Gerty Radnitz Cori: Glycogen to Glucose, and Back Again (Women in Science 37)
For a science teacher, perhaps the most dreaded question is “What Is Energy?” Sure, we have a standard answer – “The ability to do work” – but it’s a linguistic gloss over a principle so diverse in its manifestations that to go much further is to get lost amongst the equations and definitions that each branch of science has worked out for its favorite form of energy. The most mystifying form of energy, however, was long the one closest to us – the energy that runs a human body. Just how is it that we consume a bowl of cereal and then carry on with life for four or five hours? How does a carrot become energy? How is that energy used? How is it stored? We’re so used to our biology textbook answers to these questions that it’s sometimes hard to put ourselves in the mindset of a short century ago, when these questions were utterly unanswerable until a superstar couple, Gerty and Carl Cori, solved them in a series of experiments that solidified biochemistry’s place as the vital core of future biological research.
In many ways, the story of Gerty Cori (1896-1957) runs parallel to that of Nerve Growth Factor discoverer Rita Levi-Montalcini. Both were from Jewish families which encouraged education, and both had to cram years‘ worth of Latin and mathematics into a few months of concentrated study in order to meet the minimum requirements of their respective universities, Levi-Montalcini in Italy, and Gerty Radnitz in Prague. Her first year at university, she met Carl Cori, a tall and reserved student with big ideas about the future of chemistry within biology. At the time, biologists looked somewhat scornfully upon the efforts to apply chemical methods and analyses to their field, a reluctance that would waver with the discovery of the importance of vitamin deficiencies in disease in the early years of the twentieth century, and crumble with the Coris’ work on the vital role played by the chemistry of enzymes in the Twenties and Thirties.
There are so very many Bad Men in the history of Women in Science. Mary Somerville’s horrid first husband. The administration that kept Emmy Noether without an actual salary for years upon years. The cad who broke Sofia Kovalevskaya’s heart. So, it’s nice to be able to tell a story about a genuinely good human. Carl Cori loved Gerty Radnitz utterly and completely for her whole life. He married her in the midst of growing anti-Semitism, against the wishes of his family, and at serious peril to his future career. Then, when he and his wife fled to America ahead of the Nazis, he refused to take any position that did not have a job for her as well, eventually settling for a professorship in Buffalo at a meagerly equipped lab where they could work together. And when she fell dreadfully ill at the end of her life, he carried her around the house, administered her blood transfusions, and feverishly developed new medical techniques to keep her well. And throughout it all, he passionately insisted on recognition for her co-equal role in their joint momentous discoveries.
Which brings us back to the question of energy. In the Nineteenth century, glycogen had been discovered in the liver and muscles, but nobody knew what it was, or how it tied into the mysterious process of providing chemical energy for the body. Throughout the 1920s, using the excruciatingly precise chemical analysis that became Gerty Cori’s laboratorial hallmark, the newly wed couple began unfolding the mechanisms of energy storage and release, a system now known as the Cori Cycle.
We need to start by remembering the three parts of cellular respiration: Glycolysis, the Citric Acid Cycle, and Oxidative Phosphorylation. For us, the last one is vastly the most important. It uses oxygen to generate most of the ATP (energy-containing particles) we use to do chemical work in our body. But if you exercise a tissue too strenuously, it becomes difficult to deliver oxygen to that tissue fast enough, and what you’re left with is glycolysis, the first stage. Now, glycolysis can still make some ATP from glucose (the simple sugar that photosynthesis produces), but it’s not very much, and even that process will shut down fast if glycolysis’s other product, NADH, doesn’t get turned into NAD+ to start the glycolytic cycle over again.
