An Interview with Professor Manuel Varela: Tim Hunt and Cell Division and Cell Cycle

Oct 3, 2019 by

Sir Tim Hunt

Michael F. Shaughnessy –

1) First of all, Sir Tim Hunt (Knighted in England) was born in England- what do we know about his early life?

Sir Dr. Richard Timothy (Tim) Hunt was born on the 19th day of February, in the year 1943, in a small residential town of Neston on the peninsula called Wirral, located in the county of Chesire, near the famous city of Liverpool, England. Dr. Hunt’s parents were Katherine (Kit) Eva Rowland and Richard William Hunt. After the death of his father, and unbeknownst to Hunt, he learned that his father possibly had a particular role within the intelligence world of England, working at the World Service radio of the BBC, although the precise nature of this intelligence role is mostly unknown. Whatever role Hunt’s father played in this intelligence world, the secret was taken with him to the grave when he died, as he had no doubt signed the Official Secrets Act.

His father, starting in the year 1945, was based in Oxford, England, where he was a handler of Western manuscripts at Bodleian library, a collection known to be of great importance for medieval literature.

The kid Hunt was raised early on with a governess, who taught him Latin at his home, and the experience represents one of his earliest educational memories. Another early memory is of Hunt carting a pram (a baby stroller) towards a coal depot, watching large delivery vehicles getting stuck along the road during the snowy winter of 1947 and 1948.

2) Like the Beatles, he hailed from Liverpool- what do we know about his early life?

Liverpool was known at the time as a working-class industrial-based town. Hunt, in later years, recalled the food rationing that was pervasive during post-war (World War II) England. Prior to their move to Oxford, Hunt’s father had taken a lecturer (professor) position at Liverpool, England, until 1945, when Hunt was about two-years-old.

Hunt further recalled that when he was young, his father’s fellow faculty lecturers at the University of Liverpool, many of whom had expertise similar to that of his father’s, i.e., studies pertaining to medieval-based manuscripts, a discipline called paleography. Hunt related how generous his father’s colleagues were, providing food supplies that were in short supply during the post-war rationing of England. Since many of these generous medievalist lecturers were from the U.S., Hunt’s initial impressions of Americans was a most favorable one. It quite likely influenced his later decision to move to the U.S.

3) In England, for an excellent education- you go to Oxford. What transpired during his time there?

The first educational institution he recalled attending as a child, until the age of eight, was known as Oxford High School for Girls, where he stayed at the Infants Department on a daily basis. Next, he attended Dragon School, a preparatory boarding school, where he was taught Greek, Latin, English, math, history, and science. Regarding his science education, years later, he pointed out the instruction of an excellent teacher, Gerd Sommerhoff, who strongly influenced Hunt’s long-held interest in Biology.

Another area of interest was in cricket, but he recollected that he was not good at playing this sport. He also remembered that his grades in both math and history were less than stellar. Hunt attended these schools at Oxford until the age of 14.

4) He attended Magdalen College (I believe it is pronounced “maudlin”), and what did he study there?

In 1953, at the age of 14 years, Hunt moved to Magdalen College School, also located in Oxford, England. The school focused a tremendous amount of its curriculum on the sciences, such as chemistry, a course taught by an inspiring teacher named “Colonel Simmons.” In his laboratory-based courses, the students were given a certain degree of independence, and consequently, there were the occasional laboratory fires resulting from the flammable chemicals.

He enjoyed the school, developing further his interest in the biological sciences. One educational experience was spent apparently dissecting his brother’s dead rabbit, a situation that was actually warmly welcomed as it provided respite from the endless dogfish dissections. He also thoroughly enjoyed the evening guest seminars given by investigators who were also university faculty, as well as the so-called Christmas lectures, given at the museum at Oxford.

