An Interview with Manuel and Ann Varela: Otto Meyerhof: What makes those muscles twitch and burn, and what is glycolysis?

Jun 15, 2020 by

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Otto Meyerhof

Michael F. Shaughnessy –

1) Otto Meyerhof—Nobel Prize winner—came to us from Germany—when was he born, and how did he spend his youth?

Dr. Otto Meyerhof is best known for elucidating the glycolytic pathway, also named the Embden-Meyerhof-Parnas pathway in honor of him and his co-discoverers, Gustav Embden and Jacob Parnas. Otto Fritz Meyerhof was born to Jewish parents Felix (an affluent merchant) and Bettina May Meyerhof on the 12th of April in 1884 in Hannover, Germany.

Meyerhof suffered from kidney troubles in his mid-teen years and was unable to attend school. His mother was his constant companion during his recovery, and she provided him with various reading materials dealing with biology, chemistry, and medicine. He was known to write poetry and made strides with artistic endeavors as well. Thus, his mother had a significant influence on his forthcoming profession. In 1900, his physician recommended that he spend time in Egypt to build up his strength.

Meyerhof was enrolled at Wilhelms Gymnasium (classical secondary school). After high school graduation, Meyerhof attended the University of Freiburg at Breisgau, then at the University of Berlin. He also attended the University of Strasbourg. During Meyerhof’s time, it was a common practice to acquire medical training and experience at many different universities. In 1909 Meyerhof took his M.D. degree from the University of Heidelberg.

2) Early on, he seemed to show an interest in psychiatry, psychology, philosophy, and mental illness. I wonder what dissuaded him.

Before taking his medical doctorate in 1909, Meyerhof’s dissertation was focused on the psychological theory of mental disturbances and revealed his early interest in psychology and psychiatry. Meyerhof’s interests in these topics began in high school and extended into his university studies and medical school. One significant influence in these areas was imparted upon Meyerhof by Leonard Nelson. He had led a group devoted to the study of German philosophers Jacob Friedrich Fries and Immanuel Kant and their religious philosophy. The main emphasis of the Fries and Kant philosophy was that of rational thought as applied to a religious inquiry. Meyerhof’s early writings and lectures indicate these philosophical approaches in his scientific thinking.

Immediately after graduating from medical school, Dr. Meyerhof started work at Heidelberg in a medical clinic headed by Dr. Ludwig Krehl, whose expertise was in cell physiology. However, the main driving force for dissuading Meyerhof from psychiatry and psychology was Dr. Otto Warburg, whom Meyerhof had met for the first time in Krehl’s clinic in 1909. You will recall from our first book that Warburg would be famous for his discoveries about the mode and nature of respiration and who would garner a Nobel Prize in 1931 for his breakthroughs in this field. Warburg and Meyerhof worked at the prestigious Marine Zoological Laboratory at Naples, Italy, where they studied metabolism in the eggs of sea urchins.

Warburg is widely credited with converting Meyerhof’s interests in psychiatry, psychology, and philosophy into those of cellular biochemistry and physiology. Meyerhof’s new way of thinking was now centered on the problem of body heat and its liberation from the body by the consumption of food and its subsequent breakdown. Thus, with his new interests in physiology and biochemistry inspired by Warburg, Meyerhof approached the body heat problem by focusing his investigation on how exactly the energy stored food was transduced into useful energy when generating heat.

Meyerhof reasoned that the energy liberation from food involved a series of energy transformations, which in turn provided a basis for conferring life upon cells, tissues, organs, and organisms. Furthermore, Meyerhof viewed these energy transductions as a sort of dynamic process, continually in flux but somehow in an equilibrium. Thus, because Meyerhof’s thought processes now invoked new approaches inspired in 1909 by Warburg and involving biological- and chemical-based energy transformations, Meyerhof was to transform the entire fields of physiology and biochemistry fundamentally. Meyerhof would begin this new field transformation with a molecule called lactic acid, also known as lactate in modern times. For clarity, we will keep using the term lactic acid throughout.

