An Interview with Manuel Varela and Ann Varela about Jakub Karol Parnas: Died in Lubyanka!

Jul 8, 2020 by

Jakub Karol Parnas

Michael F. Shaughnessy –

1) Jakub Parnas is a famous scientist who seems to have come from a rich multicultural background. Where was he born, and what do we know about his parents?

Dr. Jakub Karol Parnas forever be known as one of the founding pioneers of the glycolytic pathway for intermediary metabolism. Various sources report that he was also known as Jakub, Jacob, Jacub, and Yakov Oskarovich Parnas. Parnas was born on January 16, 1884, in Tarnopol, which was part of Poland until the end of the eighteenth century. Then, up to World War I, it belonged to the Austro-Hungarian Empire. Amid 1918 and 1939, the region resumed back to Poland. As a result of the Soviet-German treaty in 1939, the land was changed over to the Soviet Union. From 1941 to 1944, it was called Lviv, the central city of this land where Parnas worked for 20 years, and there he made his paramount accomplishments.

Parnas’ father, Oskar, was a landowner. His mother’s name was Gabriela Bernstein. Parnas attended primary school in Tarnopol. He attended the gymnasium in Lviv until he graduated in 1902.

As an undergraduate student, Parnas went to the Institute of Technology in Berlin-Charlottenburg from 1902-1904 to study chemistry. After that, he attended the University of Strasbourg until 1905, where his studies were concentrated in the areas of organic and physiological chemistry. He attended the universities of Berlin, Strasbourg, Zurich, and Munich, where he studied chemistry and received his Ph.D. in chemistry in 1907.

2) Parnas seems to have traveled and studied quite a bit—can you provide an overview?

In 1907, Parnas was appointed as an assistant to Franz Hofmeister’s laboratory at the Institute of Physiological Chemistry in Strasbourg. At Strasbourg, Parnas was an associate professor of chemistry in 1913 and a professor of physiological chemistry at Warsaw from 1916 to 1919.

From 1920 to 1941, he was a full professor and head of the Institute of Medical Chemistry at Lviv University. After the death of his nine-year-old daughter, Parnas moved to Zurich in 1931 and devoted a year of studies as a visiting professor. In addition, Parnas found solace hiking and skiing mountains with his son. Apparently, Jan recalled his father saying, “Mountains make people better.”

By 1943 he headed the Biological and Medical Chemistry Institute of the Soviet Academy of Medical Sciences in Moscow. It was here that Parnas instituted a Laboratory of physiological Chemistry as part of the Soviet Academy of Sciences.

3) He received an honorary doctorate from the Sorbonne—which is, as I recall, part of the University of Paris—what did he do to deserve this, or was this just a global recognition of his work?

Undoubtedly, Parnas received the honorary accolade from the Sorbonne because of his pioneering work regarding intermediary metabolism of carbohydrates in tissues of the muscle. The attachment of his name to a central metabolic pathway for all life on Earth would forever tie Parnas in all scientific literature on all of the biological sciences. Parnas received honorary degrees from the universities of Athens and Paris. He was also a member of the Polish Academy of Sciences, the Soviet Academy of Sciences, the Soviet Academy of Medical Sciences, and the Academy of Medicine in Paris, and a member of the German Leopoldina Academy of Sciences.

4) There seem to be three areas of distinction in Parnas’ work—one was the mechanisms of carbohydrate metabolism in muscle tissue—why is this important?

As you pointed out, there are three significant scientific contributions of note involving studies by Parnas. These contributions include (i) biochemical mechanisms of glycolysis (ii) glycogen breakdown with phosphorolysis and (iii) a theoretical evaluation of glycolysis.

His prime interests were concerned with the anaerobic metabolism of glucose, a pathway for which he would forever be tied, the Embden-Meyerhof-Parnas pathway. Let us consider first his notable studies concerning the biochemical mechanisms for glycolysis.