At Magdalen College School, Hunt flourished. He fondly recollected great treasures to be held there, such as the famous shrunken heads collection displayed at the Pitt Rivers Museum, at Oxford. There were dinosaur bone displays that held a fascination for him. He remembered with delight the fascinating guest lectures on topics pertaining to the discovery of the famous Kreb Cycle and to evolution, the latter of which was given as a tribute on the 100-year anniversary of the publication of the Origin of the Species by Charles Darwin. He remembered Nobel Laureate Dr. George Beadle having spent a year at Oxford as a guest investigator as asking him to provide a description of his Neurospora work that led to “one-gene codes for one-enzyme” hypothesis.

5) On to Cambridge- and what is termed “Clare College”- what was his time like there?

At the age of 18, Hunt moved to the University of Cambridge, in Cambridge, England, where he attended Clare College, a school believed to be as prestigious as those in Oxford. At Clare College, Hunt majored in the Natural Sciences, emphasizing in the burgeoning field of Biochemistry. He recalled one of his teachers, Dr. Sydney Brenner, who was to be a key figure in the establishment of molecular biology as a bona fide field of investigation. Hunt recollected that Prof. Brenner’s lectures were off-limits to the biochemists! Nevertheless, Hunt would continue to concentrate on Biochemistry and graduate with his undergraduate degree (B.A.) from Cambridge University in 1964.

Next, Hunt stayed on at the Biochemistry Department at Clare College, in Cambridge, for graduate school. His graduate advisor was Dr. Asher Korner. Hunt’s choice of prof. Korner, as a supervisor for his thesis project, was a fortuitous one, as Dr. Korner’s policy was total freedom in choosing a project, as long as it dealt with the synthesis of DNA, RNA, or protein.

Hunt decided on studying protein synthesis, also known as translation, as his Ph.D. thesis project. Towards this, Hunt focused on the synthesis of the blood protein called hemoglobin. He wondered whether the heme component of the hemoglobin protein was incorporated into the mature protein early or late in the translational process. Hunt also became interested in whether the ribosomes, i.e., protein-making factories, formed a crowed line of ribosomes along the mRNA transcript during translation even if the requisite iron was left out of the hemoglobin-making equation. He found that the ribosomes did not collect in a jam on the transcript; instead, the ribosomes stayed evenly spaced along the mRNA molecule during hemoglobin synthesis.

The findings were good enough for a doctoral project, and he successfully defended his graduate thesis. Dr. Hunt received his Ph.D. in 1968, from the University of Cambridge, at Clare College.

6) The New York-based College of Medicine at Albert Einstein University is a vast research Institute. Apparently, he worked there with someone named Irving London, working on hemoglobin. First, why is hemoglobin essential, and how does it fit into the big scheme of things?

The hemoglobin protein is essential for providing needed oxygen molecules (O2) to all of our living cells in the body so that it can remain alive. As humans are considered strictly aerobic, i.e., oxygen is an absolute requirement for life, the hemoglobin molecules in our red blood cells serve this essential life-role by providing this vital substance to the body.

Virtually all mammals on Earth require oxygen molecules for life. Without oxygen, our cells, tissues, and organs would start to die within a few short minutes. Thus, knowledge of the structure and synthesis of hemoglobin is crucial for our understanding of oxygen binding and transport to the living cells.

Hunt had met Dr. Irvin London in 1966 during a scientific conference about hemoglobin in Thessaloniki, Greece. Dr. London was chair of the Medicine Department and an investigator who was housed at the Albert Einstein College of Medicine in New York. Dr. London had been interested in the genetics of hemoglobin, and he had developed a so-called reticulate experimental system for studying hemoglobin. Hunt related a story about how he had invited himself to spend a summer in Dr. London’s laboratory, hoping to learn about the reticulocytes, which are immature red blood cells, and its associated program for measuring the synthesis of proteins, a process called translation. The “invitation” was accepted, and Hunt spent the summer of 1966 in New York, residing in an un-airconditioned dormitory and spending most of his time in the air-conditioned laboratory of Dr. London’s.