Between 1909 and 1912, Meyerhof worked in a medical laboratory at the University of Heidelberg.

In 1914, Meyerhof married Hedwig Schallenberg, who was a mathematics student and painter. The couple had one daughter and two sons.

In 1912 Meyerhof became an assistant in the department of physiology at the University of Kiel. In 1913 he delivered a lecture on the energetics of living cells. It was one of the first adaptations of the physical laws of thermodynamics to physiological chemistry. From 1918 to 1924, Meyerhof was an Assistant Professor at the University of Kiel studying cellular respiration and later chemical events and heat fluctuations during muscle contraction. He worked with Archibald Vivian Hill on these experiments involving heat production in muscle tissue.

From 1924 to 1929, Meyerhof was appointed Director of the Institute of Physiology at the Keiser Wilhelm Institute of Cell Physiology. Then, he headed the department of physiology at the Max Planck, formerly Kaiser Wilhelm, Institute for Medical Research at Heidelberg, and was an Honorary Professor of the Faculty of Medicine until 1938. Due to relentless tension from the National Socialists, his teaching license was revoked in 1935, and Meyerhof eventually fled to Paris, France, in 1938, where he held the position of director of research at the Institute of Physico-Chemical Biology, until 1940. At the time of the Nazi invasion of France, Meyerhof evacuated to the United States. In 1940 Meyerhof was appointed a research professor of physiological chemistry at the School of Medicine of the University of Pennsylvania.

3) Lactic acid and muscles—where was he right, and where was he wrong?

By the time that Meyerhof had been converted by Warburg to the cellular physiological and biochemical approaches to the field of food degradation by living systems in 1909, it had already been established in 1906 that lactic acid played prominent roles in these metabolic systems. The importance of lactic acid had been demonstrated by Sir Walter Morley Fletcher and Sir Frederick Howland Hopkins (see the chapter in this book about Hopkins). They had observed that when muscles were stimulated to contract repeatedly without oxygen, lactic acid amounts increased. Still, when the muscle contraction experiments were repeated in the presence of oxygen, lactic acid concentrations dwindled. During the period when Meyerhof had become interested in the field, it had been poorly understood how, if any, biochemical reactions might be involved in food catabolism.

https://upload.wikimedia.org/wikipedia/commons/7/7a/Figure_07_05_02.png

https://upload.wikimedia.org/wikipedia/commons/7/7a/Figure_07_05_02.png

Figure Lactic Acid Fermentation

Meyerhof entered the fledging field of cellular respiration with a new laboratory method in hand. He developed a method for measuring lactic acid. The technique was called the micro-method, and it was vastly improved in terms of its accuracy and speed, providing data almost immediately, compared with waiting an entire week for results using existing older methods.

Consistent with the findings of Fletcher, Hopkins, and Hill, when Meyerhof examined contracting muscles, he observed that lactic acid was produced in proportion to the tension created during contraction. Taking Hill’s lactic acid data into account, a cyclic nature was proposed for lactic acid metabolism.

The discovery of the so-called glycogen-lactic acid cycle and its connection to respiration during heat generation and muscle contraction was the first case in which experimental data was found to support a cyclic nature to energy transduction. That is, Meyerhof provided evidence that glycogen broke down into lactic acid during intense muscle contraction and that some of it went back to glycogen during recovery. Such was the work for which Meyerhof would share the 1922 Nobel Prize in medicine or physiology with A.V. Hill.

Unfortunately, Meyerhof incorrectly concluded that lactic acid itself played a direct role in the mechanism of muscle contraction. The idea had become popularly known as the “lactic acid theory” of muscle contraction, or the “lactic acid cycle.” Scientists all over the world were under the mistaken impression that muscle contraction and energy generation were coupled directly to lactic acid—until 1934, that is—but not until a battle was fought about it, first.

