Manuel Varela: Who were Carl and Gerty Cori and what was the Cori Cycle?

Oct 10, 2017 by

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An Interview with Manuel Varela: Who were Carl and Gerty Cori and what was the Cori Cycle?

Michael F. Shaughnessy –

  1. Professor Varela, in this interview we are going to talk about the Cori Cycle- but first, what do we know about the early days of this couple growing up in Europe?

Drs. Gerty Theresa and Carl Ferdinand Cori were a wife and husband team of scientific investigators who elucidated the so-called Cori Cycle of metabolism and shared the Nobel Prize in the scientific fields of Physiology or Medicine in 1947.

Gerty Radnitz was born on the 15th of August in the year 1896.  Incidentally, other sources report that she was born on August 8. Her parents were Otto and Martha Radnitz who lived in Prague, which was located within the so-called Austro-Hungarian Empire, as it was known at the time.  Today, the location is known as the Czech Republic. Gerty Radnitz was home-schooled during her elementary school years and was then admitted to a girls Lyceum in 1912. It was during this time-period that young Gerty was influenced to become a medical doctor by a relative (an uncle) who was also a medical pediatrician. In 1914, Radnitz entered medical school at the Charles-Ferdinand University, Prague, graduated with her M.D. degree from the institution in 1920, and married Carl Cori in the month of August during her graduating year. It was during her years spent in medical training where she and Carl had met.

Carl Cori was born on the 5th of December in the year 1896 to parents Carl Isidor and Maria Lippich Cori in Prague, in the Austro-Hungarian Empire. Young Carl was raised in the town of Trieste.  Carl entered medical school at the Charles-Ferdinand University (known today simply as Charles University, Prague) during the year 1914, the same year as Gerty.  He, too, graduated with his M.D. degree in 1920.

During post World War I years the young married couple encountered hardships, including starvation and anti-Semitism, even though Carl was Catholic and Gerty, though raised Jewish had converted to Catholicism when she married Carl.  Nevertheless, these adversities of early 20th century European life compelled them to move in 1922 to the U.S. where they worked at the so-called New York State Institute for the Study of Malignant Diseases, in Buffalo, New York, nowadays called the Roswell Park Memorial Institute.  The young married couple became U.S. citizens in 1928. In 1931, the Coris moved to Washington University, in St. Louis, MI, where they worked together until her untimely death in 1957, ten years after they had garnered the Nobel.

2. Now, I understand they were initially interested in many different realms of medicine. Let’s start with the pituitary gland- why were they interested in this particular part of the human body and its function?

The anterior pituitary, among many other functions, regulates a physiological pathway known as the adrenocortical system.  In this system, a hypothalamic hormone molecule called corticotropin releasing factor (CRF), also referred to in modern times as corticotropin releasing hormone (CRH), causes the release of ACTH (adrenocorticotropic hormone) from the anterior pituitary during stress or some other physiological stimulus. The ACTH then causes the hormone cortisol to be released from the adrenal glands, which then cause the conversion of glycogen into free glucose in the liver to mediate stress physiological and behavioral responses.

The Cori research team and their laboratory associates became interested in this so-called adrenal-pituitary axis in order to examine the role of insulin on glucose metabolism. At first, the Coris tested the hypothesis that insulin enhanced the utilization of glucose by circumventing the regulatory influence of the adrenocortical players within the adrenal-pituitary axis.

They had postulated that insulin had an effect upon certain sugar metabolizing enzymes in order mediate this bypass of the regulatory effect of the adrenocortical molecules.  Unfortunately, the idea was largely incorrect as it was found later that insulin instead mediated its effects by enhancing the permeability of glucose within rat muscle cells. Later, insulin was discovered to regulate the expression and subsequent activity of glucose transporters within the cellular membranes. This work by the Coris nevertheless established the importance of using purified cellular and molecular players in order to readily and effectively study important physiological cellular mechanisms.

3. Further, they seemed interested in insulin. What advances did they offer in that realm?

Insulin from the beta cells of the pancreas decreases the glucose plasma concentrations by the insulin-receptor pathway in cells from fat, liver and muscle tissue by mediating glucose uptake into cells, thus decreasing blood glucose concentrations. The Coris’ interest in insulin was in primarily how its effects on blood glucose levels were mediated by the hormone during the breakdown of the sugar storage form, called glycogen. There were many studies involving insulin throughout the years by the Coris and their laboratory students, postdoctoral fellows and collaborators. One notable finding was that insulin enhanced glucose uptake into muscle cells, presumably by affecting the rate of transport across the membrane by glucose transporter proteins.

The experimental studies of insulin by the collaborative Cori husband and wife team, however, had an appallingly troublesome start.