Basically, if you don’t make NAD+, you’re screwed. Luckily, we have an enzyme that takes pyruvate, the end product of glycolysis, and combines it with NADH to produce NAD+ and lactate. The NAD+ is then free to go back to the beginning of glycolysis to create some more energy while we’re waiting for oxygen to reach our cells again, but what happens to the lactate? That’s the mystery the Coris uncovered. They found that the lactic acid produced is carried by the blood to the liver, where a series of enzymes is responsible for building it back to pyruvate, and thence to glucose, and ultimately to glycogen, which they found to be a molecule comprised of hundreds of glucose chained together, waiting for use. When needed, this glycogen can be broken down again (they discovered not only the process for this, but the enzyme responsible for doing it) into glucose, which can be shipped via the blood back to the skeletal muscles to enter cellular respiration and generate more energy for the cell.
It is an elegant loop, and the methods they developed to discover it became the tools of a new generation of scientists, the unabashed biochemists who escorted us to the verge of the Genetic Age of biology. Since the complicated nature of living organisms makes determining what chemicals are part of which processes horrendously difficult, Cori pioneered ways of studying chemical processes outside of living cells, culminating in the creation of glycogen in a test-tube. During the post-war era, she oversaw the pre-eminent enyzmology lab in the nation, and arguably the world, responsible for a dizzying stream of new discoveries and producing no less than eight Nobel Prize winning biochemists in the process. She proved that molecular chemistry had a place in biology, that if you were careful enough, the simplicity of the former could be brought to bear productively on the chaos of the latter, and we’ve been following that intuition ever since.
For her work in uncovering the mechanisms of the Cori cycle, as well as for her role as a pioneer in the discovery of new enzymes and the ubiquity of enzymatic functions, not to mention her part in discovering the enzyme-deficiency heart of several previously unknowable diseases, Gerty Radnitz Cori won the Nobel Prize in 1947, splitting the award with Carl, as they had split credit regularly on their joint publications. The world was recognizing her, even as her own department had dragged its feet, not giving her a tenure position until 1944 (an associate professorship), and not becoming a full professor until 1947, a decade and a half after she had started working at the University of Washington, and eighteen years after she and Carl had worked out the essential details of the Cori Cycle.
No sooner, however, did she gain a position at least moderately reflective of her massive accomplishments, than biology dealt her a cruel stroke. Her bone marrow started turning fibrous, leading to a massive and ultimately fatal case of anemia as her red blood cell producers slowly ossified. Operations could extend her life by bits and snatches, but the weakness only grew worse, and the regular blood transfusions she required only made her feel ill as her body began to reject the waves of new blood. She was, in her prime, a woman who studied everything, who crammed a day with as much art and learning as she could, all while carrying out experiments and designing preparation protocols that redefined laboratory perfection. But in her final years, at less than sixty years old, she couldn’t move from room to room without help, and could only bring her mind to bear on trashy popular novels. While Carl looked after her and carried on their joint projects, she slipped further into immobility, dying at last in 1957. She had taken enzymes from a bit part in the human story to the central actors in our biological drama, and with the discovery of how DNA codes for proteins and therefore enzymes, the modern era of biological research could truly begin. She was uncompromising and brilliant, a perfectionist who became the first woman not named Curie to win a Nobel Prize, and the Bio Lab of today is as it is because that is how Gerty Cori knew it must be.
FUTHER READING: Crucible of Science: The Story of the Cori Laboratory by John Exton is a book about Gerty and Carl Cori I have very much wanted to read, but even the Kindle edition runs $47, so I’m waiting on the softcover. When that comes out, I’ll let ya know how it is. In the meantime, there is the charming memoir by Cori Lab alumnus, and Nobel Prizewinner, Arthur Kornberg, For the Love of Enzymes. It’s lovely – a passionate account of the closing days of the Vitamin Hunters and the early days of the Enzyme Hunters, told with an earnest desire to communicate the stories of the dedicated people who made the genetic age possible, but who have been rather cast in darkness by the long shadow of their offspring. There is also a very nice writeup about Cori in Sharon Bertsch McGrayne’s unilaterally great Nobel Prize Women in Science, which is, next to The Illustrated Women in Science: Year One, my first recommendation for a detailed but not crushing survey of women in science to give to an aspiring young female scientist. (Seriously, though, buy The Illustrated Women in Science: Year One. Like, lots.)