Einar Lundsgaard, who was a professor of physiology at the University of Copenhagen, Denmark, had discovered that a compound called iodoacetate inhibited the production of lactic acid. Then, surprisingly, Lundsgaard went on to find that when the iodoacetate was added to muscles and prevented the manufacture of lactic acid, the muscles contracted anyway! The muscles should have been poisoned by the iodoacetate, if indeed lactic acid was necessary for muscle contraction, as hypothesized by Meyerhof. Instead, Lundsgaard observed no such muscular poisoning—he saw the muscles contracting without lactic acid—but he found that another compound, called creatine phosphate (also called phosphocreatine), must be degraded.

Creatine phosphate had been discovered independently by two laboratories, A.V. Hill’s laboratory at Manchester University, where Philip and Grace Palmer Eggleton worked, and the laboratory of Cyrus Fiske and Yellapragada Subbarow at Harvard Medical School. The creatine phosphate disappearance seemed to correspond to the muscle tension measured during contraction. Thus, Lundsgaard suggested that phosphocreatine (and not lactic acid) was necessary for the contractions of muscles.

Though Lundsgaard was correct in concluding that lactic acid was not needed for muscle contraction, he was not entirely correct with the postulate for phosphocreatine as the prime source of phosphate energy. Furthermore, Meyerhof was already having doubts about lactic acid and contracting muscle, especially when he read about the discovery in 1926 of creatine phosphate. Lundsgaard’s laboratory, and David Nachmansohn assisting in Meyerhof’s laboratory, studied the requirement for phosphate and soon focused on creatine phosphate.

Then, Lundsgaard had personally visited Meyerhof’s laboratory to demonstrate the results with iodoacetate, having Fritz Lipmann pick up Lundsgaard from the railway station and taking him directly to the lab to begin experiments! Meyerhof, Lipmann, and Nachmansohn focused on creatine phosphate metabolism during muscle action and measured energy release and lactic acid levels in muscle extracts and on whole muscles. The results showed that creatine phosphate was not the primary phosphate source for exercising muscles. In 1932, Meyerhof and assistant Karl Lohmann found that ATP breakdown, releasing two phosphates plus adenosine monophosphate (AMP), occurred with much heat energy.

In 1934, the importance of ATP in muscle contraction was becoming more clearly understood. Before this realization, in 1929, Lohmann observed that in muscle extracts, creatine phosphate released free phosphate if adenosine diphosphate (ADP) was present. The ADP molecules combine with creatine phosphate to form free creatine and a new ATP molecule. Next, the newly made ATP is broken down to regenerate the ADP and a compound called phosphoric acid. Lohmann had also discovered ATP hydrolysis took place before the creatine phosphate breakdown during muscle contraction. Incidentally, Lohmann is credited with having discovered ATP, in 1929, although it appears to be a matter of contention.

4) In a sense, Meyerhof’s work studying intermediate metabolism is a combination of physiology, pharmacology, physics, and pathology. Now how is it possible that one scientist could know how all these fields interact to produce muscles, and why is it important to understand the interaction of these four realms? 

You are entirely accurate about Meyerhof and his attempts to study intermediary metabolism. He needed to attain a deeper understanding of seemingly disparate fields of expertise. These vastly different fields provided a framework for his participation in one of biochemistry’s most significant discovery—glycolysis.

Before Meyerhof’s conversion to biochemistry and physiology, he was an avid fan of mental disorders as they pertained to psychiatry and psychology. Thus, Meyerhof’s earliest training dealt with pathology. Meyerhof’s lactic acid studies would be relevant to cancer biology. In healthy cells, glycolysis occurs under anaerobic conditions. Tumor cells must be continually fed to maintain their cell proliferative properties. Therefore, they rapidly acquire nutrients. Then they undergo an abnormally heightened rate of glycolysis in the presence of oxygen, i.e., under aerobic conditions, enhancing the production of lactic acid and thus of cellular division.

https://upload.wikimedia.org/wikipedia/commons/d/d5/LDH_activity-_normal_vs_canceous_cells.png

https://upload.wikimedia.org/wikipedia/commons/d/d5/LDH_activity-_normal_vs_canceous_cells.png

Figure Lactate dehydrogenase activities

To understand energy transformations during nutrient breakdown and work, Meyerhof needed to know muscle physiology. He had to know muscle contraction in greater depth than was available at the time. Meyerhof had to know how to measure muscle contraction in the lab. Thus, his contributions were such that lactic acid metabolism, as related to muscle physiology, informed biochemistry by discovering its role in its production during glycogen degradation.