In his 1969 biographical and scientific memoirs published in the Annual Reviews of Biochemistry on the topic, Carl Cori related how the married couple encountered certain difficulties in their efforts to begin work collaboratively together on insulin.

The trouble started soon after Carl had applied for a new academic position in the mid-1920s.  He was told by the departmental chair that an offer would be made to Carl but under the following provisos:  1) he take English lessons to improve upon his speaking accent 2) he terminate all studies on insulin and that 3) he and Gerty not work together in order to conduct research. Carl had replied to the potential employer that he (Carl) was certainly happy to adhere to the speaking lessons, of course, but the other two demands were most certainly untenable. During the interview process in which the Coris had visited the unnamed institution, Gerty had been brazenly pulled aside by the hiring committee representatives and had informed her in no uncertain terms that she was an obstacle to her husband’s career and, furthermore, that it was considered un-American for husband and wife to work together. Considering all that they had already been through in Europe, her treatment in this altogether new way in a new country was arguably over the top—Gerty had cried tears over the incident.

Frankly, I find it difficult to believe that seemingly intelligent investigators could somehow understand complex biochemical and physiological concepts but needed external help in understanding foreign accents by requiring Carl to improve his speech, for them. Fortunately, for the good of science and the rest of us, the Coris declined the offer.

4. Epinephrine is a very common drug that many use. How did they get involved in what is today often known as the EPI-pin? And what were some of their insights?

The Coris’ scientific interests in the hormone epinephrine involved its relationship to the sugar concentrations in the blood; they had entertained the idea that somehow there was an influence to be had by epinephrine in the release of glucose molecules from glycogen stores and movement of glucose in the blood and in the formation of lactic acid. They had called the breakdown of the glycogen stores glycogenolysis, and it had been brought about by the epinephrine.

During the glycogenolysis process they observed that a sugar called hexose monophosphate was produced in frog and rat muscle tissue preparations after the administration of epinephrine. Epinephrine also regulates the synthesis of glycogen.  The Coris had followed up on the reverse of the physiological process in which the absence of epinephrine showed the disappearance of the hexose monophosphate with the concomitant appearance of inorganic phosphate and, importantly, of glycogen.

The Coris’ seminal studies on the biochemistry and physiology of epinephrine set the stages for the discovery of new insights involving the energetics of metabolism. Epinephrine increases the availability of the sugar glucose for biological energy by promoting glycogenolysis, i.e., the breakdown of sugar storage form glycogen into smaller molecules like glucose-6-phosphate.  The Coris purified a variety of sugars, like the glucose-6-phosphate and discovered a key enzyme, called glycogen phosphorylase that functioned during glycogenolysis. They also studied the kinetic behaviors of the enzymes.

Furthermore, the epinephrine hormone stimulates the metabolic pathway called gluconeogenesis (meaning new sugar made), a biochemical process involving the biosynthesis of new carbohydrates from metabolic intermediates, like, for instance, pyruvate.

Although the Coris’ work with epinephrine was primarily geared to the metabolism of the various forms of carbohydrates, their early work did lead to the later development of the hormone for many other metabolic and physiological purposes.  The Coris did not work directly on the development of the Epipen itself.  The basis of the Epipen is to provide the hormone during cases of anaphylaxis after a case of, let us say, an extreme allergic response to a potent allergen.  Such strong immunogenic responses can be deadly if not treated right away. The Epipen is supposed to provide a rapid dose of the epinephrine straightaway. Recently, the Epipen was involved in an embarrassing overpricing scandal by its prime vendor.

5. Now, what is glycogen storage disease and why is it important?

Sadly, at almost the very same time that the Coris received word in 1947 that they had gotten the Nobel for their important work of the Cori Cycle discovery, Gerty learned that she had a debilitating and fatal type of anemia, nowadays called myelosclerosis.  It was also about this time, incidentally, that Gerty began in earnest her new work on genetic diseases, such as the so-called glycogen storage diseases.

She was primarily interested in the sugar metabolizing enzymes that may be deficient in certain glycogen storage diseases. In the laboratory, Gerty studied various clinical samples of liver and other tissues from patients with assorted glycogen storage diseases.  She then purified glycogen from the clinical samples of human liver tissue and muscle tissues.

In one of these forms of glycogen storage disease, called Von Gierke’s disease, Gerty determined that the enzyme defect lay in an enzyme called glucose-6-phosphatase, which catalyzed the production of the sugar glucose out of the overall glycogen macromolecule taken from the clinical patients. Depending upon the extent of the severity of the Von Gierke’s disease, the enzyme was either reduced in concentration in mild disease or completely deficient in its levels in fatal cases.