The preliminary work by Parnas in the 1920s on ammonia, ATP synthesis, and phosphorylation would ultimately lead to his entry into the field of glycolysis, for which he would become famous. He found in muscle that ammonia (NH3) was released by AMP (adenosine monophosphate), instead of ATP, as previously thought. For these studies, he developed the so-called Parnas-Heller apparatus, which turned out to be a widely used method for ammonia determination. Józef Heller and Parnas had modified a micro-distillation device that was previously known as the Parnas-Wagner apparatus. Heller was a senior investigator in Parnas’ lab, and Richard Wagner was a collaborator. Working with Włodzimierz Mozołowski, Parnas used the new method to find that ammonia levels were increased during muscle contraction.

Sadly, and tragically, all such work stopped in 1930. Parnas’ nine-year-old daughter Justyna contracted tuberculotic encephalomyelitis and died suddenly. Parnas was deeply affected, and it took several years for Parnas to mourn the terrible loss. When he eventually returned to the laboratory, he turned his attention to the problem of glycolysis.

One of the first studies by Parnas exploring the glycolytic pathway concerns his finding in 1934 that ATP was produced during the last stages of sugar breakdown in muscle. Parnas published the work with co-authors Thaddeus Mann and Paul Ostern. In this ATP synthesis process, the laboratory Parnas discovered that the phosphate that was attached to phosphoenolpyruvate was transferred to ADP to make ATP and pyruvate.

https://upload.wikimedia.org/wikipedia/commons/a/ab/Glycolysis-2.gif

https://upload.wikimedia.org/wikipedia/commons/a/ab/Glycolysis-2.gif

Figure Embden-Meyerhof-Parnas pathway of glycolysis

This early biochemical work by Parnas was a significant finding. The mechanism is known as substrate-level phosphorylation in which the substrate of an enzyme, pyruvate kinase, is the source of phosphate for the generation of ATP energy! Soon after, news of the discovery was received by biochemists from other laboratories. Prominent among them was Hermann Lehmann, who immediately repeated the studies of Parnas. Lehmann confirmed the findings of Parnas that phosphoenolpyruvate was the harbinger of the phosphate needed for ATP. The pyruvate kinase reaction discovered by Parnas represents a momentous discovery in biochemistry history. In modern times, the reaction mechanism is appropriately reported in virtually all textbooks dealing with all fields of the biological sciences. The significance of the substrate-level phosphorylation chemistry in living cells cannot be overstated.

Another meaningful discovery was performed by workers in the laboratory of Parnas. These investigators included Ostern, and J. A. Guthke, and Jurij (George) Tershakovec, and they discovered phosphofructokinase. In modern times, the reaction catalyzed by phosphofructokinase-1 (PFK-1) is known as a so-called committed step, in that it is essentially irreversible. Thus, once complete, the process of glycolysis is committed to proceeding to the end, ultimately making the end-product, pyruvate. The enzyme converts fructose 6-phosphate to fructose 1,6-bisphosphate, and its catalytic activity is a highly regulated reaction.

During the 1930s, investigators who discovered pyruvate kinase and phosphofructokinase made tremendous advances in biochemistry history. These scientists, nevertheless, encountered various personal fates, some tragic, during the looming Second World War. Lehmann, Tershakovec, and Mann became refugees and survived the war.

Sadly, however, Paul (Pawel) Ostern, who was Jewish working in Poland during the Nazi occupation in 1940, was not so fortunate. In 1936 Ostern had been vital in discovering phosphofructokinase, a crucial regulatory enzyme of glycolysis. Ostern and 97 professors from Lwów were summarily rounded up and murdered by the German Nazis.

5) Then with a colleague (Wladyslaw Baranowski), he looked at phosphorolysis. What did he find?

The second major area involves the elucidation of the phosphorolysis process for glycogen breakdown. The reaction involved inorganic phosphate and a prediction that glucose-1-phosphate would be formed. Parnas’ most significant discovery in this area was that during glycogen catabolism, glucose 6-phosphate came off of the more massive carbohydrate.