To understand the precise role of energy transformation, Meyerhof needed to gain a deeper grasp of pharmacology. As alluded to above, he needed to evaluate the effects of muscle poisoning with iodoacetate and the function of lactic acid. To study biological energy transduction, Meyerhof needed to know physics. Much of the characterization of muscle physiology was often described in mechanical-physical terms, like work, power, tension, energy, etc. These characterizations about muscle metabolism can be viewed from the standpoint of their counterparts in physics.

Meyerhof’s expertise in disparate fields and his energetics studies of muscle physiology paved the way to his momentous discovery. Meyerhof made a meaningful contribution to biochemistry: the glycolytic pathway. It would later be called the Embden-Meyerhof-Parnas pathway.

In 1930, Meyerhof turned his attention to the study of glycogen conversion to lactic acid. The process involved the release of sugars from glycogen stores and their subsequent conversion to lactic acid. Today, we know that the conversion of glucose into pyruvate constitutes glycolysis. At the time of Meyerhof, this had yet to be discovered.

Only a few hints into the yet-to-be-discovered glycolytic process were available. Carl Neuberg had proposed that during yeast fermentation, particular waste intermediates were possibly phosphorylated twice over and consisted of hexoses with ester chemical groups attached. Today, we know this waste product to be fructose-1,6-diphosphate, a proper glycolytic intermediate.

Treating Neuberg’s waste product idea as a serious matter, the early biochemists’ investigations into intermediary metabolism led to the emergence of two prevailing themes.

The first theme was postulated by Gustav Embden, who had proposed that a molecule he called lactocidogen was somehow related to the fructose-1,6-diphosphate production. At the time, in the late 1920s and early 1930s, Embden had, quite rightly, not held much confidence in Meyerhof’s lactic acid theory for muscle contraction. Instead, Embden had just as incorrectly believed that his lactocidogen molecule was the activation factor and thus the source of energy for muscle contraction. We know today that neither Embden (lactocidogen) nor Meyerhof (lactic acid) was correct with their choices for the energetic driving forces of muscle contraction.

The second theme was proposed by Meyerhof, who had hypothesized that glucose goes through an esterification process to produce phosphate-laden intermediates. If true, Meyerhof then elaborated that these phosphorylated intermediates must lead to pyruvate and later to lactic acid. He was correct.

During this productive era, it was still unknown what the sequence of events was for the breakdown of glucose to its putative endpoint, pyruvate. Meanwhile, in 1932, Embden had proposed a linear set of steps for glycolysis. His proposal was surprisingly closely accurate and almost complete. Meyerhof was reasonably impressed with Embden’s model for glycolysis. Unfortunately, however, before Gustav Georg Embden could commence the accumulation of the necessary evidence for his glycolytic model, he died in July of 1933.

File:Glycolysis.svg

https://commons.wikimedia.org/wiki/File:Glycolysis.svg

Figure Embden-Meyerhof-Parnas pathway of glycolysis

Meyerhof devoted the next five years to testing Embden’s glycolysis hypothesis—the sequence of its biochemical events. He identified enzymes involved in phosphorylation during the degradative process. Using yeast, he had studied, in 1927, the enzyme hexokinase, the starting point for glycolysis. The hexokinase converts glucose into glucose-6-phosphate.

In 1934, Meyerhof studied candidate intermediate substrates thought to constitute glycolysis. These intermediates were dihydroxyacetone phosphate, glyceraldehyde-3-phosphate, 2-phosphoglycerate, and phosphoenolpyruvate. Then in 1935, Meyerhof had identified phosphoglycerate mutase and enolase enzymes involved in glycolysis. In 1936, Meyerhof identified fructose bis-phosphate aldolase and triosephosphate isomerase. It became apparent that aldolase would be the enzyme that split the sugar into two pieces. Lohmann had identified glucose-phosphate isomerase. Jacob Parnas, in 1934, identified pyruvate kinase, which converted phosphoenolpyruvate onto the last product of glycolysis, called pyruvate.