During that fateful summer, in 1966, Dr. London had invited Hunt to return as a postdoctoral fellow once he had completed his Ph.D. with Dr. Korner at Cambridge. Thus, with his newly minted Ph.D. in hand in 1968, Dr. Hunt moved to New York. At the Albert Einstein College of Medicine, Dr. Hunt participated in investigative projects dealing with the regulation of hemoglobin protein synthesis and working in the London lab with Drs. Nechama and Edward Kosower, they found that translation was prevented by oxidized glutathione (denoted as GSSG) in lysates of reticulocytes. Dr. Hunt recalled that the result brought him great joy because it was an idea that he had come about by himself. He also learned that the ion of calcium, Ca2+, was a necessary requirement for an enzyme called micrococcal nuclease and that this nuclease did not affect the rate of protein synthesis in the reticulocyte system if the Ca2+ was absent from the mixture. Working with Dr. Ellie Ehrenfeld and the nuclease as a digestor of RNA, it was discovered that double-stranded RNA molecules derived from poliovirus also inhibited the synthesis of proteins in Dr. London’s cell-free reticulocyte lysate system.

Dr. Hunt stayed at the Albert Einstein College of Medicine, in Dr. London’s laboratory, until late 1970, when he returned to Cambridge, where he continued to study the conditions for controlling the process of translation.

7) I have seen sickle cells, but what do we mean by immature cells? And why are they important?

I believe you are referring to the reticulocytes that Dr. Hunt and others were using for their experiments. The reticulocytes are immature red blood cells, and they make a suitable biological system for measuring protein synthesis. Their protein synthesis machinery was considered most efficient for measuring the effects of agents that could regulate the activities of translational machinery.

Furthermore, if the reticulocytes were used as a starting point, then these immature cells could be broken up into a so-called cell-free extract material called a lysate. The reticulocyte cell-free system exhibited a high rate of translational activity if certain experimental conditions were met, and translation could, thus, be readily measured.

Thus, Dr. Hunt and other investigators could focus on studying the rates of hemoglobin protein synthesis. The was this laboratory technique, the cell-free lysates of reticulocytes, that Dr. Hunt used to find out that poliovirus double-stranded RNA was potently inhibiting translation.

8) Woods Hole- Massachusetts and mitosis- (which we all study in high school biology) but refresh our memories as to mitosis and meiosis and what was going on in Woods Hole?

While the cell-free reticulocyte system had a perfectly suitable protocol for examining the regulation of translation, Dr. Hunt found out about a better system. It involved using fertilized eggs from sea urchins. The new system was introduced to Dr. Hunt at a scientific conference, in 1966, in which Dr. Henry Borsook, who was at Caltech, in California, gave a seminar about this novel system that he had developed earlier in the 1950s. Dr. Borsook had elaborated that his sea urchin egg system was perfectly suitable for examining protein synthesis.

Years later, after Dr. Borsook’s seminar, when Dr. Hunt had been at Cambridge, sea urchins, and their eggs, however, were not entirely available for biomedical studies. Thus, Dr. Hunt bided his time when he could get his hands on the desirable sea urchin eggs. The opportunity provided itself in 1977 when Dr. Hunt was offered the chance to assist in the teaching of a summer course offered at the Marine Biological Laboratory (MBL), located in the small town of Woods Hole, Massachusetts. The course was on the topic of embryology, but more importantly, the waters around Woods Hole were teeming with sea urchins and their eggs!

Thus, Dr. Hunt co-taught the embryology course, and in his free time collecting as many sea urchin eggs as he possibly could. With the sea urchin eggs in hand, he returned home to Cambridge to conduct protein synthesis studies. Unfortunately, the efforts with the sea urchin eggs failed to demonstrate a productive translational activity. It had been a terribly disappointing result.