Another one of these forms of the glycogen storage disease is characterized by a defect in the enzyme that de-branches glycogen during its breakdown.  The so-called glycogen debranching enzyme, named amylo-1,6 glucosidase, normally works at chemical bonds located at the branch points of the long glucose chains in glycogen, to release free glucose. Gerty had taken to referring to the enzyme as ‘The Debrancher.’  A defective debrancher enzyme resulted in a toxic buildup of glycogen in critical tissues, like the liver, cardiac muscle or in skeletal muscle.

In 1949, the Coris and colleagues were able to isolate the enzyme called phosphoglucomutase, which was responsible for producing glucose-6-phosphate from the substrate glucose-1-phosphate.  The enzyme simply moved the phosphate from carbon number one to carbon number six of the glucose molecule. The biochemical reaction is always included in modern biochemistry textbooks.

Gerty and her laboratory staff worked out how the glycogen breakdown works first with the glycogen phosphorylase, releasing glucose-1-phosphate molecules and then with the debranching enzyme to free up the glucose molecules that were tied up within the glycogen.

The glycogen storage disease type III, which was due to a defective or deficient debranching enzyme in patients, was renamed in Gerty’s honor as Cori’s disease.

They also purified the relevant glucose-1-phosphate, which later became known as the so-called ‘Cori ester.’

In studying another form of the glycogen storage disease, called McArdle disease, Gerty discovered the insight that in the patients’ muscle tissue the defective enzyme, glycogen phosphorylase, must be present in two forms as encoded by two distinctive genes within the human genome. She had been correct in her prediction of the presence of the two phosphorylase encoding genes.

As Gerty’s condition continued to worsen, she was unable to maintain her enthusiastic and exuberant energy that she had possessed for most of her life and was unable to walk without becoming too exhausted.  Carl actually used to carry her from location to location.  Soon Gerty had spent less time in the laboratory and stayed home more often, at which point Carl would stay home with her to care for her. Ten years after the Nobel, Gerty passed away on the 26 of October, in 1957.

6. And the Cori Cycle- what insights did they have about this mechanism?

The Coris were instrumental in discovering the Cori Cycle and in elucidating its mechanism of operation. In the cycle, the molecules glucose and lactate (known as lactic acid in some circles) cycle between skeletal muscle and the liver.  The Cori research team used adrenaline (i.e., epinephrine) to analyze the metabolism of glucose and glycogen to elucidate the mechanism of the Cori cycle. They studied what happens with these glucose and lactate molecules during extremely intensive muscle activity.

Individuals having undergone intense muscle contractions will continue to breathe heavily, even after the period of intense activity is over, thus using up a lot of the available oxygen in order to undergo a respiratory process called oxidative phosphorylation.  The oxidative phosphorylation system in living organisms is a process that shuttles electrons from foodstuffs to the respiratory chain to oxygen, which is the final electron acceptor; meanwhile, an energy charge, called a proton gradient, builds up, as the electrons are transferred along the components of the respiratory chain.  This so-called proton-motive-force is itself used as an energy source to make ATP, the main biological energy used by living organisms in order to live.

Next, the ATP formed by this intense biological activity is now used to carry out the process called gluconeogenesis, which makes more of the sugar glucose from non-sugar metabolic precursors, like oxaloacetate (an intermediate in the Krebs cycle) or pyruvate, the end-product of glycolysis.

Finding out what happens next to the newly generated glucose molecules in this process is the insightful knowledge conferred by the Coris—the Cori Cycle.

7. I understand they shared the Nobel Prize- what were they awarded the Nobel Prize with and for what imminent discoveries?

The Coris formulated the Cori Cycle in 1929, and it is this insight that earned them each a share of the Nobel Prize in 1947.  The Cori Cycle they discovered speaks to the physiological and biochemical cooperation that occurs between the blood, liver and skeletal muscle.

In the Cori Cycle, glycogen is used to undergo anaerobic glycolysis in order to generate the ATP energy that’s needed during intense activity produced by hard-working skeletal muscles, producing lactate as a result. Lactate molecules produced by the glycolysis in the skeletal muscle is then transported through the blood circulation to the liver, where the lactate is then used to make glucose using the gluconeogenesis metabolic pathway. In this gluconeogenic pathway, ATP in the liver is utilized to generate the glucose molecules. The newly made glucose leaves the liver and goes back via the blood to the muscle to resupply it in order to replenish the depleted glycogen stores during the recovery from the exertion.

In summary, during vigorous exercise activity, the Cori Cycle kicks in and involves lactate production from glycogen stores in the muscle; the lactate then goes to the blood to reach the liver, where it produces the glucose.  Next, liver glucose goes to the blood to move the sugar back to the muscle; then the cycle starts again by making muscle lactate, repeating the process.

The importance of the Cori Cycle lies in its purpose of supplying glucose sugar as a source of energy for muscle during exercise.