In 1936, Paul Ostern, J.A. Guthke, and Jurij Terszakoweć, working in Jacob Parnas’s laboratory, discovered a key regulatory enzyme, phosphofructokinase, which converts fructose-6-phosphate to fructose 1,6-bisphosphate. In 1941, Ostern would be murdered by the Nazis. In 1939, Warburg and his laboratory had identified glyceraldehyde-3-phosphate dehydrogenase. The remaining enzyme, 3-phosphoglycerate kinase, was discovered in 1942 by Theodor Bücher. The entire pathway for the glycolytic pathway had been elucidated, and Meyerhof had a hand in identifying half of the ten enzymes involved in it—hence, the name Embden-Meyerhof-Parnas pathway.

5) We have all done some exercising—and used oxygen or breathed deeply while jogging or lifting weights—But Meyerhof looked at the interaction of our use of oxygen and, at the same time, the ongoing metabolism of lactic acid in the muscle. How exactly did he study this relationship?

As explained in our 2020 book about biomedical scientists, Professor Archibald Vivian (A.V.) Hill, in 1910, had demonstrated that the amount of heat formed was somehow linked to the amount of frog muscle contraction work that was performed. He had shown that the heat of muscle contraction occurred in two phases. First, Hill discovered a first heat, which occurred with or without oxygen during muscle contraction. Second, Hill demonstrated a delayed heat, which occurred with oxygen.

Hill also found that approximately half of the heat was generated during muscle contraction without oxygen, i.e., under anaerobic conditions. Hill then found that the other half of the heat appeared during a recovery phase with oxygen present, i.e., under aerobic circumstances. This knowledge was the state of the field regarding energetics and metabolism when Meyerhof started his investigations shortly after the end of the Great War in 1920.

Meyerhof had observed that during muscle recovery (after intense activity), under aerobic conditions, a small amount of the lactic acid produced was oxidized to form carbon dioxide and water. At the same time, however, the remaining majority of lactic acid went back to reform glycogen! Meyerhof had also established that glycogen was the precursor source for lactic acid production under anaerobic conditions.

The findings by Meyerhof also strongly supported a notion first propounded by Dr. Louis Pasteur. He noted that less glycogen is degraded by muscle glycolysis and fermentation aerobically than anaerobically. During anaerobic fermentation, more carbohydrate is degraded than if the carbohydrates are metabolized aerobically. The hypothesis had been known as the “Pasteur effect.”

Thus, in a sense, glycolysis seemed to be thwarted by aerobic respiration. Meyerhof found that, under aerobic conditions, little lactic acid is produced, but under anaerobic conditions, lactic acid is produced in significant quantities via glycolysis. This phenomenon later came to be known as the “Pasteur-Meyerhof Effect.”

6) Sadly, due to World War II, his life was disrupted. Tell us what happened.

Reluctantly, Meyerhof had to flee his beloved homeland of Germany. His family was Jewish, and they were living and working in Heidelberg, Germany, during the 1930s. Hitler and his Nazi Party were in firm control of the country, and they enjoyed the broad support of the German populace. Anti-Semitism was spreading in Germany throughout the decade. Signs of impending disruption emerged when Meyerhof watched his students, friends, and colleagues leave Germany. Among the refugees included a brain drain of talented scientists, such as Fritz Lipmann, who would share the Nobel with another refugee, Hans Krebs. Other notable investigators included the famous Carl Sandel Neuberg, who some consider a pioneering father of biochemistry for his work with ethanol and pyruvate fermentation. Nobel Laureate Severo Ochoa, who is highlighted in another chapter in this book for his discovery of RNA polymerase, fled Germany as soon as he could.

