Posts Tagged ‘History of Medicine’

Role of Inflammation in Disease

Larry H. Bernstein, MD, FCAP, Curator





The debate over the latest cure-all craze.


Medical Dispatch NOVEMBER 30, 2015 ISSUE


The National Institutes of Health recently designated inflammation a priority.


The National Institutes of Health recently designated inflammation a priority.


Several years ago, I fell at the gym and ripped two tendons in my wrist. The pain was excruciating, and within minutes my hand had swollen grotesquely and become hot to the touch. I was reminded of a patient I’d seen early in medical school, whose bacterial infection extended from his knee to his toes. Latin was long absent from the teaching curriculum, but, as my instructor examined the leg, he cited the four classic symptoms of inflammation articulated by the Roman medical writer Celsus in the first century: rubor, redness; tumor, swelling; calor, heat; and dolor, pain. In Latin, inflammatio means “setting on fire,” and as I considered the searing pain in my injured hand I understood how the condition earned its name.

Inflammation occurs when the body rallies to defend itself against invading microbes or to heal damaged tissue. The walls of the capillaries dilate and grow more porous, enabling white blood cells to flood the damaged site. As blood flows in and fluid leaks out, the region swells, which can put pressure on surrounding nerves, causing pain; inflammatory molecules may also activate pain fibres. The heat most likely results from the increase in blood flow.
The key white blood cell in inflammation is called a macrophage, and for decades it has been a subject of study in my hematology laboratory and in many others. Macrophages were once cast as humble handmaidens of the immune system, responsible for recognizing microbes or debris and gobbling them up. But in recent years researchers have come to understand that macrophages are able to assemble, within themselves, specialized platforms that pump out the dozens of molecules that promote inflammation. These platforms, called inflammasomes, are like pop-up factories—quickly assembled when needed and quickly dismantled when the crisis has passed.

For centuries, scientists have debated whether inflammation is good or bad for us. Now we believe that it’s both: too little, and microbes fester and spread in the body, or wounds fail to heal; too much, and nearby healthy tissue can be degraded or destroyed. The fire of inflammation must be tightly controlled—turned on at the right moment and, just as critically, turned off. Lately, however, several lines of research have revealed that low-level inflammation can simmer quietly in the body, in the absence of overt trauma or infection, with profound implications for our health. Using advanced technologies, scientists have discovered that heart attacks, diabetes, and Alzheimer’s disease may be linked to smoldering inflammation, and some researchers have even speculated about its role in psychiatric conditions.

As a result, understanding and controlling inflammation has become a central goal of modern medical investigation. The internal research arm of the National Institutes of Health recently designated inflammation a priority, mobilizing several hundred scientists and hundreds of millions of dollars to better define its role in health and disease; in 2013, the journal Science devoted an entire issue to the subject. This explosion in activity has captured the public imagination. In best-selling books and on television and radio talk shows, threads of research are woven into cure-all tales in which inflammation is responsible for nearly every malady, and its defeat is the secret to health and longevity. New diets will counter the inflammation simmering in your gut and restore your mental equilibrium. Anti-inflammatory supplements will lift your depression and ameliorate autism. Certain drugs will tamp down the silent inflammation that degrades your tissues, improving your health and extending your life. Everything, and everyone, is inflamed.

Such claims aside, there is genuine evidence that inflammation plays a role in certain health conditions. In atherosclerosis, blood flow to the heart or the brain is blocked, resulting in a heart attack or a stroke. For a long time, atherosclerosis was thought to result mainly from eating fatty foods, which clogged the arteries. “Atherosclerosis was all about fats and grease,” Peter Libby, a professor at Harvard Medical School and a cardiologist at Brigham and Women’s Hospital, in Boston, told me recently. “Most physicians saw atherosclerosis as a straight plumbing problem.”

During his cardiology training, Libby studied immunology, and he became fascinated with the work of Rudolf Virchow, a nineteenth-century German pathologist. Virchow speculated that atherosclerosis might be an active process, caused by inflamed blood vessels, not one caused simply by the accumulation of fat. In the mid-nineteen-nineties, in studies with mice, Libby, working in parallel with other groups of scientists, found that low-density lipoproteins—LDLs, those particles of “bad” cholesterol—can work their way into the lining of arteries. There, they sometimes trigger an inflammatory response, which can cause blood clots that block the artery. Libby and others began to understand that atherosclerosis wasn’t a mere plumbing problem but also an immune disease—“our body’s defenses turned against ourselves,” he told me.

Paul Ridker, a cardiovascular expert and a colleague of Libby’s at Harvard and Brigham and Women’s, moved the research beyond the laboratory. He found that many patients who’d had heart attacks, despite lacking factors such as high blood pressure, high cholesterol, and a history of smoking, had an elevated level of C-reactive protein, a molecule produced in response to inflammation, in their blood. After demonstrating, in a separate study, that cholesterol-reducing statins could also reduce C-reactive-protein levels, Ridker launched the Jupiter trial, in which people with elevated levels of C-reactive protein but normal cholesterol levels were given a placebo or a statin medication. In 2008, the published results showed that the subjects who received the statin saw their levels of C-reactive protein drop and were less likely three and a half years later to suffer a heart attack. This suggested that elevated cholesterol isn’t the only factor at work in cardiovascular disease, and that in some cases statins, acting as anti-inflammatory agents, could be used to treat the condition.
The benefit was modest: the statin treatment reduced the risk of heart attack in only about one per cent of the patients. Still, that figure is statistically significant, and for one in every hundred patients—a hundred in every ten thousand—it’s meaningful. An independent safety-monitoring board ended the study early, saying that it was unethical to continue once it was clear that statins provided a benefit not available to the subjects on the placebo. (Critics argue that shortening the trial, which was funded by a drug company, exaggerated the potential benefits and underestimated long-term harm, but the researchers strongly disagree.) The N.I.H. and other scientific groups are funding new studies to further explore whether anti-inflammatory drugs—for example, low doses of immunomodulatory agents that are used for treating severe arthritis—can help prevent cardiovascular disease.
Another chronic condition that has been linked to inflammation is Type II diabetes. People with this condition can’t adequately use insulin, a molecule that enables the body’s cells to take glucose out of the bloodstream and derive energy from it. Their organs fail and glucose builds to dangerous levels in the blood. Recently, researchers have found macrophages in the pancreases of people with Type II diabetes. The macrophages release inflammatory molecules that are thought to impair insulin activity. One of these inflammatory molecules is called interleukin-1, and in 2007 the New England Journal of Medicine reported on a clinical trial in which an interleukin-1 blocker proved to be modestly effective at lowering blood-sugar levels in Type II diabetics. This suggests that, by blocking inflammation, it might be possible to restore insulin activity and alleviate some of the symptoms of diabetes.

Alzheimer’s disease, too, seems to show a link to inflammation. Alzheimer’s results from the buildup of amyloid and tau proteins in the brain; specialized cells called glial cells, which are related to macrophages, recognize these proteins as debris and release inflammatory molecules to get rid of them. This inflammation is thought to further impair the working of neurons, worsening Alzheimer’s. The connection is tantalizing, but it’s important to note that it doesn’t mean that inflammation causes Alzheimer’s. Nor is there strong evidence that inflammation contributes to other forms of dementia where the brain isn’t filled with protein debris. And in clinical trials anti-inflammatory drugs like naproxen and ibuprofen have failed to ameliorate or prevent Alzheimer’s.


On September 18, 2015, scientists at the N.I.H. convened a meeting to publicly present their research priorities, one of which is to decipher the consequences of inflammation. It’s increasingly apparent that inflammation plays some role in many health conditions, but scientists are far from grasping the nature of that relationship, the mechanisms involved, or the extent to which treating inflammation is helpful.

“We really don’t know how much inflammation contributes to diabetes, Alzheimer’s, depression, and other disorders,” Michael Gottesman, a director of research at the N.I.H., told me. “We know a lot about the mouse and its immune response. Much, much less is understood in humans. As we learn more, we see how much more we need to learn.” Gottesman pointed out that, of the thousand or so proteins circulating in our bloodstream, about a third are involved in inflammation and in our immune response, so simply detecting their presence doesn’t reveal much about their potential involvement in any particular disease. “Correlation is not causation,” he emphasized. “Because you find an inflammatory protein in a certain disorder, it doesn’t mean that it is causing that disorder.”
This lack of certainty hasn’t dampened the enthusiasm of a growing number of doctors who believe that inflammation is the source of a wide range of conditions, including dementia, depression, autism, A.D.H.D., and even aging. One of the most prominent such voices is that of Mark Hyman, whose books—including “The Blood Sugar Solution 10-Day Detox Diet”—are best-sellers. Hyman serves as a personal health adviser to Bill and Hillary Clinton and to the King and Queen of Jordan. Recently, he was recruited by the Cleveland Clinic with millions of dollars in funding to establish a center based on his ideas. Trained in family medicine, Hyman told me that he considers himself a new type of doctor. “I am a doctor who treats root causes and addresses the body as a dynamic system,” he wrote in an e-mail. “Being an inflammalogist is part of that.”

Studies with human subjects clearly indicate that, in cases where inflammation underlies a chronic condition, the inflammation is local: in the arteries (heart disease); or in the brain (Alzheimer’s); or in the pancreas (diabetes). And though there are associations between various forms of inflammatory disease—for example, people with psoriasis or periodontal disease have a somewhat higher risk of heart disease—it has not been proved that there is a causal connection. Hyman and other doctors, such as the neurologist David Perlmutter, promote a more radical idea: that certain foods and environmental toxins cause smoldering inflammation, which somehow spreads to other areas of the body, including the brain, degrading one’s health, mental acuity, and life span.

The notion of a gut-brain connection seems to derive from studies with mice, including one that showed that introducing a bacterium into a mouse’s gastrointestinal tract led to behavioral changes, such as a reluctance to navigate mazes. But there’s scant evidence that anything similar happens in people, or any rigorous study to show that “anti-inflammatory diets” reduce depression. Earlier this year, the journal Brain, Behavior, and Immunity published a meta-analysis of more than fifty clinical studies that found inflammatory molecules in patients with depression. The paper revealed that there was little consistency from study to study about which molecules correlated to the condition. Steven Hyman, a former director of the National Institute of Mental Health and now the head of the Stanley Center at the Broad Institute (and no relation to Mark Hyman), in Cambridge, Massachusetts, noted that depression is “one of those topics where exuberant theorization vastly outstrips the data.”

Nonetheless, Mark Hyman holds fast to his view. “Inflammation is the final common pathway for pretty much all chronic diseases,” he told me. His recommended solution is an “anti-inflammatory diet”—omitting sugar, caffeine, beans, dairy, gluten, and processed foods, as well as taking a variety of supplements, including probiotics, fish oil, Vitamins C and D, and curcumin, a key molecule in turmeric. Hyman introduced me to one of the patients he had treated with his anti-inflammatory diet and supplements, a forty-seven-year-old hedge-fund manager in Cambridge named Jim Silverman. Two decades ago, Silverman began noticing blood in his stool. A colonoscopy resulted in a diagnosis of ulcerative colitis. In the ensuing years, Silverman was treated by gastroenterologists with aspirin-based medication, anti-inflammatory suppositories, and even corticosteroids, but the problem persisted. Then, five years ago, on a flight home from a business conference, he happened to sit next to Hyman, who told him that he could cure colitis.
“I thought, What a bullshitter,” Silverman said. He travelled anyway to Hyman’s UltraWellness Center, in Lenox, Massachusetts, to consult with him. Hyman told him that dairy was inflaming his bowel. Silverman was skeptical, but he kept track of his diet and bleeding episodes, and ultimately concluded that restricting dairy products resulted in long periods without bleeding. He now thinks that he could be suffering from a dairy allergy. In addition to avoiding dairy products, he continues to follow the anti-inflammatory regimen of supplements prescribed by Hyman. “I’m just taking it because I’m doing well,” he said. “I have no idea if it’s doing anything, but I don’t want to rock the boat.”

I asked Gary Wu, a professor of gastroenterology at the Perelman School of Medicine, at the University of Pennsylvania, and one of the world’s experts on the gut microbiome, about the alleged value of treating inflammatory bowel disease by restricting specific foods. Recently, in the journal Gastroenterology, Wu and his colleagues published a comprehensive review of scientific studies on diet and inflammatory bowel disease. They found only two dietary interventions that had been proved to reduce inflammation: an “elemental diet,” which is a liquid mixture of amino acids, simple sugars, and triglycerides, and a slightly more complex liquid diet. The liquid mixtures are typically administered with a tube placed through the nose. “The diet is not palatable,” Wu said. “And you don’t eat during the day. There is no intake of whole foods at all.”

David Agus, a cancer specialist and a professor of medicine and engineering at the University of Southern California, is equally skeptical of Hyman’s claims for the anti-inflammation diet. Agus, who is perhaps best known for being the doctor on “CBS This Morning,” recently received a multimillion-dollar grant from the National Cancer Institute to study how inflammation may spur the growth of tumors. “This notion that foods cause inflammation and foods can block inflammation, there’s zero data that it changes clinical outcomes,” he told me. “If the idea gets people to eat fruits and vegetables, I love it, but it’s not real.” Agus noted that vitamins don’t counter inflammation, and that it’s been shown, in rigorous clinical trials, that they may increase one’s risk of developing cancer.
Still, Agus views inflammation as a component not only of cancer but also of chronic diseases like diabetes and dementia. Rather than special diets, he supports preventively taking approved anti-inflammatory medications, such as aspirin and statins, and scrupulously scheduling the standard vaccinations in order to prevent infections. In “The End of Illness,” Agus encourages the reader to “reduce your daily dose of inflammation” by, among other things, not wearing high heels, since these can inflame your feet and the inflammation could possibly affect your vital organs. When I pressed him on that suggestion, he told me, “What I meant is that if your feet hurt all day it’s probably not a good thing. The downside is you just wear a different pair of shoes. The upside is it gave you an understanding of inflammation and its role in disease.”

Mark Hyman, at times, acknowledges the possible limits of his paradigm. When I asked him about the alleged link among gut inflammation, diet, and psychological disorders, he conceded that some of his evidence was anecdotal, derived from his own clinical practice. He mentioned the case of a child with asthma, eczema, and A.D.H.D., whom he treated with “an elimination diet, taking him off processed foods, and giving him supplements.” The child’s allergic problems improved and his behavior was markedly better, Hyman said: “It was a light-bulb moment. I saw secondary effects on the brain that came out of treating physical problems.”

He also cited studies of patients with rheumatoid arthritis, a painful and debilitating auto-immune condition that inflames and erodes the joints, who became less depressed after being treated with inflammatory blockers. But had the anti-inflammatory treatment directly lifted their depression, or had their mood improved simply because they were more mobile and in less pain? I told Hyman that it was hard to connect the dots. “For sure,” he said.


Connecting the dots is a challenge even for scientists who are actively involved in inflammation research. One afternoon, I visited Ramnik Xavier, the chair of gastroenterology at Massachusetts General Hospital and an expert in Crohn’s disease and ulcerative colitis. The bowel is inflamed in both conditions: ulcerative colitis affects the colon, whereas Crohn’s disease can affect any part of the digestive system. But the nature of inflammation varies almost from person to person and involves interactions among DNA, many kinds of gastrointestinal cells, and the peculiarities of the gut microbiome. “Lots of cells, lots of genes, lots of bugs,” Xavier said.

