baltimore, was that he paid attention to the literature published by pioneers of molecular biology, for instance, he read review articles about great discoveries by their actual discoverers. He also met many of these early pioneers in person, and he learned a great deal about the art of conducting science from their examples.

The other issue inherent in your question, namely, that of how, with all the associated administrative duties, was Baltimore able to make so many distinctive and important discoveries. This is, not surprisingly, a more difficult question. Dr. Baltimore seemed to make it look easy. In many of Dr. Baltimore’s scientific investigations, however, he conducted more than one at any given time. Furthermore, he relied on back-up projects, many of which he conducted in laboratories of his friends and colleagues. He also relied upon many of the techniques, practices, and strategies that he acquired early on in his career.

Many Nobel laureates specifically state that luck played a major role in their discoveries. One has to be leery of such seemingly awkward attempts to be humble. The fact of the matter is hard work, insight, creativity, time management, being in the right place at the right time, learning from the examples of pioneers and other great scientists, funding opportunities, and, yes, a certain degree of luck, all certainly come into play when making great scientific discoveries happen. Such strategies that are geared towards the garnering of scientific success, and of a Nobel in particular, are tremendously difficult to plan ahead of time.

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