The MBL at Wood Hole had its limitations at the time of Dr. Hunt’s first visit. The facilities were not terribly conducive to biochemical or molecular biological studies. The laboratories were mostly empty of essential equipment, such as deep freezers, for sample storage, or electrophoretic gel apparatuses, etc. The sea urchins had a terribly short fertilized-egg season with which to play around within the sparse laboratories. The next summer of 1978 was, thus, spent at home in Cambridge.

The vast array of excellent summer courses, however, and the exciting research being conducted at Woods Hole every summer with their daily seminars given by top-notch investigators in their fields, not to mention the allure of the nearby sea (beaches?), were all too tempting for Dr. Hunt to resist staying away for long. He returned to the MBL at Woods Hole in the summer of 1979, hoping to hone his skills learning cell and molecular and developmental biology. This time he brought the necessary laboratory supplies with him, and he made arrangements for a deep freezer to be available for his samples. While the progress with protein synthesis in sea urchin eggs was slow, Dr. Hunt did manage to discover a protein kinase, which was an important finding.

Another more critical development occurred for Dr. Hunt at the MBL during that summer of 1979 in Woods Hole. He attended a delightful seminar given by Dr. John Gerhart, in which Dr. Hunt first learned about the nuances of the cell cycle and its known mechanisms for control. Dr. Gerhart told of his troubles trying to purify a cell cycle-related protein, called maturation promoting factor, MPF. The seminar inspired Dr. Hunt to consider a biochemical approach to the study of the cell cycle. Dr. Hunt speculated that there might possibly be an enzyme that could catalyze the process of mitosis, working at the level of control with the cell cycle.

The insight made Dr. Hunt return to Woods Hole for subsequent summers. He became a fixture in the famous Physiology Course at the MBL. It was during the summer of 1982, however, that Dr. Hunt would make his Nobel Prize-winning discovery at Woods Hole.

9) The Nobel Prize- was apparently shared with two others- what did the three of them basically discover?

Dr. Hunt shared the Nobel Prize in Physiology or Medicine in 2001 with co-Laureates Drs. Leland (Lee) Hartwell and Sir Paul Nurse.

Dr. Hartwell’s primary contributions towards the Nobel involved his interests in the control of the cell cycle during the development of an organism. He discovered numerous genes and their corresponding proteins that are involved in this control process, such as the famous checkpoint protein, CDC28, which is necessary for directing the beginning stages of the cell cycle. He further showed that when DNA becomes damaged in any way, the cell cycle checkpoints come into play to halt its further progression.

Dr. Nurse’s main contributions regarding the Nobel concerned his discovery of the famous cdc2 gene in the yeast microbe called Schizosaccharomyces pombe. The cdc2 genetic element was discovered to regulate the progression of the cell cycle from the so-called G1 phase to the DNA-synthesizing S phase and from the G2 phase into the mitotic phase. Furthermore, Dr. Nurse was instrumental in discovering the human version of the gene, now called cdK1, which encodes the Cdk1 protein. The human protein is also known as a so-called cyclin-dependent kinase enzyme.

Dr. Hunt earned his Nobel Prize for having discovered one of the most famous proteins that cell cycle biologists and biomedical scientists have ever known, namely, that of the protein called cyclin. The experimental work was performed at the MBL during the summer of 1982.

The aim of Dr. Hunt’s 1982 work in Woods Hole was to examine whether any interesting patterns of protein synthesis could be discerned in fertilized sea urchin eggs during their cellular growth, a process called mitosis, which invokes the cell cycle. Dr. Hunt’s famous experimentation is briefly described below.

The investigational method involved first adding radioactively labeled amino acid called methionine to sterile seawater harboring fertilized sea urchin eggs. Periodically, at different time points, samples of the radioactive methionine-eggs mixture were removed, and the resultant protein levels were measured. The data were startling, if not puzzling.

With time, during cell division, the measured protein levels increased, and then surprisingly, at some point later in time, the protein levels simply went away! Dr. Hunt spent an afternoon trying to make sense of these results. Insight into the problem occurred that night at the weekly Friday Evening Lecture.