Xavier, a compact man with a laconic manner and thick black hair marked by streaks of gray, initially studied the role of specialized white blood cells, known as T-cells and B-cells, in defending the body against the development of colitis. Eventually, with Mark Daly, a geneticist at the Broad Institute, Xavier began to search for genes that predispose people to inflammatory bowel disease and for genes that might protect them against it. The two scientists, as part of an international consortium, have identified at least a hundred and sixty areas of DNA that are associated with an increased risk of inflammatory bowel disease; Xavier’s lab has zeroed in on about two dozen genes within these regions of DNA.
One of the frustrations of treating inflammation is that our weapons against it are so imprecise. Drugs like naproxen and ibuprofen are the equivalent of peashooters. At the other extreme, cannon-like steroids shut down the immune system, raising the risk of infection, eroding the bones, predisposing the patient to diabetes, and causing mood swings. Even the peashooters can cause collateral damage: aspirin may help to protect against colon cancer, heart attack, and stroke, but it also raises the risk of gastrointestinal bleeding. Ibuprofen, naproxen, and similar drugs were labelled by the F.D.A. as increasing the risk of heart attack and stroke in people who’ve never suffered either condition, and clinical trials failed to show that they prevent or ameliorate dementia. (Although these drugs reduce inflammation, they may also alter the lining of blood vessels and increase the risk of clots.) Statins lower the chance of a heart attack, but there is growing concern not only about the side effect of muscle pain but also about increasing the likelihood of diabetes. And the absolute benefits of these preventive medications is slight, measured in single digits.

In the lab at the Broad Institute, Xavier and his team were trying to discover new treatments that can block inflammation in a targeted manner. The day I visited, they were assessing molecules associated with colitis, especially one called interleukin-10, or IL-10, which is known to decrease inflammation. In a cavernous room, I watched as a robotic arm moved among racks of plastic plates, each containing hundreds of small wells in which chemical compounds were being tested. Some people with Crohn’s disease have genetic mutations that disable the salubrious effects of IL-10. Xavier is trying to identify molecules that can compensate for this deficiency, in the hope that such molecules might eventually be turned into drugs to treat this subset of patients.

But other patients suffer from a different manifestation of Crohn’s—they can’t fully clear debris from cells in their gut, so it builds up, triggering inflammation. In a neighboring lab, members of Xavier’s research team were trying to develop drugs for that condition, too. A robotic arm was handling plates that contained genetically engineered cells and moving them under a fluorescent microscope. The images appeared on a computer screen—fields of cells studded with yellow and green dots, like the sky in van Gogh’s “Starry Night.”

On another visit, Xavier took me to his clinic at Mass General. Patients, ranging from the very young to the elderly, were reclining in Barcaloungers as nurses and physicians intravenously administered potent anti-inflammatory drugs. Later, I spoke by phone to one of Xavier’s patients, a forty-nine-year-old woman named Maria Ray, who received a diagnosis of colitis in 1998. She was treated with sulfa drugs and corticosteroids, which controlled the problem for several years, but in 2004, after a series of flare-ups, she underwent surgery to remove her colon. Soon after, she developed ulcers on her skin, arthritis of her knees and elbows, and inflammation in both eyes. Xavier prescribed other drugs, and for two years her condition improved, but lately her skin lesions and eye inflammation have returned. “We hoped surgery would cure her ulcerative colitis,” Xavier said. “But we don’t really understand why there is such an overactive immune system now inflaming these other parts of her body.”
At the very least, the fact that Ray has symptoms in many organs, despite the removal of her colon, complicates the simplistic view that treating the gut will suppress inflammation elsewhere. Moreover, there’s no evidence that patients with Crohn’s or colitis are more likely than average to develop dementia and other cognitive disorders. “What we see in mice is not always reproduced in people,” Xavier said.


Perhaps no aspect of inflammation is more compelling, or illusory, than the idea that it may be responsible for aging. An internist friend in Manhattan told me that healthy patients occasionally come in to her office carrying Mark Hyman’s books, eager to live longer by following his anti-inflammation life style. When I asked Hyman if he could introduce me to someone who follows his longevity regimen, he readily offered himself. “I’m aiming to live to a hundred and twenty,” he said.

The notion stems from grains of evidence, such as studies that have shown an increase in inflammation with age. The genesis of aging is still a mystery. It may occur for a host of reasons—a waning of the energy generated by the mitochondria within cells, the tendency of DNA to grow fragile and more mutation-prone over time—and it’s much too simplistic to attribute the process to inflammation alone. Luigi Ferrucci, the scientific director of the National Institute on Aging, conducted some of the early research on inflammation and aging, and for a while, he told me, he believed the avenue held promise. On the morning we spoke, he had just finished his daily six-mile run. Sixty-one years old, born in Livorno, on the coast of Tuscany, Ferrucci is an animated man with a stubbly beard who favors crew-neck sweaters. In the past four decades, he has studied thousands of people in order to identify the biological processes that result in aging. He measured scores of molecules in the blood, hoping to find clues that would lead him to the cause of aging’s hallmarks, particularly sarcopenia, or loss of muscle mass, and cognitive decline.

His most illuminating studies involved people in late middle age who showed no sign of heart disease, diabetes, dementia, or other conditions that might be associated with inflammation. He found that a single inflammatory molecule, called interleukin-6, was the most powerful predictor of who would eventually become disabled. Healthy patients with high levels of the IL-6 molecule aged more quickly and grew sicker than those without the inflammatory molecule. “I thought I had discovered the cause of aging and was going to win the Nobel Prize,” Ferrucci said, laughing.
But then he found other subjects with no evidence of inflammation, and without elevated levels of IL-6 or other inflammatory molecules, whose bodies nevertheless began to decline. “We are looking at the layer, not at the core of the problem,” he said. “Inflammation may accelerate aging in some people—but it is a manifestation of something that is occurring underneath.” He reiterated the point that correlation is not causation. “If you have the curiosity of the scientist, you can’t stop there, because you want to know why,” he said. “You want to break the toy so you can see how it’s working inside.”

Toward that end, Ferrucci recently organized a large team of collaborators and launched a new clinical study, GESTALT, which stands for Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing. Groups of healthy people will be studied intensively as they age, with detailed analyses of their DNA, RNA, proteins, metabolic capacity, and other sophisticated parameters, every two years for at least a decade. “Then we can say what mechanisms account for increased inflammation with aging, and the loss of muscle mass, or the loss of memory, or the loss of energy capacity or fitness,” Ferrucci said. “These have never really been addressed on a deep level in humans.”

In the meantime, he sticks to a Mediterranean diet, mainly out of fealty to his heritage. (Ferrucci is known among his N.I.H. colleagues as a gourmet Italian cook.) The media recently gave much attention to a study, published in 2013 in the New England Journal of Medicine, on the benefits of a Mediterranean diet in preventing heart attack or stroke. But, as Ferrucci noted, the benefits weren’t clearly related to inflammation and they accrued to a very small percentage of the subjects on the diet. “Believe me, if there were a diet that prevented aging, I would be on it,” he said.

We’d all like a simple solution for complex medical problems. We’re desperate to feel in command of our lives, particularly as we age and see friends and family afflicted by Alzheimer’s, stroke, and heart failure. “My patients, understandably, are very focussed on the foods they eat, wanting control, hoping they won’t have to take immune-suppressive treatments,” Gary Wu, the University of Pennsylvania gastroenterologist, told me.

Some years ago, I became obsessed with a restrictive diet—no bread, cheese, ice cream, cookies—in an attempt to lower my cholesterol levels. (My father died of a heart attack in his fifties, and I was haunted by his fate.) After nearly six months, I’d lost some fifteen pounds, but my cholesterol level had hardly budged, and I’d become so vigilant about everything I ate that I stopped enjoying meals. Gradually, I resumed a balanced and more reasonable diet and regained an appreciation for one of life’s fundamental pleasures.

Scientists may yet discover that inflammation contributes to disease in unexpected ways. But it’s important to remember, too, that inflammation serves a vital role in the body. “We are playing with one of the primary mechanisms selected by nature to maintain the integrity of our body against the thousand environmental attacks that we receive every day,” Ferrucci said. “Inflammation is part of our maintenance and repair system. Without it, we can’t heal.”


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Opening Ceremony and Award Presentations from the 2015 AACR Meeting in Philadelphia PA; Pennsylvania Convention Center, Sunday April 19, 2015: 8:15 AM


Reporter: Stephen J. Williams, Ph.D.

The following contain notes from the Sunday April 19, 2015 AACR Meeting (Pennsylvania Convention Center, Philadelphia PA) 8:15 AM Opening Ceremony and Awards Presentation

Ninth Annual AACR Team Science Award

Recipient: Designing Androgen Receptor (AR) Inhibitor Team

The Designing AR Inhibitors Team is a multi-institutional team that is composed of Charles Sawyers, MD, PhD, team leader, director of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center in New York, AACR past-president, and Howard Hughes Medical Institute investigator; Howard Scher, MD, chief of genitourinary oncology service and D. Wayne Calloway chair in urologic oncology at Memorial Sloan Kettering; and Michael Jung, PhD, distinguished professor in the Department of Chemistry and Biochemistry at the UCLA.

The team was honored for their collective work in discovering and developing the novel antiandrogen enzalutamide (Xtandi) for the treatment of metastatic castration-resistant prostate cancer in a collaboration that started ten years ago.

Twelfth Annual AACR Award for Lifetime Achievement in Cancer Research

Recipient: Mario R. Capecchi, Ph.D.

Dr. Capecchi is a geneticist who won the Nobel prize for creating technologies that resulted in the first knockout mouse. For this work, Capecchi won the 2007 Nobel prize for medicine or physiology, along with Martin Evans and Oliver Smithies, who also contributed.

AACR Distinguished Public Service Award

Recipient : Miri Ziv Director General of Israel Cancermiri_ziv_180_s_002

  • Instrumental in getting national Israeli mammography screening
  • Efforts led to national skin cancer screening program in Israel
  • Prevention/control programs
  • In 1995 representative to European Breast League

Ninth Annual AACR Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research

Recipient: Donald S. Coffey, Ph.D.

Dr. Coffey discovered the nuclear matrix and made pivotal discoveries understanding the process of DNA synthesis. He is the leader of the National Prostate Coalition and efforts led to the development of the Prostate Specific Antigen (PSA) as a prostate cancer biomarker. Now his lab is assessing the role of chaos, fractals and complexity in the self-organization of DNA, cells and tissue in relation to tumor biology.

In a side note, both Dr. Foti and Dr. Coffey had the same mentor, Dr. Sydney Weinhouse and Professor Leslie Helleman, who both studied the oxidation of free fatty acids and took Otto Warburg’s hypothesis a step further to understand how more complex cancer metabolism was than Otto had imagined.

Other award winners were:

Dr. Richard Pasdur of the FDA who won the Public Service Award

In memorial

Dr. Upton (M.D.) pathologist head of NCI and established EPA

Dr. Emmanuel Farber, M.D., Ph.D. – biology of tobacco control and issued the historical Surgeon

General’s report on smoking

Dr. June Biedler, Ph.D. – showed multidrug resistance and defined cytogenetics of  neuroblastoma


Other related articles on Cancer History and Social Media Coverage were published in this Open Access Online Scientific Journal, include the following:

Cancer Biology and Genomics for Disease Diagnosis

Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

Methodology for Conference Coverage using Social Media: 2014 MassBio Annual Meeting 4/3 – 4/4 2014, Royal Sonesta Hotel, Cambridge, MA

List of Breakthroughs in Cancer Research and Oncology Drug Development by Awardees of The Israel Cancer Research Fund

2013 American Cancer Research Association Award for Outstanding Achievement in Chemistry in Cancer Research: Professor Alexander Levitzki


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Highlights in the History of Physiology

Larry H. Bernstein, MD, FCAP, Curator

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William Harvey can be credited with founding modern physiology, then Claude Bernard, and then the great anatomist John Hunter, all before the twentieth century.

In the 19th century, curiosity, medical necessity, and economic interest stimulated research concerning the physiology of all living organisms. Discoveries of unity of structure and functions common to all living things resulted in the development of the concept of general physiology, in which general principles and concepts applicable to all living things are sought. Since the mid-19th century, therefore, the word physiology has implied the utilization of experimental methods, as well as techniques and concepts of the physical sciences, to investigate causes and mechanisms of the activities of all living things.
One view of the history of physiology is that it was shortened from a macro-
to a microstructural view with the developments of biochemistry and then molecular biology.  Though that view is attractive, it is not really compliant with a holistic view
of human and mammalian development.  But form and function are the concern of anatomy and physiology, even with the emergence of a subcellular domain.

William Harvey

William Harvey, discoverer of blood circulation and heart function, was born in 1578 in England. He graduated in Padua in 1602, returned to England, and practiced medicine for a long time. Among his patients were two kings of England (James I and Charles I), and Francis Bacon. He published the work “Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (An Anatomical Dissertation Upon the Movement of the Heart and Blood in Animals)  in 1682. It is identified as the beginning of modern experimental physiology. Harvey’s study was based only on anatomical experiments; despite increased knowledge in physics and chemistry during the 17th century, physiology remained closely tied to anatomy and medicine.

The seminal work  lays a basic foundation accurately explaining the circulation. In 1609 Harvey was appointed to the staff of St. Bartholomew’s Hospital. He was elected a fellow of the Royal College of Physicians in 1607. His ideas about circulation of the blood were first publicly expressed in lectures he gave in 1616. The work of Aristotle was the basis for Galen’s De usu partium (“On the Use of Parts”) and a source for many early misconceptions in physiology. Galen, the leading physician in ancient times, never thought that the blood circulates.

Harvey first formulated an opinion about the blood circulation by making a simple calculation. Harvey first studied the heartbeat, establishing the existence of the pulmonary (heart-lung-heart) circulation process and noting the one-way flow of blood. When he also realized how much blood was pumped by the heart, he realized there must be a constant amount of blood flowing through the arteries and returning through the veins of the heart, a continuing circular flow. He estimated that the amount of blood that is emitted by each heartbeat about 2 ounces. Because the heart beats 72 times per minute, the sum is about 540 pounds per hour of emitted blood into the aorta. After formulating this hypothesis, he performed experiments and conducted thorough investigation to determine the details of the circulation of the blood.

Harvey stated that arteries carry blood away from the heart while veins carry blood back to the heart. Although Harvey could not visualize the capillaries, the smallest blood vessels that connect the arterioles to small veins, he concluded that there must be capillaries. Harvey pointed out that the function of the heart is to pump blood into the arteries. His theory of the circulation was not readily accepted, Harvey’s work got recognition at the end of his life. The discovery of capillaries by Marcello Malpighi in 1661 provided factual evidence to confirm Harvey’s theory of blood circulation.

Harvey was also involved in the field of Embryology, although less important than the investigation in terms of the circulation of the blood, not something that should be underestimated. He was a careful observer, and his book On the Generation of Animals (On-generation animal world), published in 1651 showed the beginning of the actual field of Embryology. Harvey rejected the theory that the overall structure of the animal body are the same as young and adult animals, the only difference being size. He rightly declared that an embryo grows to its final structure step by step.

Herman Boerhaave is sometimes referred to as the father of physiology due to his exemplary teaching in Leiden and his textbook Institutiones medicae (1708).