At first, Meyerhof and his family felt that they somewhat protected from the Nazi German authorities because of the 1922 Nobel Prize and their productive work at the Physiology Institute at Heidelberg. Meyerhof was gathering a tremendous amount of data making pioneering breakthroughs with glycolysis. He had amassed a great deal of data to support Embden’s model for the sequence of reactions of glycolysis.

But in 1937, the situation with Hitler’s Germany was untenable for Meyerhof. He had just completed the identification and characterization of half the enzymes in glycolysis! Then he had to cease the work abruptly and instead place his efforts towards making a secret plan to escape from Germany!

First, Meyerhof had previously planned for his two older children, a daughter, and son, to leave the country under the guise of attending boarding school. This phase of the secret plan worked, and it did not seem to catch the attention of the German Nazi authorities. However, Meyerhof had been denied permission to leave the country to attend a high-status scientific conference, the International Physiological Congress, to be held in Zurich in 1938. Then, Meyerhof’s former laboratory assistant, David Nachmansohn, now working in Paris, France, at the Sorbonne, made arrangements with the Josiah Macy, Jr. Foundation for Meyerhof to be offered a new post of director of research at the Institute of Physico-Chemical Biology, in Paris.

To keep the escape plan a secret, Nachmansohn and Meyerhof corresponded with each other in code! Furthermore, Meyerhof told none of his colleagues in Heidelberg of the secret getaway plan. To keep his colleagues and any spying German Nazis ignorant of the secret plot, Meyerhof made the painful decision to abandon all of his scientifically collected data and leave them behind in his office and the lab. He also decided to leave behind all the family’s possessions at home, lest anyone get suspicious of their flight from Nazi Germany. Then, in 1938, securing permission papers for Meyerhof, Hedwig and their youngest son to travel to Switzerland for the child to acquire medical treatment, the remaining members of the Meyerhof family made good their escape across the border, after which they journeyed safely to Paris!

Unfortunately, when the Germans invaded France, the Meyerhof family had to flee the Nazis again. In June of 1940, the Meyerhof family took a taxi from Paris to Toulouse, where he was befriended by welcoming sympathizers there at the Medical Faculty. The brief escape from Paris, however, was tenuous as many other refugees were in the same precarious situation. With help from the Unitarian Service Committee, the Meyerhofs secured passage into Spain but had to plead and argue with the authorities there to not be sent back to France. The story is told that Hedwig Meyerhof tactfully undertook the delicate negotiations and prevented their deportation!

Fortunately, Meyerhof was offered a position at the University of Pennsylvania, and in 1940 the Meyerhofs moved to the U.S. Professor David Wright Wilson was the chair of the physiological chemistry department during these years. He introduced the Meyerhofs to Woods Hole, MA, where Meyerhof would research during the summer months at the famed Marine Biological Laboratory. In 1944, he suffered his first of two heart attacks. Meyerhof spent the rest of his life in the U.S. until his death at 67 on the 6th of October, in 1951.

7) He was fairly ahead of his time in that he also studied the effects of narcotics on oxidation processes. What specific narcotics, and what did he find?

By “narcotics,” Meyerhof, in 1911, was referring to substances meant to influence oxidation of cysteine and not necessarily what the term means for us today in modern times. Working well into the year 1919, Meyerhof studied oxidation in sea urchin eggs, bacteria, and yeast. Meyerhof used “narcotics,” such as phenyl-, dimethyl- and diethyl-urea derivatives, acetamide, valeramide, acetone, methyl-phenyl ketone, ethanol, amyl alcohol, acetonitrile, and valeronitrile in his investigations on oxidation.

With these substances, he measured the inhibition of invertase activity, which breaks down table sugar. Thus, he used these “narcotic” substances to inhibit fermentation and respiration in microbes. Meyerhof employed these agents to make connections between oxygen respiration in frog muscle and ethanol fermentation in live and dead yeast. He collected a variety of data on the energetics of live yeast cells, making comparisons with extracts composed of dead yeast cells. The substances inhibited biochemical reactions of enzymes in living and dead yeast cells. He made the astute observation that enzymes must participate in both processes. He had referred to the respiratory enzymes as “respiration bodies.”