Early work by Parnas, published in 1914 and 1915 showed that as glycogen broke down, the levels of glucose from the glycogen store decreased while the levels of lactic acid increased. This observation was confirmed by others, such as Embden, Meyerhof, Hopkins, and others. The work by Parnas was interrupted by the Great War, and he did not resume it until later in the 1920s.

Another significant finding by Parnas included his pioneering use of radioactive phosphorous atoms in the late 1930s to study phosphorylation. Parnas also demonstrated the transfer of phosphate from a metabolic substrate to ADP, as described above.

Using phosphate in which the phosphorous atom was radiolabeled (denoted as 32P for phosphorous-32), Parnas and Baranowski demonstrated the phosphorolytic breakdown mechanism for glycogen. In biological circles, glycogen is composed of long shards of glucose molecules connected by glycosidic bonds, making long polymers in the form of chains and branches. Thus, glycogen represents a massive storage form of glucose, which could be a prime source of glucose to be used for ATP energy production, such as during muscle contraction. Glycogen breakdown, therefore, represents an excellent process for liberating stored sugars for generating biological energy by glycolysis.

Parnas found in 1938 that glycogen was degraded piecemeal by the cleavage of glucose molecules from the larger glycogen sugar stores. He observed the radioactive phosphates ended up coming off the glycogen and accompanying the cleaved glucose. Furthermore, he found glucose came off glycogen as glucose 6-phosphate. He published this pioneering work, naming the process glycogen phosphorolysis.

The glycogen breakdown (lysis) involved phosphorylation of sugar, hence, the term phosphorolysis. Gerty and Carl Cori extended the findings to discover that glycogen breakdown directly produced glucose 1-phosphate, which then quickly formed glucose 6-phosphate, thus, confirming the work of Parnas.

6) In a more theoretical vein—he looked at the analysis of glycolysis—first of all, what is glycolysis, and why is it important, and what were his insights?

The third significant contribution by Parnas was his theoretical analysis of the glycolytic pathway. The metabolic pathway of glycolysis can be defined as an oxidative breakdown of sugars like glucose and other nutrients into pyruvate and a simultaneous release of ATP energy. Glycolysis is a central pathway in the overall field of intermediary metabolism. Its prime relevance lies in the fact that virtually all nutrients, i.e., sugars, amino acids, fats, and nucleic acids, go through the pathway during catabolism.

In a groundbreaking paper published in 1938 by Parnas in the journal called Enzymologia, he organized the various categories of biochemical reaction types and coalesced them together to formulate the glycolytic pathway. The order of these reactions was put together surprisingly accurately by Embden, and Meyerhof subsequently provided much of the evidence for the various biochemical steps.

Parnas considered the published scientific literature, including his own mentioned above, up to that point in 1938, and came up with a collection of crucial biochemical reactions. These reactions included the following types.

First, he considered phosphorylation by kinase enzymes involved in the transfer of phosphate between molecules, from ATP to a substrate, or from a substrate to ADP. He also contemplated the process of isomerization, the movement of atoms within sugar to form new molecules, such as the conversion of an aldose to a ketose sugar. A third reaction, a “mutation,” was performed by mutase. Here, phosphate is moved from one oxygen atom to another in the same substrate.

Cleavage of molecules, breaking them, was an essential process and catalyzed by the enzyme aldolase. A critical reaction was oxidation, which converted a sugar molecule with an aldehyde into a phosphorylated moiety. The enzyme was dehydrogenase, which sent hydrogen atoms from NAD+ to NADH, releasing free protons (H+). Lastly, Parnas thought about dehydration, loss of water, between 2-phosphoglycerate to phosphoenolpyruvate by enolase. Therefore, with these fundamental biochemical reactions, he provided an ideal platform for experimental analysis.

7) Interestingly enough, he may have met Josef Stalin and was given a laboratory—What did he study or research there in that lab?