In the United States, the first physiology professorship was founded in 1789 at the College of Philadelphia, and in 1832, Robert Dunglison published the first comprehensive work on the subject, Human Physiology (Encyclopedia of American History, 2007). In 1833, William Beaumont published a classic work on digestive function.

In the 19th century, physiological knowledge began to accumulate at a rapid rate, in particular with the 1838 appearance of the Cell theory of Matthias Schleiden and Theodor Schwann. It radically stated that organisms are made up of units called cells. Claude Bernard’s (1813–1878) further discoveries ultimately led to his concept of milieu interieur (internal environment), which would later be taken up and championed as “homeostasis” by American physiologist Walter Cannon.

Claude Bernard

Claude Bernard’s first important work was on the functions of the exocrine pancreas; this achievement won him the prize for experimental physiology from the French Academy of Sciences. His most famous work was on the glycogenic function of the liver; in the course of his study he was led to the conclusion that the liver is the seat of an internal secretion, by which it prepares sugar from the elements of the blood passing through it.

In 1851, while examining the effects produced in the temperature of various parts of the body by section of the nerve or nerves belonging to them, he noticed that division of the cervical sympathetic nerve gave rise to more active circulation and more forcible pulsation of the arteries in certain parts of the head, and a few months afterwards he observed that electrical excitation of the upper portion of the divided nerve had the contrary effect. In this way he established the existence of vasomotor nerves, both
vasodilator and vasoconstrictor.

Milieu intérieur is the key process with which Bernard is associated. He wrote, “The stability of the internal environment [the milieu intérieur] is the condition for the free and independent life.”

The living body, though it has need of the surrounding environment, is nevertheless relatively independent of it. This independence which the organism has of its external environment, derives from the fact that in the living being, the tissues are withdrawn from external influences and are protected by a veritable internal environment. The constancy of the internal environment is the condition for free and independent life: the mechanism that makes it possible is that which assures the maintenance, within the internal environment, of all the conditions necessary for the life of the elements.

The constancy of the environment presupposes a perfection of the organism such that external variations are at every instant compensated and brought into balance. In consequence, the higher animal is in a close relation with its environment so that its equilibrium results from a continuous and delicate compensation established as if the most sensitive of balances.

In his major discourse on the scientific method, An Introduction to the Study of Experimental Medicine (1865), Bernard described what makes a scientific theory good and what makes a scientist important, a true discoverer. Unlike many scientific writers of his time, Bernard wrote about his own experiments and thoughts, and used the first person.

Physiology as a distinct discipline utilizing chemical, physical, and anatomical methods began to develop in the 19th century. Claude Bernard in France; Johannes Müller, Justus von Liebig, and Carl Ludwig in Germany; and Sir Michael Foster in England may be numbered among the founders of physiology as it now is known. At the beginning of the 19th century, German physiology was under the influence of the romantic school of Naturphilosophie. In France, on the other hand, romantic elements were opposed by rational and skeptical viewpoints. Bernard’s teacher, François Magendie, the pioneer of experimental physiology, was one of the first men to perform experiments on living animals. Both Müller and Bernard, however, recognized that the results of observations and experiments must be incorporated into a body of scientific knowledge, and that the theories of natural philosophers must be tested by experimentation. Many important ideas in physiology were investigated experimentally by Bernard, who also wrote books on the subject. He recognized cells as functional units of life and developed the concept of blood and body fluids as the internal environment (milieu intérieur) in which cells carry out their activities. This concept of physiological regulation of the internal environment occupies an important position in physiology and medicine; Bernard’s work had a profound influence on succeeding generations of physiologists in France, Russia, Italy, England, and the United States.

Müller’s interests were anatomical and zoological, whereas Bernard’s were chemical and medical, but both men sought a broad biological viewpoint in physiology rather than one limited to human functions. Although Müller did not perform many experiments, his textbook Handbuch der Physiologie des Menschen für Vorlesungen and his personal influence determined the course of animal biology in Germany during the 19th century.

It has been said that, if Müller provided the enthusiasm and Bernard the ideas for modern physiology, Carl Ludwig provided the methods. During his medical studies at the University of Marburg in Germany, Ludwig applied new ideas and methods of the physical sciences to physiology. In 1847 he invented the kymograph, a cylindrical drum that still is used to record muscular motion, changes in blood pressure, and other physiological phenomena. He also made significant contributions to the physiology of circulation and urine secretion. His textbook of physiology, published in two volumes in 1852 and 1856, was the first to stress physical instead of anatomical orientation in physiology. In 1869 at Leipzig, Ludwig founded the Physiological Institute (neue physiologische Anstalt), which served as a model for research institutes in medical schools all over the world. The chemical approach to physiological problems, developed first in France by Lavoisier, was expanded in Germany by Justus von Liebig, whose books on Organic Chemistry and its Applications to Agriculture and Physiology (1840) and Animal Chemistry (1842) created new areas of study both in medical physiology and agriculture. German schools devoted to the study of physiological chemistry evolved from Liebig’s laboratory at Giessen.

The British tradition of physiology is distinct from that of the continental schools. In 1869 Sir Michael Foster became Professor of Practical Physiology at University College in London, where he taught the first laboratory course ever offered as a regular part of instruction in medicine. The pattern Foster established still is followed in medical schools in Great Britain and the United States. In 1870 Foster transferred his activities to Trinity College at Cambridge, England, and a postgraduate medical school emerged from his physiology laboratory there. Although Foster did not distinguish himself in research, his laboratory produced many of the leading physiologists of the late 19th century in Great Britain and the United States. In 1877 Foster wrote a major book (Textbook of Physiology), which passed through seven editions and was translated into German, Italian, and Russian. He also published Lectures on the History of Physiology (1901). In 1876, partly in response to increased opposition in England to experimentation with animals, Foster was instrumental in founding the Physiological Society, the first organization of professional physiologists. In 1878, again due largely to Foster’s activities, the Journal of Physiology, which was the first journal devoted exclusively to the publication of research results in physiology, was initiated.

Foster’s teaching methods in physiology and a new evolutionary approach to zoology were transferred to the United States. in 1876 by Henry Newell Martin, a professor of biology at Johns Hopkins University in Baltimore, Md. The American tradition drew also on the continental schools. S. Weir Mitchell, who studied under Claude Bernard, and Henry P. Bowditch, who worked with Carl Ludwig, joined Martin to organize the American Physiological Society in 1887, and in 1898 the society sponsored publication of the American Journal of Physiology. In 1868 Eduard Pflüger, professor at the Institute of Physiology at Bonn, founded the Archiv für die gesammte Physiologie, which became the most important journal of physiology in Germany.

Physiological chemistry followed a course partly independent of physiology. Müller and Liebig provided a stronger relationship between physical and chemical approaches to physiology in Germany than prevailed elsewhere. Felix Hoppe-Seyler, who founded his Zeitschrift für physiologische Chemie in 1877, gave identity to the chemical approach to physiology. The American tradition in physiological chemistry initially followed that in Germany; in England, however, it developed from a Cambridge laboratory founded in 1898 to complement the physical approach started earlier by Foster.

Physiology in the 20th century is a mature science; during a century of growth, physiology became the parent of a number of related disciplines, of which of comparative physiology and ecophysiology, biochemistry, biophysics, and molecular biology are examples. Major figures in these fields include Knut Schmidt-Nielsen and George Bartholomew. Most recently, evolutionary physiology has become a distinct subdiscipline.

Physiology, however, retains an important position among the functional sciences that are closely related to the field of medicine. Although many research areas, especially in mammalian physiology, have been fully exploited from a classical-organ and organ-system point of view, comparative studies in physiology may be expected to continue. The solution of the major unsolved problems of physiology will require technical and expensive research by teams of specialized investigators. Unsolved problems include the unravelling of the ultimate bases of the phenomena of life. Research in physiology also is aimed at the integration of the varied activities of cells, tissues, and organs at the level of the intact organism. Both analytical and integrative approaches uncover new problems that also must be solved. In many instances, the solution is of practical value in medicine or helps to improve the understanding of both human beings and other animals.

Among areas that have shown significant growth in the twentieth century are endocrinology (study of function of hormones) and neurobiology (study of function of nerve cells and the nervous system).

Fye, B. W. 1987. The Development of American Physiology: Scientific Medicine in the Nineteenth Century. Baltimore: Johns Hopkins University Press.

Rothschuh, K. E. 1973. History of Physiology. Huntington, N.Y.: Krieger.