At the MBL, the Friday Evening Lectures have been a long-held tradition in which virtually the entire town of Woods Hole congregates in the grand auditorium of Lillie Hall to enjoy an excellent keynote lecture, followed by wine and cheese for students and, importantly, a unique chance to interact with the speaker and with fellow colleagues.

During the wine and cheese session that evening, Dr. Hunt learned from Dr. John Gerhart that Drs. Mike Wu and Marc Kirschner had, too, observed a new appearance of MPF protein activity was necessary for meiosis to start a new round of cell division between meiosis I and meiosis II. They had also found that if protein synthesis was inhibited, then the MPF failed to materialize itself again. These findings predicted that protein was degraded at first and that new protein synthesis was essential for the next stage involved in the cell cycle to manifest itself.

At this point, Dr. Hunt formulated his Nobel-Prize-winning hypothesis. He predicted the existence of cyclin.

Furthermore, he postulated that the presence and absence of cyclin had something to do with the behavior that MPF was exhibiting. Dr. Hunt observed cyclin to oscillate in its appearance and disappearance! Next, they examined other species, and cyclin did its oscillations in, for example, clams, just as well.

In 1986, Dr. Hunt’s laboratory cloned the gene that encoded the cyclin sub-unit B. The cloning of the cyclin A gene followed soon afterward. The cyclins have been a prime focus of study in many disparate fields, including biomedical science, ever since.

10) His later work in London focused on what makes cells go cancerous, or what makes cells go crazy—or am I off on this underlying causal factor in cancer? (I think the scientific term is “proliferate uncontrollably”? What did he find?

Dr. Hunt’s discovery of the cyclins had direct relevance to cancer. The cyclins are critical to the growth of cells. Thus, he began to focus on cancer biology research in the early 1990s when he had moved to Cancer Research UK London Research Institute, known then as the Imperial Cancer Research Fund. Tumor cells like cancer may “proliferate uncontrollably” in that such cells fail to stop growing when they should have otherwise. Normal healthy cells actually do stop growing when they are supposed to, while tumors, unfortunately, do not.

One of his first forays into cancer biology involved the study of a healthy version of a cell cycle control gene, a proto-oncogene called c-mos, which encodes a protein kinase enzyme. Dr. Hunt’s laboratory found that the C-Mos protein phosphorylates another essential protein called mitogen-activated protein (MAP) kinase, which in turn participates in a protein cascade system that regulates the cell cycle progression. The work led to the discovery of another critical protein called p38, which is a homologous member of the MAP kinase superfamily of related proteins. Dr. Hunt was also involved in the discovery of the so-called MO15 kinase protein, which in turn participates in the activation of mutated versions of Cdk2 and Cdc2 cell cycle control proteins. Thus, Dr. Hunt’s cancer biology work has dealt primarily with faulty cell cycle checkpoints, and specific breakdowns in the various steps within the cell cycle may lead to uncontrolled cell growth, causing tumorigenesis.

11) What have I neglected to ask about Sir Tim Hunt of Oxford? 

Dr. Hunt had recalled in later years that while he much enjoyed teaching his courses in Cell Biology and Biochemistry at Oxford, he nevertheless found that the process of learning was much more of an enjoyable task. At Oxford and at the MBL, he incorporated teaching with learning new aspects to the cell cycle, as well.

He wrote in a supplemental postscript to his Nobel speech that he felt rather fortunate to have met so many bright and talented investigators during the course of his career, especially at Oxford but also at the MBL in Woods Hole. In his speech he had given credit to many investigators, such as Drs. Joan Ruderman and Andrew Murray. This is an experience to which I personally can relate. When I had been a fellow of the American Society for Cell Biology (ASCB) at the MBL during the summer of 1991, I had the great fortune of meeting Drs. Ruderman and Murray, and I found both investigators to be extraordinarily brilliant and amicable.

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