8. What have I neglected to ask?

Many hardships were encountered and endured by Gerty Cori throughout her life. I mentioned above the anti-Semitism she encountered in Europe and the inappropriate treatment she received by Carl’s interviewers during his application for a new post. These are, however, only the tip of the iceberg.

First, while a postdoc in Europe in 1920 after the Great War, food shortages were common, and Gerty had developed a condition known as xerophthalamia, characterized by a vitamin A deficiency and blindness. Fortunately, her condition had improved with a proper diet.

During their efforts to move to the U.S. in 1922, only Carl was able to make the migration, while Gerty had to stay behind in Europe, as there was no available research or academic post for her in the U.S. In those days, it was considered inappropriate for a married couple to be separated from each other for an extended period of time.

After six months of separation through no fault of their own, Gerty was finally able to join her husband already in Buffalo at New York State Institute for the Study of Malignant Diseases.  Gerty’s new post in the department of Pathology grew precarious, however, when she had failed to find any evidence of an Amoebic cause of cancer, her supervisor’s favorite but untenable theory. As a result, Gerty was threatened with a prompt dismissal unless she ceased working with Carl.

The same institute in New York, and probably many other institutions at the time, categorically frowned upon married couples collaborating together on work, and the Coris became a target of such a policy. A rare exception, however, was made for the Coris, and they began their extremely successful collaborative studies on the Nobel Prize winning Cori Cycle.

In addition to their work on sugar metabolism in cancer, Gerty had also conducted studies examining the effects of X-rays upon tissue, leading historians of science to speculate whether her exposure to X-rays contributed to her fatal anemia.

Prior to the Nobel, Gerty’s status was frequently on a sub-par basis compared to that of Carl’s. For instance, at the time it was often standard to include the names of expert research personnel  on letterhead stationary—Gerty’s name was omitted, despite their equal status within the Cori laboratory. In correspondence to the Coris, Carl was consistently addressed as ‘Dr. Cori’ while Gerty was frequently ‘Mrs. Cori.’  Her academic credentials were routinely ignored.

In another incident, a letter from an editor of the Journal of Experimental Medicine informing Gerty and her co-authors of the acceptance of the manuscript for publication, all authors were addressed as ‘Dr.’ except Gerty, who was addressed as ‘Mrs. Cori,’ even though she held a bona fide M.D. degree.

Even though Carl and Gerty Cori were a team and worked together as equals in their research laboratory, his career rapidly moved through the academic ranks and with much greater speed than did hers.  In fact, Gerty’s full academic rank as professor did not transpire until the Nobel, whereas Carl had been made full professor and departmental chair many years prior to the Nobel.

After receipt of the Nobel, the Cori research laboratory became a magnet for many excellent and eager young students wishing to study science under the Coris supervision. Many colleagues who were fortunate to have studied science in the Cori laboratory went on to have quite prominent careers of their own. For example, Arthur Kornberg, who earned a Nobel in 1959 for his discovery of DNA polymerase, attributes his success to the Coris’ glycogen phosphorylase enzyme, and not necessarily DNA base pairing, which led him to his discovery of the Nobel-winning DNA polymerase.

Others who were fortuitous enough to enjoy the training and inspiration of the Cori lab include the following Nobel Laureates: Christian de Duve, discoverer of sub-cellular fractionation technology; Severo Ochoa, discoverer of RNA polymerase, a key enzyme for transcription; Luis Leloir discoverer the role of sugar nucleotides in the synthesis of carbohydrate molecules; Edwin Krebs (unrelated to Hans Krebs), discoverer of the enzyme phosphorylase kinase, a key enzyme in the conversion of phosphorylase b to phosphorylase a; and Earl Sutherland, discoverer of cAMP (cyclic adenosine monophosphate) as a regulator of sugar metabolism.

Many colleagues have written rather fondly about their experiences in the Cori laboratory throughout the years. Students, postdocs, collaborators, visiting scientists, etc. have all conveyed essentially the same motif within the Cori laboratory of hard work, dedication, and especially of the excitement to be had from learning new facts on thresholds of the biomedical sciences, like biochemistry and physiology. As a whole, their scientific work was productive and far-reaching. Indeed, the lifework performed by the Coris and their colleagues are still completely relevant today.

It is written that, after Gerty’s early death at 61 years of age, Carl did not take it well. After she died, he was not surprisingly devastated by the loss and took an extended leave of absence from the laboratory. He eventually remarried, and his new marriage to Anne Fitzgerald Jones was known to be a happy one. After his retirement in 1966, Carl became a visiting professor at Harvard Medical School, in Boston, and continued working in a lab housed at the famous Massachusetts General Hospital until his death on the 20th of October, in 1984, at 87 years of age.

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