The Nobel Prize in Physiology or Medicine

Year Laureate[A] Country[B] Rationale[C]
1901 Emil Adolf von Behring Germany “for his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and deaths”[10]
1902 Sir Ronald Ross United Kingdom “for his work on malaria, by which he has shown how it enters the organism and thereby has laid the foundation for successful research on this disease and methods of combating it”[11]
1903 Niels Ryberg Finsen Denmark
(Faroe Islands)
“[for] his contribution to the treatment of diseases, especially lupus vulgaris, with concentrated light radiation, whereby he has opened a new avenue for medical science”[12]
1904 Ivan Petrovich Pavlov Russia “in recognition of his work on the physiology of digestion, through which knowledge on vital aspects of the subject has been transformed and enlarged”[13]
1905 Robert Koch Germany “for his investigations and discoveries in relation to tuberculosis[14]
1906 Camillo Golgi Italy “in recognition of their work on the structure of the nervous system[15]
Santiago Ramón y Cajal Spain
1907 Charles Louis Alphonse Laveran France “in recognition of his work on the role played by protozoa in causing diseases”[16]
1908 Ilya Ilyich Mechnikov Russia “in recognition of their work on immunity[17]
Paul Ehrlich Germany
1909 Emil Theodor Kocher Switzerland “for his work on the physiology, pathology and surgery of the thyroid gland[18]
1910 Albrecht Kossel Germany “in recognition of the contributions to our knowledge of cell chemistry made through his work on proteins, including the nucleic substances[19]
1911 Allvar Gullstrand Sweden “for his work on the dioptrics of the eye[20]
1912 Alexis Carrel France “[for] his work on vascular suture and the transplantation of blood vessels and organs[21]
1913 Charles Richet France “[for] his work on anaphylaxis[22]
1914 Robert Bárány Austria “for his work on the physiology and pathology of the vestibular apparatus[23]
1919 Jules Bordet Belgium “for his discoveries relating to immunity[24]
1920 Schack August Steenberg Krogh Denmark “for his discovery of the capillary motor regulating mechanism”[25]
1921 Not awarded
1922 Archibald Vivian Hill United Kingdom “for his discovery relating to the production of heat in the muscle[26]
Otto Fritz Meyerhof Germany “for his discovery of the fixed relationship between the consumption of oxygen and the metabolism of lactic acid in the muscle”[26]
1923 Sir Frederick Grant Banting Canada “for the discovery of insulin[27]
John James Rickard Macleod Canada
1924 Willem Einthoven The Netherlands “for the discovery of the mechanism of the electrocardiogram[28]
1925 Not awarded
1926 Johannes Andreas Grib Fibiger Denmark “for his discovery of the Spiroptera carcinoma[29]
1927 Julius Wagner-Jauregg Austria “for his discovery of the therapeutic value of malaria inoculation in the treatment of dementia paralytica[30]
1928 Charles Jules Henri Nicolle France “for his work on typhus[31]
1929 Christiaan Eijkman The Netherlands “for his discovery of the antineuritic vitamin[32]
Sir Frederick Gowland Hopkins United Kingdom “for his discovery of the growth-stimulating vitamins[32]
1930 Karl Landsteiner Austria “for his discovery of human blood groups[33]
1931 Otto Heinrich Warburg Germany “for his discovery of the nature and mode of action of the respiratory enzyme[34]
1932 Sir Charles Scott Sherrington United Kingdom “for their discoveries regarding the functions of neurons[35]
Edgar Douglas Adrian United Kingdom
1933 Thomas Hunt Morgan United States “for his discoveries concerning the role played by the chromosome in heredity[36]
1934 George Hoyt Whipple United States “for their discoveries concerning liver therapy in cases of anaemia[37]
George Richards Minot United States
William Parry Murphy United States
1935 Hans Spemann Germany “for his discovery of the organizer effect in embryonic development[38]
1936 Sir Henry Hallett Dale United Kingdom “for their discoveries relating to chemical transmission of nerve impulses[39]
Otto Loewi Austria
1937 Albert Szent-Györgyi von Nagyrapolt Hungary “for his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid[40]
1938 Corneille Jean François Heymans Belgium “for the discovery of the role played by the sinus and aortic mechanisms in the regulation of respiration[41]
1939 Gerhard Domagk Germany “for the discovery of the antibacterial effects of prontosil[42]
1943 Carl Peter Henrik Dam Denmark “for his discovery of vitamin K[43]
Edward Adelbert Doisy United States “for his discovery of the chemical nature of vitamin K[43]
1944 Joseph Erlanger United States “for their discoveries relating to the highly differentiated functions of single nerve fibres[44]
Herbert Spencer Gasser United States
1945 Sir Alexander Fleming United Kingdom “for the discovery of penicillin and its curative effect in various infectious diseases[45]
Sir Ernst Boris Chain United Kingdom
Howard Walter Florey Australia
1946 Hermann Joseph Muller United States “for the discovery of the production of mutations by means of X-ray irradiation[46]
1947 Carl Ferdinand Cori United States “for their discovery of the course of the catalytic conversion of glycogen[47]
Gerty Theresa Cori, née Radnitz United States
Bernardo Alberto Houssay Argentina “for his discovery of the part played by the hormone of the anterior pituitary lobe in the metabolism of sugar[47]
1948 Paul Hermann Müller Switzerland “for his discovery of the high efficiency of DDT as a contact poison against several arthropods[48]
1949 Walter Rudolf Hess Switzerland “for his discovery of the functional organization of the interbrain as a coordinator of the activities of the internal organs”[49]
António Caetano Egas Moniz Portugal “for his discovery of the therapeutic value of leucotomy (lobotomy) in certain psychoses”[49]
1950 Philip Showalter Hench United States “for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects”[50]
Edward Calvin Kendall United States
Tadeusz Reichstein Switzerland
Year Laureate[A] Country[B] Rationale[C]
1951 Max Theiler South Africa “for his discoveries concerning yellow fever and how to combat it”[51]
1952 Selman Abraham Waksman United States “for his discovery of streptomycin, the first antibiotic effective against tuberculosis[52]
1953 Sir Hans Adolf Krebs United Kingdom “for his discovery of the citric acid cycle[53]
Fritz Albert Lipmann United States “for his discovery of co-enzyme A and its importance for intermediary metabolism”[53]
1954 John Franklin Enders United States “for their discovery of the ability of poliomyelitis viruses to grow in cultures of various types of tissue”[54]
Frederick Chapman Robbins United States
Thomas Huckle Weller United States
1955 Axel Hugo Theodor Theorell Sweden “for his discoveries concerning the nature and mode of action of oxidation enzymes”[55]
1956 André Frédéric Cournand United States “for their discoveries concerning heart catheterization and pathological changes in the circulatory system[56]
Werner Forssmann Federal Republic of Germany
Dickinson W. Richards United States
1957 Daniel Bovet Italy “for his discoveries relating to synthetic compounds that inhibit the action of certain body substances, and especially their action on the vascular system and the skeletal muscles”[57]
1958 George Wells Beadle United States “for their discovery that genes act by regulating definite chemical events”[58]
Edward Lawrie Tatum United States
Joshua Lederberg United States “for his discoveries concerning genetic recombination and the organization of the genetic material of bacteria[58]
1959 Arthur Kornberg United States “for their discovery of the mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid[59]
Severo Ochoa Spain
United States
1960 Sir Frank Macfarlane Burnet Australia “for discovery of acquired immunological tolerance[60]
Sir Peter Brian Medawar Brazil
United Kingdom
1961 Georg von Békésy United States “for his discoveries of the physical mechanism of stimulation within the cochlea[61]
1962 Francis Harry Compton Crick United Kingdom “for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material”[62]
James Dewey Watson United States
Maurice Hugh Frederick Wilkins New Zealand
United Kingdom
1963 Sir John Carew Eccles Australia “for their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane[63]
Sir Alan Lloyd Hodgkin United Kingdom
Sir Andrew Fielding Huxley United Kingdom
1964 Konrad Bloch United States “for their discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism[64]
Feodor Lynen Federal Republic of Germany
1965 François Jacob France “for their discoveries concerning genetic control of enzyme and virus synthesis[65]
André Lwoff France
Jacques Monod France
1966 Peyton Rous United States “for his discovery of tumour-inducing viruses[66]
Charles Brenton Huggins United States “for his discoveries concerning hormonal treatment of prostatic cancer[66]
1967 Ragnar Granit Finland/Sweden “for their discoveries concerning the primary physiological and chemical visual processes in the eye[67]
Haldan Keffer Hartline United States
George Wald United States
1968 Robert W. Holley United States “for their interpretation of the genetic code and its function in protein synthesis[68]
Har Gobind Khorana India
Marshall W. Nirenberg United States
1969 Max Delbrück United States “for their discoveries concerning the replication mechanism and the genetic structure of viruses[69]
Alfred D. Hershey United States
Salvador E. Luria Italy
United States
1970 Julius Axelrod United States “for their discoveries concerning the humoral transmittors in the nerve terminals and the mechanism for their storage, release and inactivation”[70]
Ulf von Euler Sweden
Sir Bernard Katz United Kingdom
1971 Earl W. Sutherland, Jr. United States “for his discoveries concerning the mechanisms of the action of hormones[71]
1972 Gerald M. Edelman United States “for their discoveries concerning the chemical structure of antibodies[72]
Rodney R. Porter United Kingdom
1973 Karl von Frisch Federal Republic of Germany “for their discoveries concerning organization and elicitation of individual and social behaviour patterns”[73]
Konrad Lorenz Austria
Nikolaas Tinbergen United Kingdom
1974 Albert Claude Belgium “for their discoveries concerning the structural and functional organization of the cell[74]
Christian de Duve Belgium
George E. Palade Romania
1975 David Baltimore United States “for their discoveries concerning the interaction between tumour viruses and the genetic material of the cell”[75]
Renato Dulbecco Italy
United States
Howard Martin Temin United States
1976 Baruch S. Blumberg United States “for their discoveries concerning new mechanisms for the origin and dissemination of infectious diseases[76]
D. Carleton Gajdusek United States
1977 Roger Guillemin United States “for their discoveries concerning the peptide hormone production of the brain[77]
Andrew V. Schally United States
Rosalyn Yalow United States “for the development of radioimmunoassays of peptide hormones[77]
1978 Werner Arber Switzerland “for the discovery of restriction enzymes and their application to problems of molecular genetics[78]
Daniel Nathans United States
Hamilton O. Smith United States
1979 Allan M. Cormack South Africa “for the development of computer assisted tomography[79]
Sir Godfrey N. Hounsfield United Kingdom
1980 Baruj Benacerraf Venezuela “for their discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions[80]
Jean Dausset France
George D. Snell United States
1981 Roger W. Sperry United States “for his discoveries concerning the functional specialization of the cerebral hemispheres[81]
David H. Hubel Canada “for their discoveries concerning information processing in the visual system[81]
Torsten N. Wiesel Sweden
1982 Sune K. Bergström Sweden “for their discoveries concerning prostaglandins and related biologically active substances”[82]
Bengt I. Samuelsson Sweden
Sir John R. Vane United Kingdom
1983 Barbara McClintock United States “for her discovery of mobile genetic elements[83]
1984 Niels K. Jerne Denmark “for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies[84]
Georges J.F. Köhler Federal Republic of Germany
César Milstein Argentina
United Kingdom
1985 Michael S. Brown United States “for their discoveries concerning the regulation of cholesterol metabolism[85]
Joseph L. Goldstein United States
1986 Stanley Cohen United States “for their discoveries of growth factors[86]
Rita Levi-Montalcini Italy
1987 Susumu Tonegawa Japan “for his discovery of the genetic principle for generation of antibody diversity”[87]
1988 Sir James W. Black United Kingdom “for their discoveries of important principles for drug treatment[88]
Gertrude B. Elion United States
George H. Hitchings United States
1989 J. Michael Bishop United States “for their discovery of the cellular origin of retroviral oncogenes[89]
Harold E. Varmus United States
1990 Joseph E. Murray United States “for their discoveries concerning organ and cell transplantation in the treatment of human disease”[90]
E. Donnall Thomas United States
1991 Erwin Neher Federal Republic of Germany “for their discoveries concerning the function of single ion channels in cells”[91]
Bert Sakmann Federal Republic of Germany
1992 Edmond H. Fischer Switzerland
United States
“for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism”[92]
Edwin G. Krebs United States
1993 Sir Richard J. Roberts United Kingdom “for their discoveries of split genes[93]
Phillip A. Sharp United States
1994 Alfred G. Gilman United States “for their discovery of G-proteins and the role of these proteins in signal transduction in cells”[94]
Martin Rodbell United States
1995 Edward B. Lewis United States “for their discoveries concerning the genetic control of early embryonic development[95]
Christiane Nüsslein-Volhard Federal Republic of Germany
Eric F. Wieschaus United States
1996 Peter C. Doherty Australia “for their discoveries concerning the specificity of the cell mediated immune defence[96]
Rolf M. Zinkernagel Switzerland
1997 Stanley B. Prusiner United States “for his discovery of Prions – a new biological principle of infection”[97]
1998 Robert F. Furchgott United States “for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system”[98]
Louis J. Ignarro United States
Ferid Murad United States
1999 Günter Blobel Germany/United States “for the discovery that proteins have intrinsic signals that govern their transport and localization in the cell”[99]
2000 Arvid Carlsson Sweden “for their discoveries concerning signal transduction in the nervous system[100]
Paul Greengard United States
Eric R. Kandel United States
Year Laureate[A] Country[B] Rationale[C]
2001 Leland H. Hartwell United States “for their discoveries of key regulators of the cell cycle[101]
Sir Tim Hunt United Kingdom
Sir Paul M. Nurse United Kingdom
2002 Sydney Brenner South Africa “for their discoveries concerning ‘genetic regulation of organ development and programmed cell death‘”[102]
H. Robert Horvitz United States
Sir John E. Sulston United Kingdom
2003 Paul Lauterbur United States “for their discoveries concerning magnetic resonance imaging[103]
Sir Peter Mansfield United Kingdom
2004 Richard Axel United States “for their discoveries of odorant receptors and the organization of the olfactory system[104]
Linda B. Buck United States
2005 Barry J. Marshall Australia “for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease[105]
J. Robin Warren Australia
2006 Andrew Z. Fire United States “for their discovery of RNA interference – gene silencing by double-stranded RNA”[106]
Craig C. Mello United States
2007 Mario R. Capecchi United States “for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells.”[107]
Sir Martin J. Evans United Kingdom
Oliver Smithies United States
2008 Harald zur Hausen Germany “for his discovery of human papilloma viruses causing cervical cancer[108]
Françoise Barré-Sinoussi France “for their discovery of human immunodeficiency virus[108]
Luc Montagnier France
2009 Elizabeth H. Blackburn United States
“for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase[109]
Carol W. Greider United States
Jack W. Szostak United States
2010 Sir Robert G. Edwards United Kingdom “for the development of in vitro fertilization[110]
Bruce A. Beutler United States “for their discoveries concerning the activation of innate immunity[111]
Jules A. Hoffmann France
Ralph M. Steinman United States
“for his discovery of the dendritic cell and its role in adaptive immunity[111]
(awarded posthumously)[112][113]
2012 Sir John B. Gurdon United Kingdom “for the discovery that mature cells can be reprogrammed to become pluripotent[114]
Shinya Yamanaka Japan
2013 James E. Rothman United States “for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells[5]
Randy W. Schekman United States
Thomas C. Südhof United States
2014 John O’Keefe United States
United Kingdom
“for their discoveries of cells that constitute a positioning system in the brain”
May-Britt Moser Norway
Edvard I. Moser Norway


  1. In chronological order with prizes not given during war years.
  2. There are distinct categories to observe: infectious disease; vitamins; neurophysiology; biochemistry and molecular biology; immunology and pharmacology; cancer; endocrinology.
  3. There were deserving scientists who did not receive the Nobel Prize:  Most notable – were…
    Rosalind Franklin, Britton Chance, Bernard Horacker, Allan Wilson, perhaps others..

Excerpt from “Sound and Hearing”, Stevens, S. S., & Warshofsky, Fred,eds., Time-Life Books, NY, 1965. p54  “The molder of the modern theory of basilar-membrane “resonance” is Georg von Bekesy. In 1928 Bekesy was a communications engineer in Budapest, studying the mechanical and electrical adaptation of telephone equipment to the demands of the human hearing mechanism. One day, in the course of a casual conversation, an acquantance asked him whether a major improvement would soon be forthcoming in the quality of telephone systems. The idle remark strarted a chain of thought that eventually posed to Bekesy a more fundamental question: “How much better is the quality of the human ear than that of any telephone system?” His search for the answer has added volumes to our present-day knowledge of hearing.”

a sound impulse sends a wave sweeping along the basilar membrane. As the wave moves along the membrane, its amplitude increases until it reaches a maximum, then falls off sharply until the wave dies out. That point at which the wave reaches its greatest amplitude is the point at which the frequency of the sound is detected by the ear. And as Helmholtz had postulated, Bekesy found that the high-frequency tones were perceived near the base of the cochlea and the lower frequencies toward the apex.”
For his studines of the traveling wave, Georg von Bekesy received the Nobel Prize in 1961. His incredible delicate and elegant experiments had traced sound to the very threshold of sensation. …”

In the 1950s, Wald and his colleagues used chemical methods to extract pigments from the retina. Then, using a spectrophotometer, they were able to measure the light absorbance of the pigments. Since the absorbance of light by retina pigments corresponds to thewavelengths that best activate photoreceptor cells, this experiment showed the wavelengths that the eye could best detect. However, since rod cells make up most of the retina, what Wald and his colleagues were specifically measuring was the absorbance of rhodopsin, the main photopigment in rods. Later, with a technique called microspectrophotometry, he was able to measure the absorbance directly from cells, rather than from an extract of the pigments. This allowed Wald to determine the absorbance of pigments in the cone cells (Goldstein, 2001).

Schack August Steenberg Krogh ForMemRS (November 15, 1874 – September 13, 1949) was a Danish professor at the department of zoophysiology at the University of Copenhagen from 1916-1945.[3][4][5] He contributed a number of fundamental discoveries within several fields of physiology, and is famous for developing the Krogh Principle. In 1920 August Krogh was awarded the Nobel Prize in Physiology or Medicine for the discovery of the mechanism of regulation of the capillaries in skeletal muscle. Krogh was first to describe the adaptation of blood perfusion in muscle and other organs according to demands through opening and closing the arterioles and capillaries.

Although neurobiology (as it is now called) has always been subsumed under physiology, its rapid growth in the twentieth century, along with its institutionalization in separate university departments and separate funding programs, has made it an almost completely autonomous discipline. Neurobiology can be divided into two major areas: neurophysiology, or the study of the process by which nerve cells transmit a message; and neurology, the study of the structure and organization of the nervous system. A general work is The Neurosciences: Paths of Discovery, edited by Frederic G. Worden, Judith P. Swazey, and George Adelman (Cambridge, Mass.: MIT Press, 1975). Two articles in this collection stand out as particularly interesting: Richard Jung’s “Some European Neuroscientists: A Personal Tribute” (pp. 477-511), and Judith P. Swazey and Frederic G. Worden’s “On the Nature of Research in Neuroscience” (pp. 569-587). Swazey and Worden look at the development of twentieth-century neurobiology in terms of Thomas Kuhn’s concept of scientific revolution.

Two major questions confronted neurologists at the end of the nineteenth and beginning of the twentieth centuries: What was the basic anatomical element of the nervous system (individual cells, or a continuous nerve network)? How were parts of the nervous system (e.g., peripheral nerves and spinal cord) integrated to produce an overall functioning system? The first question involved considerable debate in the period of the 1870s through the 1890s, though it was resolved ultimately in favor of the neuron theory (individual nerve cells as the basic structural and functional unit of the nervous system) by the early 1909.

Central to that debate was the work of the Spanish cytologist Santiago Ramón y Cajal (1852-1934), whose autobiography Recollections of My Life, translated by E. Horne Craigie with the assistance of Juan Cano (Philadelphia: American Philosophical Society, 1937), contains considerable information about the debate, the clash of paradigms, and Ramón y Cajal’s exquisite techniques for bringing about the resolution. A more recent and historically oriented account is Susan Billings’s “Concepts of Nerve Fiber Development 1839- 1930,” Journal of the History of Biology, 1971, 4:275-306, which shows how study of the embryological development of the nervous system (which Ramón y Cajal wisely exploited) helped to demonstrate that the nervous system arises from many discrete individual cells.

The structural and functional organization of the nervous system has been an area of great advancement during the twentieth century. Much work on the mode of action of the reflex response (as well as on how reflexes are learned) and on the relation between inhibition and excitation of nerve tracks was done by Russian neurologists in the latter part of the nineteenth and especially the early part of the twentieth century. The chief figures there were Ivan Michailovich Sechenov (1829-1905) and Ivan P. Pavlov (1849-1936). Pavlov’s inerest in digestion led him, under Sechenov’s infuence, to study the now-classic conditioned reflex involved in salivation. Pavlov’s life and work is the subject of one English-language volume: B.P. Babkin’s Pavlov, A Biography (Chicago: Univ. Chicago Press, 1949). This source provides valuable insight into a whole school of neurological work that has had as much influence on psychology as on neurobiology in this century.

While the general features and functions of the reflex were understood by the turn of the century, its manner of organization (especially in terms of connections with the brain) was not. A towering figure in elucidating the relationship between central and peripheral nervous systems, and especially the integrative function of the spinal cord, was the British physiologist Charles Scott Sherrington (1857-1952). Regnar Granit’s biography, Charles Scott Sherrington, An Appraisal (London: Nelson, 1967), and  Judith Swayze’s Reflexes and Motor Integration: Sharington’s Concept of Integrative Action (Cambridge, Mass.: Harvard Univ. Press, 1969) are significant sources. Swayze concentrates on a detailed but clear and insightful analysis of Sherrington’s scientific background, his experimental methods, and the development of his hypotheses about integrative action.

Concerning the development of the neurotransmitter hypothesis (conduction across the synapse between adjacent neurons occurs by a chemical process), its antagonists and protagonists, see Michael V. L. Bennett’s “Nicked by Occam’s Razor: Unitarianism in the Investigation of Synaptic Transmission,” Biological Bulletin, Suppl., June 1985, 168:159-167.