Unfortunately, the claim that Parnas and Stalin met personally is unverifiable. So, too, is the claim that he was given a laboratory by the Stalinist regime. Interestingly, one source does relate that Parnas may have met Lviv mayor Stanisław Ostrowski, who would, in later years, become an exiled president of Poland.

We do know that during World War II, with the advancing German army, the Parnas family in 1941 was forced to retreat from Lviv (also known as Lwów, Lemberg) and move deep into Russian territory, near Ufa, where they stayed until 1944. We also know that during the Second World War, the Soviet Union was given Poland in the German-Soviet treaty of 1939. Yet, Germany had occupied Poland territory for the duration of the war.

At first, Parnas had to deal with the Soviets. Their government had actively tried to recruit him and claim Parnas as a Soviet scientist. They promised to enhance his department and provide equipment, laboratory chemicals, and even laboratory animals, but these never came to fruition. Worse, access to scientific journals was weak, and lab supplies were meager. Then, the Germans invaded in June of 1941, and Parnas fled to Ufa. Within a month of occupation, scores of Polish professors were rounded up and executed by the German Nazis. At Ufa, Parnas tried to continue his studies, but conditions were more meager than those at Lviv.

Further, his son Jan Oskar Parnas, now a medical student, had been drafted into the Polish army and sent to the front, where he was injured in battle, taking several months to recover. At the end of the war, Jan returned to Poland and took his M.D. degree to become a surgeon.

In 1943, Parnas moved to Moscow and was embraced by the Soviet officials. While his research program was all but non-existent during the remainder of World War II, he was elected to the Academy of USSR Medical Sciences. He took the time to write critical reviews on muscle biochemistry. Further, he honed his lecturing skills, and he would be highly regarded by his students and colleagues alike for his public speaking skills. After the war, he returned tried to return permanently to Poland but, unfortunately, was refused permission by the Soviet authorities.

8) Despite all his accomplishments and achievements, Parnas was accused by the KGB of being a spy for the US and was hauled off to Lubyanka, a famous prison near the Kremlin, where he apparently died of heart failure (perhaps due to harsh interrogation methods). How has he been recognized after his death?

Sadly, Parnas was reported to have died during interrogation on the 29th of January, in 1949. It was the same day that he had been arrested by the Soviet KGB and accused of being a spy for the West. He had been taken to Lubyanka, the notorious Moscow prison during the Stalinist Doctors’ purge.

The circumstances are dubious and clouded in mystery. The death was kept secret—even his widow did not learn of his passing until years later. The “official” death certificate had stated he suffered a cardiac arrest.

Parnas published about 120 scientific papers and several critical reviews. Among those publications in 1922 was the first textbook ever written in Polish, Physiological Chemistry with Special Reference to Animal Physiology.

While a Nobel for Parnas did not materialize—perhaps due to his untimely death—he was most certainly deserving of one. He has, however, been honored in two significant ways.

First, immediately after his death, the life, and scientific works of Parnas were warmly revered in numerous biographical summaries in a variety of biochemical journals and popular books. The authors who knew him personally positively described his temperament as always pleasant and most certainly approachable, signifying that Parnas was greatly respected and admired not only by those who were close but also by the broader community of biochemists.

The second way in which Parnas has been recognized after his death was the coining of one of nature’s most important biochemical pathway after him, the Embden-Meyerhof-Parnas pathway. As we mentioned above, virtually all good scientific textbooks include the designation of glycolysis as the Embden-Meyerhof-Parnas pathway, as well. We do not anticipate that the E.M.P. pathway name will go away any time in the foreseeable future of science. As such, Parnas will forever go down in scientific history as being acutely associated with the ever critical-for-life glycolytic pathway.

In 1982, the glycolytic pathway was described in lyrics by Prof. Harold Baum to a song with the tune “The British Grenadiers” but re-titled “In Praise of E.M.P.,” clearly giving due notice to the contributions of Parnas.

https://web.csulb.edu/~cohlberg/Songs/glycolysis.mp3

For additional information about this history-changing scientist, visit the following links:

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