In one experiment, Meyerhof grew yeast cells and prepared versions of living versus dead cells. Then he added “narcotics” to inhibit respiration and fermentation. He used the method of washing acetone-incubated yeast with water to attain respiration inhibition. Next, measured respiration and observed its depletion by both methods. Then, he added back yeast extract containing his Atmungskörper “respiration bodies” (enzymes) and observed a restoration of respiration. He found that the yeast extract was susceptible to heat, whereas the enzymes were thermostable, i.e., impervious to heat treatment, and able to undergo the respiration restoration.

In a follow-up experiment, he added a hexose phosphate, probably glucose-6-phosphate, and, again, it restored the respiratory activity.

These findings led to his subsequent focus on lactic acid as a central participant in muscle physiology and microbial-based alcohol fermentation. These experimental studies represented some of his first forays into biochemistry research and helped to launch his scientific career.

8) Further, he looked at the impact of methylene blue on oxidation processes—and the impact of this on killed cells. (As an aside, is methyl blue the same as methylene blue?)

When Meyerhof had tested the effects of the “narcotic” agents mentioned above in 1918, he used methylene blue to detect the degree of the microbial respiration activity that was affected by these “narcotics.” Before, methylene blue had been observed by the great Dr. Paul Ehrlich in 1885 to be reduced in tissues, presumably because it served as a good acceptor of hydrogens harboring electrons. In 1912, Dr. Heinrich Wieland had hypothesized that cellular respiration involved hydrogen. In contrast, Meyerhof hypothesized that such respiration was attributable to oxygen.

We know today that when methylene blue is oxidized, it appears as a blue color, but when it is reduced, it becomes colorless. We also know in modern times that aerobic respiration involves electron transfer along the respiratory chain to oxygen, with a concomitant hydrogen ion (proton) transport across the membrane. Thus, it seems that both Wieland and Meyerhof had been correct all along.

Although it might make sense that they are identical if not similar, we know that methylene blue and methyl blue are entirely different chemicals. While both substances are indeed blue, they are otherwise structurally and functionally dissimilar compounds. They each have their distinctive uses.

Methylene blue is also known as basic blue 9, Swiss blue, urolene blue, and methylthioninium chloride, with a molecular formula of C16H18ClN3S and molecular weight of 319.9 Daltons. In addition to its use as an oxidation-reduction reagent, it is an antioxidant, an old anti-malarial drug, and an anti-depressant agent. Other properties of methylene blue include its inhibition of monoamine oxidase, as a pH indicator, a cardioprotective activity, and neuroprotection.

Methyl blue is also known as Helvetia blue, cotton blue, and acid blue 93, with a proper chemical name called disodium ((4-(bis(4-((sulphonatophenyl) amino) phenyl) methylene) cyclohexa-2,5-dien-1-ylidene) amino) benzenesulphonate. The molecular weight of methyl blue is 799.8 Daltons, with a chemical formula C37H27N3Na2O9S3. Along with other chemicals, methyl blue is used to prepare histological stains, such as aniline blue, for the staining collagen fibers and connective tissue.

9) What have I neglected to ask about this Nobel Prize winner?

When one of us (M.F.V.) was a postdoctoral fellow at Harvard Medical School in the mid-1990s, he was told by his lab mentor Professor Thomas Hastings Wilson that his father Professor David Wright Wilson had hired Meyerhof. Indeed, the story is supported by documentation in a biographical memoir written by Eric G. Ball and John M. Buchanan and published in 1973 by the National Academy of Sciences. Drs. D. Wright Wilson and A.N. Richards at the University of Pennsylvania had worked with the Rockefeller Foundation to arrange for funding of a new position to offer Meyerhof. In 1940, Nobel Laureate Otto Meyerhof accepted the offer as a research professor in the Department of Physiological Chemistry, where he worked for the remainder of his life. Meyerhof published 50 papers during his ten years in the United States. Overall, he published 400 papers in scientific journals.

For further information on this extraordinary scientist, go to the following links:

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