Sir John Carew Eccles (27 January 1903 – 2 May 1997) was an Australian neurophysiologist who won the 1963 Nobel Prize in Physiology or Medicine for his work on the synapse. He shared the prize with Andrew Huxley and Alan Lloyd Hodgkin. Eccles and colleagues used the stretch reflex as a model. When Eccles passed a current into the sensory neuron in the quadriceps, the motor neuron innervating the quadriceps produced a small excitatory postsynaptic potential (EPSP). When he passed the same current through the hamstring, the opposing muscle to the quadriceps, he saw an inhibitory postsynaptic potential (IPSP) in the quadriceps motor neuron. Although a single EPSP was not enough to fire an action potential in the motor neuron, the sum of several EPSPs from multiple sensory neurons synapsing onto the motor neuron could cause the motor neuron to fire, thus contracting the quadriceps. On the other hand, IPSPs could subtract from this sum of EPSPs, preventing the motor neuron from firing.

However, neuroscience has been repositioned in the 21st century. Arvid Carlsson, 77, of the University of Gothenburg in Sweden, as well as Paul Greengard of Rockefeller University in New York City, and Eric Kandel of New York’s Columbia University, shared the 2000 Nobel Prize in Physiology or Medicine.

Carlsson overturned conventional wisdom in 1950 by proving that dopamine–once thought to be a mere building block in the synthesis of the neurotransmitter norepinephrine–was an important nervous system messenger in its own right. He and others later discovered that Parkinson’s disease, which causes rigidity and tremors, results from a lack of dopamine in the brain.

Greengard, 74, took Carlsson’s insights several steps further in the 1960s by exploring how dopamine, norepinephrine, and serotonin control transmission of nerve signals at the synapse, the junction between communicating nerve cells. Greengard showed that the three neurotransmitters trigger the addition or removal of phosphate groups to proteins involved in nerve signaling, prompting them to interact with other proteins in a cascade of phosphorylation in and around the synapse.

The discovery that protein phosphorylation is key to nerve cell signaling helped inspire the research of Kandel, 70, who found that the ease with which ions such as calcium pass through a cell membrane– depends on whether the proteins forming the membrane’s pore are phosphorylated. Based on these findings, Kandel showed that short-term and long-term memory are related to the strength and duration of nerve impulses, and that new proteins are synthesized to maintain long-term memory.

Neuroscientist Thomas Südhof, MD, professor of molecular and cellular physiology at the Stanford University School of Medicine, shared the 2013 Nobel Prize in Physiology or Medicine with James Rothman, PhD, a former Stanford professor of biochemistry, and Randy Schekman, PhD, who earned his doctorate at Stanford under the late Arthur Kornberg, MD, another winner of the Nobel Prize in Physiology or Medicine. They were awarded the prize “for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells.” Rothman is now a professor at Yale University, and Schekman is a professor at UC-Berkeley.

“Tom Südhof has done brilliant work that lays a molecular basis for neuroscience and brain chemistry,” said Roger Kornberg, PhD, Stanford’s Mrs. George A. Winzer Professor in Medicine. Kornberg was awarded the Nobel Prize in Chemistry in 2006. He is the son of Arthur Kornberg, in whose lab Schekman received his doctorate.

“The brain works by neurons communicating via synapses,” Südhof said in a phone conversation this morning shortly after the announcement. “We’d like to understand how synapse communication leads to learning on a larger scale. How are the specific connections established? How do they form? And what happens in schizophrenia and autism when these connections are compromised?” In 2009, he published research describing how a gene implicated in autism and schizophrenia alters mice’s synapses and produces behavioral changes in the mice, such as excessive grooming and impaired nest building, that are reminiscent of these human neuropsychiatric disorders.

Südhof, along with other researchers worldwide, has identified integral protein components critical to the membrane fusion process. Südhof purified key protein constituents sticking out of the surfaces of neurotransmitter-containing vesicles, protruding from nearby presynaptic-terminal membranes, or bridging them. Then, using biochemical, genetic and physiological techniques, he elucidated the ways in which the interactions among these proteins contribute to carefully orchestrated membrane fusion.

The Nobel Prize in Physiology or Medicine 2014 was divided, one half awarded to John O’Keefe, the other half jointly to May-Britt Moser and Edvard I. Moser “for their discoveries of cells that constitute a positioning system in the brain.”

In 1971, John O’Keefe discovered the first component of this positioning system. He found that a type of nerve cell in an area of the brain called the hippocampus that was always activated when a rat was at a certain place in a room. Other nerve cells were activated when the rat was at other places. O’Keefe concluded that these “place cells” formed a map of the room.

More than three decades later, in 2005, May-Britt and Edvard Moser discovered another key component of the brain’s positioning system. They identified another type of nerve cell, which they called “grid cells”, that generate a coordinate system and allow for precise positioning and pathfinding. Their subsequent research showed how place and grid cells make it possible to determine position and to navigate.

History of Physiology
Lois N Magner,
Purdue University, West Lafayette, USA
Published online: April 2001

Major developments in the history of physiology include William Harvey’s demonstration of the circulation of the blood in the seventeenth century and Claude Bernard’s discovery of internal secretions in the nineteenth century.

For a neglected side of the story, see Seymour S. Cohen’s “The Biochemical Origins of Molecular Biology (Introduction),” Trends in Biochemical Sciences, 1984, 9:334-336, which argues that many of the histories of molecular biology have ignored the contributions of biochemistry to molecular genetics in general and to the discovery of DNA in particular.

Rather than covering the vast array of subjects that rightfully fall under the history of physiology (such as plant physiology and pathology, etc.), I focus on three areas that have been major concerns in the twentieth century: general physiology, neurobiology and endocrinology. For a brief introduction and overview of twentieth-century physiology, it is worthwhile to consult Karl E. Rothschuh’s History of Physiology (Huntington, N.Y.: Krieger, 1973). Chapter 7 (pp. 264-361) deals with the twentieth century; while it does not provide in-depth coverage, the broad outline establishes the framework within which more specialized topics can be placed.

The Prussian-born American physiologist Jacques Loeb (1859-1924), a long-time investigator at the Rockefeller Institute and a close professional friend of such figures as T. H. Morgan, Boss Harrison, J. McKeen Cattell, and W.J. V. Osterhout, set the style of experimental and quantitative biology that influenced a whole generation of biologists, especially in the United States. Loeb championed what he called “the mechanistic conception of life”–the title of a major address he gave in 1911 and of a book of essays collected in 1912 (Cambridge, Mass.: Harvard Univ. Press, 1964). The reprint edition benefits from a superb introduction by Donald Fleming. The Mechanistic Conception of Life was a celebration of the mechanistic materialist viewpoint in twentieth-century biology. A new biography of Loeb is Philip J. Pauly’s Controlling Life: Jacques Loeb and the Engineering Ideal in Biology (New York: Oxford Univ. Press, 1987). As the title suggests, Pauly emphasizes that Loeb’s guiding ideal was the scientific control of life.

Opposition to the “mechanistic conception of life” came from a number of sources–principally embryology and areas of general physiology–from the 1920s onward. Prominent among those who advanced a more holistic approach were the physiologist Walter Bradford Cannon (1871-1942) and the physiological chemist Lawrence J. Henderson (1878-1942). Cannon’s work, is summarized in his popular book The Wisdom of the Body (1932; New York: Norton, 1960). Henderson’s work is summarized, along with a number of other chemical topics, in his “The Fitness of the Environment” (1913; Boston: Beacon Press, 1958). The development of the idea of homeostasis is the subject of a superb essay by Donald Fleming, “Walter B. Cannon and homeostasis,” Social Research, 1984, 51:609-640.

Henderson’s work has been the subject of several studies. John Parascandola’s “Organismic and Holistic Concepts in the Thought of L. J. Henderson,” Journal of the Histoty of Biology, 1971, 4:63-113, relates Henderson’s scientific to his philosophical work. Henderson and Cannon were strongly interested in social regulation and equilibrium, as was fitting for products of the “Progressive Era,” and sought in physiological processes analogies for the notion of social and economic balance. A specific discussion of Henderson’s view of the interrelationship between social and physiological equilibrium theory can be found in Cynthia Eagle Russett’s The Concept of Equilibrium in American Social Thought (New Haven, Conn.: Yale Univ. Press, 1968). See also Stephen J. Cross and William R. Albury, “Walter B. Cannon, L.J. Henderson, and the Organic Analogy,” Osiris, 1987, N.S. 3:165-192.

Endocrinology (the study of the nature and effect of hormones, or “chemical messengers,” produced by the endocrine glands) is an area of general physiology that has shown enormous growth in the twentieth century. It has also been the subject of numerous historical studies. Arthur F. Hughes has prepared a brief but useful introduction titled “A History of Endocrinology,” Journal of the History of Medcine and Allied Sciences, 1977, 32(3): 292-313. While it is largely descriptive and chronological, Hughes’s study demonstrates the close link between clinical pathology and the gradual discovery of the role of hormones in maintaining physiological balance.

The history of endocrinology is the subject of a special issue of the Journal of the History of Biology, 1976, 9. A general introduction to the historiography of endocrinology is provided for the volume by Diana Long Hall and Thomas F. Click (pp. 229-233). Hall has explored some social and technical aspects of the history of sex-hormone research in “Biology, Sex Hormones, and Sexism in the 1920s,” Philosophical Forum 1974, 5:81-96. She suggests that sexist biases about the importance of male over female hormones proved to be a barrier to the technical solution of problems associated with extracting, isolating, and characterizing the chemical nature of sex hormones (principally testosterone and estrogen) in the 1920s.

On a somewhat more specific aspect of endocrinology, Michael Bliss’s The Discovery of Insulin (Chicago: Univ. Chicago Press, 1982) provides a close picture of the technical problems that investigators in any field of endocrinology had to surmount in order to identify, isolate, and purify a given hormone. The insulin story also provides a fascinating picture of the role of drug companies in encouraging and financing hormone research in the period (1920s) before government subsidy of basic scientific research.
Cardiovascular Physiology
The Frank–Starling law of the heart (also known as Starling’s law or the Frank–Starling mechanism or Maestrini heart’s law) states that the stroke volume of the heart increases in response to an increase in the volume of blood filling the heart (the end diastolic volume) when all other factors remain constant.  It is based on the late19th century studies by Otto Frank, who found using isolated frog hearts that the strength of ventricular contraction was increased when the ventricle was stretched prior to contraction. This observation was extended by the elegant studies of Ernest Starling and colleagues in the early 20th century who found that increasing venous return, and therefore the filling pressure of the ventricle, led to increased stroke volume in dogs.

The increased volume of blood stretches the ventricular wall, causing cardiac muscle to contract more forcefully. The stroke volume – contractile force model of  Ernest Starling was also based on the earlier observations of Maestrini in 1914.  The hypothesis states that “the mechanical energy set free in the passage from the resting to the active state is a function of the length of the fiber.”  This allows the cardiac output to be synchronized with the venous return without depending upon external regulation to make alterations. Initial length of myocardial fibers determines the initial work done during the cardiac cycle.

The stroke volume may also increase as a result of greater contractility of the cardiac muscle during exercise, independent of the end-diastolic volume. The Frank–Starling mechanism appears to make its greatest contribution to increasing stroke volume at lower work rates, and contractility has its greatest influence at higher work rates.

The first formulation of the law was theorized by the Italian physiologist Dario Maestrini, who on December 13, 1914, started the first of 19 experiments that led him to formulate the “legge del cuore”. Starling, the holder of the Physiology chair at London University, traced Maestrini’s work in 1918. While Starling was identified for the proposed award of the Nobel Prize, Maestrini never received his recognition, and today the “law of the heart” is known worldwide as “Starling’s Law,” though, among the Italian doctors, it is known by the nickname “Legge di Maestrini”.

One mechanism to explain how preload influences contractile force is that increasing the sarcomere length increases troponin C calcium sensitivity, which increases the rate of cross-bridge attachment and detachment, and the amount of tension developed by the muscle fiber (see Excitation-Contraction Coupling).  The effect of increased sarcomere length on the contractile proteins is termed length-dependent activation

It has traditionally been taught that the Frank-Starling mechanism is due to changes in the number of overlapping actin and myosin units within the sarcomere as in skeletal muscle. According to this view, changes in the force of contraction do not result from a change in inotropy. Because we now know that changes in preload are associated with altered calcium handling and troponin C affinity for calcium, a sharp distinction cannot be made mechanistically between length-dependent (Frank-Starling mechanism) and length-independent changes (inotropic mechanisms) in contractile function.

There is no single Frank-Starling curve on which the ventricle operates. There is actually a family of curves, each of which is defined by the afterload and inotropic state of the heart (Figure 2). For example, increasing afterload or decreasing inotropy shifts the curve down and to the right. Decreasing afterload and increasing inotropy shifts the curve up and to the left. To summarize, changes in venous return cause the ventricle to move along a single Frank-Starling curve that is defined by the existing conditions of afterload and inotropy.

Frank-Starling curves show how changes in ventricular preload lead to changes in stroke volume. This graphical representation, however, does not show how changes in venous return affect end-diastolic and end-systolic volume. In order to do this, it is necessary to describe ventricular function in terms of pressure-volume diagrams. When venous return is increased, there is increased filling of the ventricle along its passive pressure curve leading to an increase in end-diastolic volume (Figure 3). If the ventricle now contracts at this increased preload, and the afterload is held constant, the ventricle will empty to the same end-systolic volume, thereby increasing its stroke volume. The increased stroke volume is manifested by an increase in the width of the pressure-volume loop. The normal ventricle, therefore, is capable of increasing its stroke volume to match physiological increases in venous return.



Starling's Law of the heart

Starling’s Law of the heart

Starling's Law of the heart

Starling’s Law of the heart

Skeletal Muscle Contraction

Muscle Contraction and Relaxation

Step 1

A nerve impulse travels down and axon and causes the release of acetylcholine.

Step 2

Acetylecholine causes the impulse to spread across the surface of the sarcolemma.

Step 3

The nerve impulse enters the T Tubules and Sarcoplasmic Reticulum, stimulating the release of calcium ions.

Step 4

Calcium ions combine with Troponin, shifting troponin and exposing the myosin binding sites on the actin.

Step 5

ATP breaks down ADP + P. The released energy activates the myosin cross bridges and results in the sliding of thin actin myofilament past the thick myosin myofilaments.

Step 6

The sliding of the myofilaments draws the Z lines towards each other, the sarcomere shortens, the muscle fibers contract and therefore muscle contracts.

Step 7

ACh is inactivated by Acetylcholinesterase, inhibiting the nerve impulse conduction across the sarcolemma.

Step 8

Nerve impulse is inhibited, calcium ions are actively transported back into the Sarcoplasmic Reticulum, using the energy from the earlier ATP breakdown.

Step 9

The low calcium concentration causes the myosin cross bridges to separate from the think actin myofilaments and the actin myofilaments return to their relaxed position.

Step 10

Sarcomeres return to their resting lengths, muscle fibers relax and the muscle relaxes.

muscle contraction

muscle contraction

sarcomere structure

sarcomere structure



Pulmonary Gas Exchange

Inhalation (breathing in) is usually an active movement. The contraction of the diaphragm muscles causes the thoracic cavity to increase in volume, thus decreasing the pressures within the lung (Intrapleural and Alveolar Pressures). This negative pressure within the lungs acts as a Pressure Gradient, thus pulling air into the lungs. As air fills the lungs, the negative alveolar pressure moves back towards atmospheric pressure, and air flow into the lungs slows down. In contrast, expiration (breathing out) is usually a passive process.

Where Pel equals the product of elastance E (inverse of compliance) and volume of the system V, Pre equals the product of flow resistance R and time derivate of volume V (which is equivalent to the flow), Pin equals the product of inertance I and second time derivate of V. R and I are sometimes referred to as Rohrer’s constants.





Pulmonary circulation

Gas exchange/transport (primarily oxygen and carbon dioxide)




Oxygen-hemoglobin dissociation curve
(Bohr effect, Haldane effect)

The Young–Laplace equation (/ˈjʌŋ ləˈplɑːs/) is a nonlinear partial differential equation that describes the capillary pressure difference sustained across the interface between two static fluids, such as water and air, due to the phenomenon of surface tension or wall tension, although usage on the latter is only applicable if assuming that the wall is very thin. The Young–Laplace equation relates the pressure difference to the shape of the surface or wall and it is fundamentally important in the study of static capillary surfaces. It is a statement of normal stress balance for static fluids meeting at an interface, where the interface is treated as a surface (zero thickness).

The equation is named after Thomas Young, who developed the qualitative theory of surface tension in 1805, and Pierre-Simon Laplace who completed the mathematical description in the following year. It is sometimes also called the Young–Laplace–Gauss equation, as Gauss unified the work of Young and Laplace in 1830, deriving both the differential equation and boundary conditions using Johann Bernoulli‘s virtual work principles.

Dalton’s law (also called Dalton’s law of partial pressures) states that in a mixture of non-reacting gases, the total pressure exerted is equal to the sum of the partial pressures of the individual gases. This empirical law was observed by John Dalton in 1801 and is related to the ideal gas laws. Dalton’s law is not strictly followed by real gases with deviations being considerably large at high pressures.

Histidine residues in hemoglobin can accept protons and act as buffers. Deoxygenated hemoglobin is a better proton acceptor than the oxygenated form.

In red blood cells, the enzyme carbonic anhydrase catalyzes the conversion of dissolved carbon dioxide to carbonic acid, which rapidly dissociates to bicarbonate and a free proton:
CO2 + H2O → H2CO3 → H+ + HCO3
By Le Chatelier’s principle, anything that stabilizes the proton produced will cause the reaction to shift to the right, thus the enhanced affinity of deoxyhemoglobin for protons enhances synthesis of bicarbonate and accordingly increases capacity of deoxygenated blood for carbon dioxide. The majority of carbon dioxide in the blood is in the form of bicarbonate. Only a very small amount is actually dissolved as carbon dioxide, and the remaining amount of carbon dioxide is bound to hemoglobin.

In addition to enhancing removal of carbon dioxide from oxygen-consuming tissues, the Haldane effect promotes dissociation of carbon dioxide from hemoglobin in the presence of oxygen. In the oxygen-rich capillaries of the lung, this property causes the displacement of carbon dioxide to plasma as low-oxygen blood enters the alveolus and is vital for alveolar gas exchange.

The general equation for the Haldane Effect is: H+ + HbO2 ←→ H+Hb + O2; however, this equation is confusing as it reflects primarily the Bohr effect. The significance of this equation lies in realizing that oxygenation of Hb promotes dissociation of H+ from Hb, which shifts the bicarbonate buffer equilibrium towards CO2 formation; therefore, CO2 is released from RBCs, so it can diffuse out into the lungs (vs the Bohr effect being most relevant at non high O2 environment tissues; useful comparison to not confuse the 2 concepts of Haldane vs Bohr- Haldane@lung and Bohr@tissues for their physiological relevance).


In 1957, the french surgeon Claude Couinaud described 8 liver segments. Since then, radiographic studies describe an average of twenty segments based on distribution of blood supply. Each segment has its own independent vascular and biliary branches. Surgeons utilize these independent segments when performing liver resection for tumor or transplantation.

There are at least three reasons why segmental resection is superior to simple wedge resection. First, segmental resection minimizes blood loss because vascular density is reduced at the borders between segments. Second, it results in improved tumor removal for those cancers which are disseminated via intrasegmental branches of the portal vein. Third, segmental resection spares normal liver allowing for repeat partial hepatectomy.

liver triad

liver triad

Each segment of the liver is further divided into lobules. Lobules are usually represented as discrete hexagonal aggregations of hepatocytes. The hepatocytes assemble as plates which radiate from a central vein. Lobules are served by arterial, venous and biliary vessels at their periphery. Human lobules have little connective tissue separating one lobule from another. The paucity of connective tissue makes it more difficult to identify the portal triads and the boundaries of individual lobules. Central veins are easier to identify due to their large lumen and because they lack connective tissue that invests the portal triad vessels.

Lobules consist of hepatocytes and the spaces between them. Sinusoids are the spaces between the plates of hepatocytes. Sinusoids receive blood from the portal triads. About 25% of total cardiac output enters the sinusoids via terminal portal and arterial vessels. Seventy-five percent of the blood flowing into the liver comes through the portal vein; the remaining 25% is oxygenated blood that is carried by the hepatic artery. The blood mixes, passes through the sinusoids, bathes the hepatocytes and drains into the central vein. About 1.5 liters of blood exit the liver every minute.

The liver is central to a multitude of physiologic functions, including:

Clearance of damaged red blood cells & bacteria by phagocytosis

Nutrient management

Synthesis of plasma proteins such as albumin, globulin, protein C, insulin-like growth factor, clotting factors etc.

Biotransformation of toxins, hormones, and drugs

Vitamin & mineral storage


Renal physiology (Latin rēnēs, “kidneys”) is the study of the physiology of the kidney. This encompasses all functions of the kidney, including reabsorption of glucose, amino acids, and other small molecules; regulation of sodium, potassium, and other electrolytes; regulation of fluid balance and blood pressure; maintenance of acid-base balance; the production of various hormones including erythropoietin, and the activation of vitamin D.

Much of renal physiology is studied at the level of the nephron, the smallest functional unit of the kidney. Each nephron begins with a filtration component that filters blood entering the kidney. This filtrate then flows along the length of the nephron, which is a tubular structure lined by a single layer of specialized cells and surrounded by capillaries. The major functions of these lining cells are the reabsorption of water and small molecules from the filtrate into the blood, and the secretion of wastes from the blood into the urine.

Proper function of the kidney requires that it receives and adequately filters blood. This is performed at the microscopic level by many hundreds of thousands of filtration units called renal corpuscles, each of which is composed of a glomerulus and a Bowman’s capsule. A global assessment of renal function is often ascertained by estimating the rate of filtration, called the glomerular filtration rate (GFR).



vit D and receptor complex

vit D and receptor complex

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Outline of Medical Discoveries between 1880 and 1980

Curator: Larry H Bernstein, MD, FCAP

This is the first of a two part series tracing the developments in medical diagnosis and treatment, and herein, tracing the scientific events of the 19th century that accelerated and created the emergent events that brought together physics, organic and physical chemistry, electronics, computational biology.

Part I. Anatomy and Physiology

The first Nobel Prize in Physiology was awarded to Ivan Pavlov for work on digestion in 1904.  The presentation speech refers to the groundbreaking work of Vesalius and Harvey in his presentation address, citing their passionate pursuit of knowledge.  He credits the work of a young American physician, William Beaumont, who served as the only doctor on Michigan’s Mackinac Island in the French and Indian war in 1822, and who observed the gastric secretion from the gastric fistula of a wounded soldier. (see John Karlawish, Open Wound, University of Michigan Press, 2011). This was the basis for the work by Pavlov on dogs that extends our understanding of the telationship of the central nervous system to the digestive processes.

The Nobel Prize in Physiology or Medicine 1906 was awarded jointly to Camillo Golgi and Santiago Ramón y Cajal “in recognition of their work on the structure of the nervous system”. Golgi first opened the field of neuroanatomy with the silver staining method, and Cajal contributed equally to establishing the foundation for this research of great complexity.

The Nobel Prize in Physiology or Medicine 1909 was awarded to Emil Theodor Kocher for his work on the physiology, pathology, and surgery  of the thyroid gland. It had already been established that the enlargement of the thyroid compresses the trachea, and that complete removal has morbid effects. It was expressed by Kocher in 1883 that removal of the thyroid as a consequence of surgery must leave behind a functioning portion of the gland.

This was later followed by the establishment of a great medical institution Dr. William Worrall Mayo, a frontier doctor, and his two sons, Dr. William J. Mayo and Dr. Charles H. Mayo, Mayo Clinic.

The elder Dr. Mayo emigrated from his native England to the United States in 1846. He became a doctor in 1850. In 1863 he was appointed a surgeon for the enrollment board in southern Minnesota, to examine recruits for the Union Army, and settled in Rochester, Minn. His dedication to medicine became a family tradition when his sons, Drs. William James Mayo and Charles Horace Mayo, joined his practice in 1883 and 1888, respectively.

In 1883, a tornado swept through Rochester leaving in its wake many deaths and injuries. Temporary hospital quarters were set up in offices and hotels. Nuns from the Sisters of St. Francis, a teaching order, were recruited as nurses. The experience inspired Mother Alfred Moes to request that the Drs. Mayo join with the Sisters to build the first general hospital in southeastern Minnesota. The 27-bed Saint Mary’s Hospital opened in 1889 as a result of this partnership.



As the demand for their services increased, they asked other doctors and basic science researchers to join them in the world’s first private integrated group practice. In 1919, the Mayo brothers dissolved their partnership and turned the clinic’s name and assets, including the bulk of their life savings, to a private, not-for-profit, charitable organization now known as Mayo Foundation. It is worth noting that the Mayo Clinic became a favored place to have thyroid surgery, as its location is in the “goiter belt”.

Patients discovered the advantages to a “pooled resource” of knowledge and skills among doctors. In fact, the group practice concept that the Mayo family originated has influenced the structure and function of medical practice throughout the world.

The Nobel Prize in Physiology or Medicine 1912 was awarded to Alexis Carrel “in recognition of his work on vascular suture and the transplantation of blood vessels and organs”. He demonstrated the technique used to suture together open vessels, and even to transplant whole organs from one animal to another with excellent results.

The Nobel Prize in Physiology or Medicine 1920 was awarded to August Krogh “for his discovery of the capillary motor regulating mechanism”.  Harvey had shown in 1628 that the blood traverses the circulation returning to the heart in one minute. Malpighi showed that blood passes from the artery to the vein by capillaries  in 1661.  Krogh demonstrated by very elegant experiments that the quantity of gas that diffuses across the pulmonary alveoli is the same amount of gas that is released to the alveolar space. The importance of this is that the investigations having the aim to determine the process by which the oxygen requirement of the tissues is satisfied.

The Nobel Prize in Physiology or Medicine 1922 was divided equally between Archibald Vivian Hill “for his discovery relating to the production of heat in the muscle” and Otto Fritz Meyerhof “for his discovery of the fixed relationship between the consumption of oxygen and the metabolism of lactic acid in the muscle”. One need not be a physiologist to recognize that muscular activity is essentially bound up with the development of heat, or even with combustion. AV Hill determined the time relationships of heat production in muscle contraction measured galvanometrically, and Otto Meyerhof determined the oxygen consumption in the production of lactic acid. The muscle is regarded as a machine that converts chemical energy to mechanical energy (tension) with the production of heat. The development of heat entirely fails to appear if the supply of oxygen to the muscle is cut off, while the development of heat during the actual twitch, is independent of the presence of oxygen (consistent with Meyerhof’s glycolysis). The relaxation phase is consistent with oxygen uptake during recovery.

Fletcher and Hopkins had shown earlier that muscle not only forms, but also uses lactic acid in the presence of oxygen. Meyerhof determined by parallel determination of the lactic acid metabolism and the oxygen consumption during the recovery of the muscle, which yielded the result that the oxygen consumption does not account for more than1/3 – 1/4 of the lactic acid formed. When lactic
acid is formed an equivalent amount of glycogen in muscle disappears, and when lactic acid disappears, the quantity of
carbohydrate increases by the difference between lactic acid and quantity used in oxygen consumption.

The Nobel Prize in Physiology or Medicine 1923 was awarded jointly to Frederick Grant Banting and John James Rickard
Macleod “for the discovery of insulin”.  In 1857, Claude Bernard discovered that the liver contains glycogen, which converted to glucose, enters the blood stream (and thereby, the urine). Glycosuria became a starting point for the study of diabetes. It is of interest that he could not produce glycosuria by ligation of the pancreatic duct. But in 1889 Mering and Minkowsky did an operation on dogs that removed the pancreas, resulting in glycosuria, and creating a disease comparable to diabetes in humans. If part of the pancreas was left behind, it failed to produce diabetes. Brown-Sequard had called attention to ductless organs in the 1880s that are glands. These were
endocrine glands secreting hormones. Langerhans had shown in 1869 that the pancreas has glands that have no secretion into the pancreatic ducts, and in the beginning of the 1890s Languese surmised that these glands were involved in diabetes mellitus. Schulze and Ssobolev had shown that ligation of the duct resulted in atrophy of the pancreas sparing the islets. Frederick Banting at this time postulated that trypsin degraded the hormone, and with Best and Collip, under MacLeod’s guidance, Banting pursued his idea, and the effective extract was obtained in 1921, and demonstrated in 1922.

Arch Anat Histol Embryol. 1993-1994;75:151-82.

[History of histology in Strasbourg].

Le Minor JM.

Since the cellular theory was formulated in 1839, the University of Strasbourg has held a pioneer place in histology. This new morphological science has had, since its origin, close relations with physiology, and from 1846 to 1871, an original histophysiological school was organized in Strasbourg. The microscope and the study of tissues were considered as a fundamental approach for the progress of biological and medical knowledge. After the German annexation of Alsace, the scientists from this school participated in the renewal of histology in Nancy, Montpellier, and Paris. In 1872, when the new German university was created, an anatomical institute regrouped all aspects of normal morphology: anatomy, histology, and embryology. This was the case until 1918. In 1919, when the Faculty of Medicine was reorganized after Alsace was restored to France, a specific chair and institute of histology were created. This was the beginning of a school of histophysiology which was internationally renowned in the rise of experimental endocrinology. Great discoveries followed one after another: folliculin in 1924 and demonstration of the duality of ovarian hormones, the prominent place of the anterior part of the hypophysis and the demonstration of prolactin in 1928, thyreostimulin in 1929, then study of the other stimulins. In 1946 a chair and institute of medical biology were created. In 1948, a service of electron microscopy was opened.
P. Bouin (1870-1962), M. Aron (1892-1974), J. Benoit (1896-1982), R. Courrier (1895-1986) et M. Klein (1905-1975), were among the famous scientists who worked in histology in Strasbourg in the
period after the French restoration.
The Nobel Prize in Physiology or Medicine 1947

Bernardo Alberto Houssay

“for his discovery of the part played by the hormone of the anterior pituitary lobe in the metabolism of sugar”

He had already begun studying medicine and, in 1907, before completing his studies, he took up a post in the Department of Physiology. He began here his research on the hypophysis which resulted in his M.D.-thesis (1911), a thesis which earned him a University prize.

In 1919 he became Professor of Physiology in the Medical School at Buenos Aires University. He also organized the Institute of Physiology at the Medical School, making it a center with an international reputation. He remained Professor and Director of the Institute until 1943.  He made a lifelong study of the hypophysis and his most important discovery concerns the role of the anterior lobe of the hypophysis in carbohydrate metabolism and the onset of diabetes.

The Nobel Prize in Physiology or Medicine 1950

Edward Calvin Kendall, Tadeus Reichstein and Philip Showalter Hench

“for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects”

As late as in 1854 the German anatomist, Kölliker, was able to claim in a review of the subject that although the function of the adrenals was still unknown, yet in certain respects great advances had been made. Two quite different parts were now distinguished, an outer part, a fairly firm cortex, and an inner, softer medulla. Kölliker classified the adrenal cortices as ductless glands, which we now call the endocrine organs.

Thomas Addison, the English doctor, observed a rare disease with a fatal course, which was characterized chiefly by anemia, general weakness and fatigue, disturbances in the digestive apparatus, enfeebled heart activity and a peculiar dark pigmentation of the skin. He published a paper 1n 1855, suggesting that this morbid picture made its appearance in persons the greater part of whose adrenals was destroyed. Subsequent experiments in animals showed that removal of the adrenals led to speedy death, the symptoms recalling those known from Addison’s disease.

In 1894 Oliver and Schäfer proved that the injection of a watery extract from the adrenals had extremely pronounced effects. Within a few years adrenaline had been produced from the extract, its composition had been ascertained, and its artificial production accomplished. The more detailed analysis showed effects of the same kind as those resulting on increased activity of the so-called sympathetic nervous system, which innervates internal organs such as the heart and vessels, the intestinal canal, etc.  Attempts to prevent by means of adrenaline the deficiency symptoms following on the removal of the adrenals failed completely. The explanation of this was given when Biedl and others showed that it is the cortex which is of vital importance, not the medulla.

The isolation of the cortin proved to be a difficult task, calling for the combined efforts of a number of research workers. Particularly important contributions were made in this field by Wintersteiner and Pfiffner, and also by Edward Kendall at the Mayo Clinic in Rochester, and Tadeus Reichstein in Basel, and their co-workers. As early as in 1934, Kendall and his group succeeded in preparing from cortex extract what was at first assumed to be pure cortin in crystalline form. They found that it contained carbon, hydrogen, and oxygen, and indicated its empirical formula. But that was only a beginning. There was no reason to suspect that the cortin was not homogeneous; as further experiments proved. In reality Kendall and his co-workers had produced a mixture of different substances closely related to one another, and their work represents the early steps in the crystallization of a whole series of cortin substances. There is at least one active cortical substance – the best known of them all, first named Compound E and now called cortisone or cortone – which was isolated at four different laboratories, among them Kendall’s and Reichstein’s.

As all the cortin substances are closely related to one another, Reichstein’s finding implies that, like the sex hormones, they belong to the large and important group of steroids. The D vitamins and the bile acids, like our most important heart remedies, the active substances in Digitalis leaves and Strophanthus seeds, are also intimately associated with the steroids

The six definitely active cortical hormones are characterized, inter alia, by a double bond in the steroid skeleton; if this double bond disappears, inactive substances are obtained. They differ very inconsiderably from each other chemically. They are built up of 21 carbon atoms, but the number of oxygen atoms in the molecule is three, four, or five. The position of the additional oxygen atoms in the molecule was first established by Reichstein and Kendall, and thus a way was opened for semisynthetic production e.g. from the more easily obtainable bile acids or material from a certain species of Strophanthus. This is of particular importance, since the yield from the adrenals is very poor, at most about 1:1,000,000.

Thanks to the work of Kendall and his school, it has emerged that the comparatively inconsiderable dissimilarities in the matter of the structure of the cortical hormones are accompanied by material differences in respect of the effect. Thus some act especially strongly on the metabolism of sugar, others on the salt and fluid balances, and there are also several other differences. This was illustrated when Compound E was first tested. Pfiffner and Wintersteiner, like the Reichstein group, found that the substance had no, or extremely inconsiderable, life-prolonging effects on animals deprived of the adrenals. On the other hand, Ingle, Kendall’s coworker, observed that it stimulated the muscular work of such animals very strongly.

In the April of 1949, Hench, Kendall, Slocumb and Polley published their experiences in respect of the dramatic effects of cortisone in cases of chronic rheumatoid arthritis. A rapid improvement set in, pains and tenderness in the joints abated or disappeared, mobility increased, so that patients who had previously been complete invalids could walk about freely, and their general condition was also favourably affected. Similar results were obtained with a preparation from the anterior lobe of the pituitary, the so-called ACTH (Adreno-Cortico-Tropic Hormone), which, as the name indicates, stimulates the adrenal cortex to increased activity.

The value of a discovery lies not only in the immediate practical results, but equally much in the fact that it points out new lines of research. This is strikingly illustrated by the research during the last few decades into the cortical hormones, which has already led to unexpected and important new results within widely different spheres.

Nobel Prize in Physiology or Medicine 1966

Charles Huggins

Endocrine-Induced Regression of Cancers

The net increment of mass of a cancer is a function of the interaction of the tumor and its soil. Self-control of cancers results from a highly advantageous competition of host with his tumor. There are multiple factors which restrain cancer – enzymatic, nutritional, immunologic, the genotype and others.Prominent among them is the endocrine status, both of tumor and host – the subjects of this discourse.

The second quarter of our century found the biological sciences much pre-occupied with two noble topics :

  • chemistry and physiology of steroids and
  • biochemistry of organo-phosphorus compounds.

The key to the puzzle of the steroid hormones in cancer was the isolation of crystalline estrone by Doisy et al.2 from extracts of urine of pregnant women. In the phosphorus field there were magnificent findings of hexose phosphates, nucleotides, coenzymes and high-energy phosphate intermediates. These wonderful discoveries provided the Zeitgeist for our work.

Through the portal of phosphorus metabolism we entered on a series of interconnected observations in steroid endocrinology. A program was not prepared in advance for this basic physiologic study. The work was fascinating and informative so that it provided its own momentum and served as an end in itself.

The prostatic cell does not die in the absence of testosterone, it merely shrivels. But the hormone-dependent cancer cell is entirely different. It grows in the presence of supporting hormones but it dies in their absence and for this reason it cannot participate in growth cycles.

A remarkable effect of testosterone is the promotion of growth of its target cells during complete deprival of food. Androstane derivatives conferred on the prostate of puppies a selective nutritional advantage during starvation of 3 weeks whereby abundant growth of this gland-occurred while there was serious cell breakdown in most of the tissues of the body.

At first it was vexatious to encounter a dog with a prostatic tumor during a metabolic study but before long such dogs were sought. It was soon observed that orchiectomy or the administration of restricted amounts of phenolic estrogens caused a rapid shrinkage of canine prostatic tumors.

The experiments on canine neoplasia proved relevant to human prostate cancer; there had been no earlier reports indicating any relationship of hormones to this malignant growth.

Kutscher and Wolbergs9 discovered that acid phosphatase is rich in concentration in the prostate of adult human males. Gutman and Gutman10 found that many patients with metastatic prostate cancer have significant increases of acid phosphatase in their blood serum. Cancer of the prostate frequently metastasizes to bone.

Human prostate cancer which had metastasized to bone was studied at first. The activities of acid and alkaline phosphatases in the blood were measured concurrently at frequent intervals. The methods are reproducible and not costly in time or materials; both enzymes were measured in duplicate in a small quantity (0.5 ml) of serum. The level of acid phosphatase indicated activity of the disseminated cancer cells in all metastatic loci. The titer of alkaline phosphatase revealed the function of the osteoblasts as influenced by the presence of the prostatic cancer cells that were their near neighbors. By periodic measurement of the two enzymes one obtains a view of overall activity of the cancer and the reaction of non-malignant cells of the host to the presence of that cancer. Thereby the great but opposing influences of, respectively, the administration or deprival of androgenic hormones upon prostate cancer cells were revealed with precision and simplicity. Orchiectomy or the administration of phenolic estrogens resulted in regression of cancer of the human prostate whereas, in untreated cases, testosterone enhanced the rate of growth of the neoplasm.

The first indication that advanced cancer can be induced to regress was the beneficial effect of oöphorectomy on cancer of the breast of two women. This empirical observation17 of Beatson in 1896 was remarkable since it was made before the concept of hormones had been developed. The beneficial action of removal of ovaries was not understood until steroid hormones had been isolated 4 decades later.

But why does breast cancer thrive in folks who do not possess ovarian function – in men, old women, and females who have had oöphorectomy?

Farrow and Adair observed that benefits of great magnitude frequently follow orchiectomy in mammary cancer in the human male. Thereby, they established that testis function can sustain mammary cancer.

A half century after the classic invention of Beatson it was found out that adrenal function can maintain and promote growth of human mammary cancer. The adrenal factor supporting growth of cancer was identified when it was shown that bilateral adrenalectomy (with glucocorticoids as substitution therapy) can result in profound and prolonged regression of mammary carcinoma in men and women who do not possess gonadal function. In developing the idea of adrenalectomy for treatment of advanced cancer in man we were considerably influenced by the discovery of Woolley et al. that adrenals can evoke cancer of the breast in the mouse.

Mammary cancers induced in the male rat by aromatics were not influenced by orchiectomy and hypophysectomy; by definition, these neoplasms are hormone-independent. In contrast to male rat, most mammary cancers of men wither impressively after deprival of supporting hormones.

The hormone-responsiveness of established mammary cancers induced in female rat by aromatics or ionizing radiation is identical; it was a newly recognized property of experimental breast cancers. Prior to this finding, clinical study of patients with mammary cancer was the only material available for investigation of hormonal-restraint of neoplasms of the breast.

In female rat, many but far from all of the induced mammary cancers vanished after removal of ovaries or the pituitary. In our experiments hypophysectomy was the most efficient of all methods to cure rat’s mammary cancer.

Malignant cells which succumb to hormone-deprival, by definition, are hormone-dependent. The quality of hormone-dependence resides in the tumor cells whereas their growth is determined by the host’s endocrine status.

Both man and the animals can have some of their cancer cells which are hormone-dependent while other neoplastic cells in the same organism are not endocrine-responsive.

The cure of a cancer after hormone-deprival results from death of the cancer cells whereas their normal analogues in the same animal shrivel but survive. It is a basic proposition in endocrine-restraint of malignant disease that cancer cells can differ in a crucial way from ancestral normal cells in response to modification of the hormonal milieu intérieur of the body.

Cancer is not necessarily autonomous and intrinsically self-perpetuating. Its growth can be sustained and propagated by hormonal function in the host which is not unusual in kind or exaggerated in rate but which is operating at normal or even subnormal levels.

The control of cancer by endocrine methods can be described in three propositions:

  • Some types of cancer cells differ in a cardinal way from the cells from which they arose in their response to change in their hormonal environment.
  • Certain cancers are hormone-dependent and these cells die when supporting hormones are eliminated.
  • Certain cancers succumb when large amounts of hormones are administered.

The Nobel Prize in Physiology or Medicine 1971

Earl W. Sutherland, Jr.

“for his discoveries concerning the mechanisms of the action of hormones”

Part II. Vitamins

The Nobel Prize in Physiology or Medicine 1929

Christiaan Eijkman “for his discovery of the antineuritic vitamin”

Sir Frederick Gowland Hopkins “for his discovery of the growth-stimulating vitamins”

When the 20th century began, the prevailing thought about nutrition rested on the importance of energy requirements, as elucidated by  Rubner, Benedict and others, in the United States, that entails the quantitative measurement of the food value of carbohydrates, fats, and proteins. But there was a misconception of the process in its detail. The quantitative studies of the energetics and of respiratory exchange were not sufficient to explain problems that arise as a result of deficiencies of micronutrients in food intake.  The complexity of these nutritional needs as we now view them is indeed astonishing.

There is a need for indispensable organic substances specific in nature and function of which the quantitative supply is so small as to contribute little or nothing to the energy factor in nutrition. These substances, following the suggestion of Casimir Funk, we have agreed to call vitamins.

In 1881, Lunin, and associate of Bungel noted that a diet of milk was not sufficient to sustain the life of mice, even if the caloric nutrients were adequate. The main lesson taken from the findings was concerned with inorganic nutrients had not been determined that would answer the question. A decade later, Socin, in Bunge’s group, concluded that the deficiency was in the quality of protein.  In an important paper by Professor Pekelharing in 1905 published an astonishing paper following on the work in Bungel’s lab. He noted that there is a substance in milk in small quantities that he was unable to identify that is essential for life.  It is noteworthy that Pekelharing records prolonged endeavours towards the isolation of a vitamin.

Eikman’s work came in the 1880s. He did not at first visualize beriberi clearly as a deficiency disease. The view that the cortical substance in rice supplied a need rather than neutralized a poison was soon after put forward by Grijns and ultimately accepted by Professor Eijkman himself.  The prevailing thinking about nutritional requirements was preoccupied by the methods of calorimetry at the turn of the century.  The idea of “deficiency diseases” was obscured as a result. There was no concept of an indispensable portion of the food supply other than calories, proteins and minerals until 1911-1912.  Hopkins was convinced that the science of nutrition had to come to terms with an explanation for scurvy and rickets, and he needed to use the new science of biochemistry, which was ongoing at Cambridge.

In 1906-1907, he carried out studies of feeding rats casein, along the lines of Bungel.s experiments, and he found variability in the results with different casein preparations.  He next washed the casein so that any soluble substance was extracted and the rats died, but if he added the extract they grew.  He also used butter, with results more favorable than casein, and lard, with unfavorable results.  At the same time he was studying polyneuritis in birds, which took up much time.  He know that he had to extract the substance, but was unaware of the fat solubility in 1910. He published his work in 1912. Soon after the publication of his work, and duting WWI, much research was done in US, by Osborn and Mendel at Harvard, and by McCollum at Johns Hopkins, and the vitamins were separated into “water soluble” and “fat soluble”.

The Nobel Prize in Physiology or Medicine 1937

Albert von Szent-Györgyi Nagyrápolt

“for his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid”

Szent Gyorgyi was a biochemist who worked with Otto Warburg and others, and had a special interest in muscle metabolism. He delineated a portion of the Krebs cycle (Krebs was also associated with Warburg), that which involves the conversion of fumaric acid to succinate.  He also purified vitamin C (ascorbic acid) from paprika in his native region of Hungary. He later turned his interest to cancer research, for which he was honored by the MD Anderson Cancer Center.

The Nobel Prize in Physiology or Medicine 1934

George Hoyt Whipple, George Richards Minot and William Parry Murphy

“for their discoveries concerning liver therapy in cases of anaemia”

The Nobel Prize in Physiology or Medicine 1943

Henrik Carl Peter Dam “for his discovery of vitamin K”

Edward Adelbert Doisy “for his discovery of the chemical nature of vitamin K”

To further his studies of the metabolism of sterols, Dam obtained a Rockefeller Fellowship and worked in Rudolph Schoenheimer’s Laboratory in Freiburg, Germany, during 1932-1933, and later worked with P. Karrer, of Zurich, in 1935. He discovered vitamin K while studying the sterol metabolism of chicks in Copenhagen. When he returned to Denmark after WWII in 1946, Dam’s main research subjects were vitamin K, vitamin E, fats, cholesterol.

Part III.  Microbiology and Plague

The Nobel Prize in Physiology or Medicine 1901

Emil Adolf von Behring

“for his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and deaths”

The Nobel Prize in Physiology or Medicine 1902

Ronald Ross

“for his work on malaria, by which he has shown how it enters the organism and thereby has laid the foundation for successful research on this disease and methods of combating it”

The Nobel Prize in Physiology or Medicine 1905

Robert Koch

“for his investigations and discoveries in relation to tuberculosis”

The Nobel Prize in Physiology or Medicine 1908

The Nobel Prize in Physiology or Medicine 1928

Charles Jules Henri Nicolle

“for his work on typhus”

The Nobel Prize in Physiology or Medicine 1939

Gerhard Domagk

“for the discovery of the antibacterial effects of prontosil”

The Nobel Prize in Physiology or Medicine 1945

Sir Alexander Fleming, Ernst Boris Chain and Sir Howard Walter Florey

“for the discovery of penicillin and its curative effect in various infectious diseases”

The Nobel Prize in Physiology or Medicine 1951

Max Theiler

“for his discoveries concerning yellow fever and how to combat it”

The Nobel Prize in Physiology or Medicine 1952

Selman Abraham Waksman

“for his discovery of streptomycin, the first antibiotic effective against tuberculosis”

The Nobel Prize in Physiology or Medicine 1954

John Franklin Enders, Thomas Huckle Weller and Frederick Chapman Robbins

“for their discovery of the ability of poliomyelitis viruses to grow in cultures of various types of tissue”

The Nobel Prize in Physiology or Medicine 1976

Baruch S. Blumberg and D. Carleton Gajdusek

“for their discoveries concerning new mechanisms for the origin and dissemination of infectious diseases”

Part IV.

Ilya Ilyich Mechnikov and Paul Ehrlich

“in recognition of their work on immunity”

The Nobel Prize in Physiology or Medicine 1919

Jules Bordet

“for his discoveries relating to immunity”

The Nobel Prize in Physiology or Medicine 1930 was awarded to Karl Landsteiner “for his discovery of human blood groups”.

In 1901, in the course of his serological studies Landsteiner observed that when, under normal physiological conditions, blood serum of a human was added to normal blood of another human the red corpuscles in some cases coalesced into larger or smaller clusters. This observation of Landsteiner was the starting-point of his discovery of the human blood groups. In the following year, i.e. 1901, Landsteiner published his discovery that in man, blood types could be classified into three groups according to their different agglutinating properties. These agglutinating properties were identified more closely by two specific blood-cell structures, which can occur either singly or simultaneously in the same individual.

Landsteiner’s discovery of the blood groups was immediately confirmed but it was a long time before anyone began to realize the great importance of the discovery. The first incentive to pay greater attention to this discovery was provided by von Dungern and Hirszfeld when in 1910 they published their investigations into the hereditary transmission of blood groups. Thereafter the blood groups became the subject of exhaustive studies, on a scale increasing year by year, in more or less all civilized countries. In order to avoid, in the publication of research on this subject, detailed descriptions which would otherwise be necessary – of the four blood groups and their appropriate cell structures, certain short designations for the blood groups and corresponding specific cell structures have been introduced. Thus, one of the two specific cell structures, characterizing the agglutinating properties of human blood is designated by the letter A and another by B, and accordingly we speak of «blood group A» and «blood group B». These two cell structures can also occur simultaneously in the same individual, and this structure as well as the corresponding blood group is described as AB.

The fourth blood-cell structure and the corresponding blood group is known as O, which is intended to indicate that people belonging to this group lack the specific blood characteristics typical of each of the other blood groups. Landsteiner had shown that under normal physiological conditions the blood serum will not agglutinate the erythrocytes of the same individual or those of other individuals with the same structure. Thus, the blood serum of people whose erythrocytes have group structure A will not agglutinate erythrocytes of this structure but it will agglutinate those of group structure B, and where the erythrocytes have group structure B the corresponding serum does not agglutinate these erythrocytes but it does agglutinate those with group structure A. Blood serum of persons whose erythrocytes have structures A as well as B, i.e. who have structure AB, does not agglutinate erythrocytes having structures A, B, or AB. Blood serum of persons belonging to blood group O agglutinates erythrocytes of persons belonging to any of the group.

The group characteristics are handed down in accordance with Mendel’s laws. The characteristics of blood groups A, B, and AB are dominant, and opposing these dominant characteristics are the recessive ones which characterize blood group O. An individual cannot belong to blood group A, B, or AB, unless the specific characteristics of these groups are present in the parents, whereas the recessive characteristics of blood group O can occur if the parents belong to any one of the four groups. If both parents belong to group O, then the children never have the characteristics of A, B, or AB. The children must then likewise belong to blood group O. If one of the parents belongs to group A and the other to group B, then the child may belong to group A or B or it may possess both characteristics and therefore belong to group AB. If one of the parents belongs to group AB and the other to group O, then in accordance with Mendel’s law of segregation the AB characteristic can be segregated and the components can occur as separate characteristics in the children.

Even while he was a student he had begun to do biochemical research and in 1891 he published a paper on the influence of diet on the composition of blood ash. To gain further knowledge of chemistry he spent the next five years in the laboratories of Hantzsch at Zurich, Emil Fischer at Wurzburg, and E. Bamberger at Munich.

In 1896 he became an assistant under Max von Gruber in the Hygiene Institute at Vienna. Even at this time he was interested in the mechanisms of immunity and in the nature of antibodies. From 1898 till 1908 he held the post of assistant in the University Department of Pathological Anatomy in Vienna, the Head of which was Professor A. Weichselbaum, who had discovered the bacterial cause of meningitis, and with Fraenckel had discovered the pneumococcus. Here Landsteiner worked on morbid physiology rather than on morbid anatomy. In this he was encouraged by Weichselbaum, in spite of the criticism of others in this Institute.

Up to the year 1919, after twenty years of work on pathological anatomy, Landsteiner with a number of collaborators had published many papers on his findings in morbid anatomy and on immunology. He discovered new facts about the immunology of syphilis, added to the knowledge of the Wassermann reaction, and discovered the immunological factors which he named haptens (it then became clear that the active substances in the extracts of normal organs used in this reaction were, in fact, haptens). He made fundamental contributions to our knowledge of paroxysmal haemoglobinuria.

He also showed that the cause of poliomyelitis could be transmitted to monkeys by injecting into them material prepared by grinding up the spinal cords of children who had died from this disease, and, lacking in Vienna monkeys for further experiments, he went to the Pasteur Institute in Paris, where monkeys were available. His work there, together with that independently done by Flexner and Lewis, laid the foundations of our knowledge of the cause and immunology of poliomyelitis.

His discovery of the differences and identification of the groups that were alike made it possible for blood transfusions to become a routine procedure.  This paved the way for many other medical procedures that we don’t even think twice about today, such as surgery, blood banks, and transplants.

While in medical school, Landsteiner began experimental work in chemistry, as he was greatly inspired by Ernst Ludwig, one of his professors. After receiving his medical degree, Landsteiner spent the next five years doing advanced research in organic chemistry for Emil Fischer, although medicine remained his chief interest. During 1886-1897, he combined these interests at the Institute of Hygiene at the University of Vienna where he researched immunology and serology. These fields were developing rapidly in the late 1800s as scientists explored numerous physiological changes associated with bacterial infection. Immunology and serology then became Landsteiner’s lifelong focus. Landsteiner was primarily interested in the lack of safety and effectiveness of blood transfusions.

Landsteiner is known as the “melancholy genius” because he was so sad and intense, yet he was so systematic, thorough, and dedicated. He wrote 346 papers during his long career contributing to many areas of scientific knowledge. He is considered the father of Hematology (the study of blood), Immunology (the study of the immune system), Polio research, and Allergy research.

The fundamental contribution of Robert A. Good to the discovery of the crucial role of thymus in mammalian immunity

Domenico Ribatti

Immunology. Nov 2006; 119(3): 291–295.

Robert Alan Good was a pioneer in the field of immunodeficiency diseases. He and his colleagues defined the cellular basis and functional consequences of many of the inherited immunodeficiency diseases. His was one of the groups that discovered the pivotal role of the thymus in the immune system development and defined the separate development of the thymus-dependent and bursa-dependent lymphoid cell lineages and their responsibilities in cell-mediated and humoral immunity.

Keywords: bursa of Fabricius, history of medicine, immunology, thymus

Robert A. Good (Fig. 1) began his intellectual and experimental queries related to the thymus in 1952 at the University of Minnesota, initially with paediatric patients. However, his interest in the plasma cell, antibodies and the immune response began in 1944, while still in Medical School at the University of Minnesota in Minneapolis, with his first publication appearing in 1945.

Robert Good

Robert Good

Figure 1

Robert A. Good with two young patients. Source:

Good described a new syndrome that would carry his name: ‘Good syndrome: thymoma with immunodeficiency’.7 The clinical characteristics of Good syndrome are increased susceptibility to bacterial infections by encapsulated organisms and opportunistic viral and fungal infections. Subsequently, Good saw several patients with thymic tumours, which regularly presented with immunodeficiencies, leukopenia, lymphopenia and eosinophylopenia. Plasma cells, however, were not completely absent: the patient was severely hypogammaglobulinaemic rather than agammaglobulinaemic.

The association of thymoma with profound and broadly based immunodeficiency provoked Good’s group to ask what role the thymus plays in immunity.

Good and others found that the patients lacked all of the subsequently described immunoglobulins. These patients were found not to have plasma cells or germinal centres in their haematopoietic and lymphoid tissues. They possessed circulating lymphocytes in normal numbers.

In the mouse and other rodents, immunological depression is profound after thymectomy in neonatal animals, resulting in considerable depression of antibody production, plus deficient transplantation immunity and delayed-type hypersensitivity. Speculation on the reason for immunological failure following neonatal thymectomy has centred on the thymus as a source of cells or humoral factors essential to normal lymphoid development and immunological maturation.

Three independent groups of experiments showed that neonatal thymectomy has a significant effect on immunological reactivity: (i) the studies of Fichtelius et al. in young guinea-pigs showed that the depression of antibody response is slight, but significant; (ii) the experiments of Archer, Good and co-workers in rabbits and mice; and (iii) the studies by Miller at the Chester Beatty Research Institute in London.

Stutman, in Good’s laboratory, demonstrated that non-lymphoid thymomas induced the restoration of immunological functions in neonatally thymectomized mice and that when thymomas were grafted into allogenic hosts, immunological restoration was mediated by lymphoid cells of host type. Comparable results were obtained with free thymus grafts.

Cooper et al. postulated that a lymphoid stem cell population exists that is induced to differentiate along two distinct and separate cell lines related to two central lymphoid organs. In birds this developmental influence is exercised by the thymus and the bursa of Fabricius. Removal of one or both in the early post-hatching period has strikingly different influences on immunological function in the maturing animals. The thymus in the chicken functions exactly as does the thymus of the mouse. It represents the site of differentiation of a population of lymphocytes that subserve largely the functions of cell-mediated immunity.

The athymic children described by Di George, who lacked lymphoid cells in the deep cortical areas of the nodes but not at the peripheral areas, seemed the equivalent of the neonatally thymectomized mice and chickens. These patients had severe deficiencies of small T lymhocytes and profound deficiencies of all cell-mediated immunities, including delayed allergies, deficient allograft immunities and deficiencies in resistance to viruses, fungi and opportunistic infections.

The Nobel Prize in Physiology or Medicine 1960

Sir Frank Macfarlane Burnet and Peter Brian Medawar

“for discovery of acquired immunological tolerance”

The Nobel Prize in Physiology or Medicine 1980

Baruj Benacerraf, Jean Dausset and George D. Snell

“for their discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions”

Part V.

Biochemistry and Molecular Biology

The Nobel Prize in Physiology or Medicine 1922

Archibald Vivian Hill

“for his discovery relating to the production of heat in the muscle”

Otto Fritz Meyerhof

“for his discovery of the fixed relationship between the consumption of oxygen and the metabolism of lactic acid in the muscle”

The Nobel Prize in Physiology or Medicine 1931

Otto Heinrich Warburg

“for his discovery of the nature and mode of action of the respiratory enzyme”

The Nobel Prize in Physiology or Medicine 1933

Thomas Hunt Morgan

“for his discoveries concerning the role played by the chromosome in heredity”

The Nobel Prize in Physiology or Medicine 1947

Carl Ferdinand Cori and Gerty Theresa Cori, née Radnitz

“for their discovery of the course of the catalytic conversion of glycogen”

The Nobel Prize in Physiology or Medicine 1953

Hans Adolf Krebs

“for his discovery of the citric acid cycle”

Fritz Albert Lipmann

“for his discovery of co-enzyme A and its importance for intermediary metabolism”

The Nobel Prize in Physiology or Medicine 1955

Axel Hugo Theodor Theorell

“for his discoveries concerning the nature and mode of action of oxidation enzymes”

The Nobel Prize in Physiology or Medicine 1958

George Wells Beadle and Edward Lawrie Tatum

“for their discovery that genes act by regulating definite chemical events”

The Nobel Prize in Physiology or Medicine 1959

Severo Ochoa and Arthur Kornberg

“for their discovery of the mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid”

Joshua Lederberg

“for his discoveries concerning genetic recombination and the organization of the genetic material of bacteria”

The Nobel Prize in Physiology or Medicine 1962

Francis Harry Compton Crick, James Dewey Watson and Maurice Hugh Frederick Wilkins

“for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material”

The Nobel Prize in Physiology or Medicine 1963

Sir John Carew Eccles, Alan Lloyd Hodgkin and Andrew Fielding Huxley

“for their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane”

The Nobel Prize in Physiology or Medicine 1964

Konrad Bloch and Feodor Lynen

“for their discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism”

The Nobel Prize in Physiology or Medicine 1965

François Jacob, André Lwoff and Jacques Monod

“for their discoveries concerning genetic control of enzyme and virus synthesis”

The Nobel Prize in Physiology or Medicine 1967

Ragnar Granit, Haldan Keffer Hartline and George Wald

“for their discoveries concerning the primary physiological and chemical visual processes in the eye”

The Nobel Prize in Physiology or Medicine 1968

Robert W. Holley, Har Gobind Khorana and Marshall W. Nirenberg

“for their interpretation of the genetic code and its function in protein synthesis”

The Nobel Prize in Physiology or Medicine 1969

Max Delbrück, Alfred D. Hershey and Salvador E. Luria

“for their discoveries concerning the replication mechanism and the genetic structure of viruses”

The Nobel Prize in Physiology or Medicine 1970

Sir Bernard Katz, Ulf von Euler and Julius Axelrod

“for their discoveries concerning the humoral transmittors in the nerve terminals and the mechanism for their storage, release and inactivation”

The Nobel Prize in Physiology or Medicine 1972

Gerald M. Edelman and Rodney R. Porter

“for their discoveries concerning the chemical structure of antibodies”

The Nobel Prize in Physiology or Medicine 1974

Albert Claude, Christian de Duve and George E. Palade

“for their discoveries concerning the structural and functional organization of the cell”

The Nobel Prize in Physiology or Medicine 1975

David Baltimore, Renato Dulbecco and Howard Martin Temin

“for their discoveries concerning the interaction between tumour viruses and the genetic material of the cell”
The Nobel Prize in Physiology or Medicine 1977

Rosalyn Yalow

“for the development of radioimmunoassays of peptide hormones”

The Nobel Prize in Physiology or Medicine 1978

Werner Arber, Daniel Nathans and Hamilton O. Smith

“for the discovery of restriction enzymes and their application to problems of molecular genetics”

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