Book review: Science thriller

Publiceret Maj 2017

Lucky choices – The story of my life in science by Jens Chr. Skou, Nobel Laureate

Memoirs by a Nobel Laureate create excitement and expectations to read about the life, views and reflections of an outstanding scientist. They represent the elite among our mentors in the scientific community, and reading or listening to their scientific achievement and life experience is always inspiring. The book written by Jens Christian Skou fullfils this goal completely. The memoirs are written in an entertaining, fluent, light and informal style reflecting Skou’s personality and general education characterized by curiosity, modesty, originality and persistence, as well as his ‘bildung’ and an open mind. It is a rich and comprehensive autobiography with a lovely description of his personal life, a thrilling account for his groundbreaking discovery of the Na,K-ATPase, a detailed story of his impressive career in science, and his critical reflections on research and education.

The central part of Skou’s memoirs ‘Lucky choices – The story of my life in science’ is his discovery and research on the Na,K-ATPase, an enzyme involved in membrane transport of sodium and potassium. The ion-transporting enzyme is vital for life as the active transport maintains the intracellular concentrations of sodium and potassium in all cells of multicellular organisms. The active transport depends on energy formed by adenosine triphosphate (ATP) breakdown by the ATPase. Indeed the Na,K-ATPase consumes on average 15-20% of ATP produced in the organism for Na+ and K+ transport, and in the central nervous system almost 60% of ATP is used to transport ions. Consequently, conditions impairing the ATP formation have severe consequences for the cell since the sodium and potassium gradients maintaining the membrane potential and cell volume are destroyed.

Science thriller

The hunt for the Na,K-ATPase or Na+ + K+ ATPase, which covers 65 pages or one-third of the book, is like a science thriller with all the emotions it creates, particularly those of apprehension and exhilaration, of excitement and breathlessness, all designed to generate that all-important thrill. This form is common to all kinds of thrillers including the legal thriller, spy thriller, medical thriller, romantic thriller, historical thriller, political thriller, religious thriller, high-tech thriller, etc. Jens Christian Skou is the ‘good guy’ in this story of the search for the Na,K-ATPase treasure supported by collaborators, whereas the ‘bad guys’ include adversaries and competitors. In the end of this thriller Skou wins the big glory when he is awarded the Nobel prize in 1997.

The plot begins with Jens Christian Skou reading about an enzyme in the membrane of the squid giant axon that catalyzes the breakdown of ATP resulting in release of energy in the cell; the enzyme called ATPase. This happens during a visit to the marine biology research station in Woods Hole located on the coast of New England south of Boston in the Summer 1953. Skou was invited by Professor David Nachmanson, Columbia University in New York to follow experiments on nerve excitation.

During off-days with no experimental work he spent the time reading a book written by his host on the occasion of the 70th anniversary of Otto Warburg’s birth. He discovered that Benjamin Libet from University of California San Francisco had in 1948 described the ATP-ase in the axolemma of the giant nerve fiber of the squid. Libet’s experiments were performed during a stay at Woods Hole in the Summer of 1948, but only published in two abstracts. To Skou’s astonishment no one had yet studied the enzyme further, and he decided to study the ATPase activity in the membrane of crab nerves at home in Aarhus.

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Figure 1. Doctoral thesis 1954. Jens Christian Skou at the defense of his doctoral dissertation: Local Anesthetics: Experimental Studies of the Anesthetic and Toxic Action with his two opponents and moderator. From left: Søren L. Ørskov, Professor of Physiology, University of Aarhus, Jens Christian Skou, Knud Ove Møller, Professor of Pharmacology, University of Copenhagen, and Willy Munck Dean of the Faculty of Medicine, Aarhus University.

This unexpected observation by serendipity during the Summer 1953 at Woods Hole hit a curious and prepared mind: Skou had studied the anesthetic and toxic mechanism of action of local anesthetics and published five papers for his doctorate dissertation, which he defended in 1954 (Figure 1). Furthermore, he had initiated work on acetylcholinesterase purified from electric eel during his visit in Nachmansohn’s laboratory in New York in 1953. However, Skou was eager to get on with studies of the ATP-cleaving enzyme in the giant axon. He wondered what the energy liberated by this cleavage was for. It was this particular fascination that had the most far-reaching consequences for him, eventually leading to the Nobel prize.

Crab nerve enzyme

The pursuit for the identification of the membrane Na,K-ATPase and its role in active transport of Na+ and K+ displays all the action and drama of important discoveries in science, which generates the thrill. In three chapters Jens Christian Skou describes in a breathless, elegant and comprehensive style the research by himself and others leading to the characterisation of the Na,K-ATPase as a membrane channel involved in active transport of Na+ and K+.

In his first experiments in 1954 on nerves extracted from the crab he was able to establish that the enzyme Benjamin Libet had found in squid nerve membranes was also hydrolyzing ATP in crab nerves. This was followed by measurements of the ATPase activity in the presence of either Na+ or K+, and after a year and a half he finally was able to show that the enzyme’s maximum effect was dependent on a combination of Na+ and K+.

Skou interpreted his results that the enzyme has two binding sites to which the ions can bind. He speculated that the ATPase was involved in active transport of ions based on three observations: the enzyme was in the nerve membrane; the substrate for the enzyme was ATP like in active transport; the hydrolysis of ATP was due to a combined effect of Na+ and K+, the two ions being transported against their electrochemical gradients. Skou concluded that it was a bold theory, and a speculative one, but he had an intuition that it might be right.

His investigation and conclusion were published in 1957 in Biochimica Biophysica Acta (1). During 10 years of intense research Skou published four papers on the Na,K-ATPase, and ultimately a review in Physiologal Reviews in 1965 under the title ‘Enzymatic Basis for Active Transport of Na+ and K+ Across the Cell Membrane (2); it later became a ‘Citation Classic’.


Jens Christian Skou was born October 8, 1918 in Lemvig, Denmark to a wealthy family. His father Magnus Martinus Skou was a timber and coal merchant. His mother Ane-Margrethe Skou took over the company after the death of his father. At the age of 15 Skou entered a boarding school in Haslev, Zealand. He graduated in medicine from the University of Copenhagen in 1944 and received his doctorate in 1954. He married Ellen-Margrethe Nielsen in 1948, and they had two daughters Hanne and Karen. Skou began working at Aarhus University in 1947, and was appointed professor of biophysics in 1977. He retired from Aarhus University in 1988, but he has kept his offices at the Department of Physiology. In 1997 he received the Nobel Prize in Chemistry (together with Paul D. Boyer and John E. Walker) for his discovery of Na+,K+-ATPase. Source: http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1997/skou-bio.html


Scientific competition

Other scientists worked on the Na,K-ATPase and its role in active transport of Na+ and K+ in the 1950’s, but Skou had not thought of science as competitive. Later he realized his mistake and the risks of his naïvity. First, he did not realize the unnecessary risk of talking about his work on the Na,K-ATPase at two meetings before he published his results. The risk, of course, was that others with that knowledge by publishing first could get the priority on the discovery. In fact, H. H. Hess published an abstract lecture in 1957 on ATPase activated by Na+ and K+ in brain tissue. Fortunately, she did not publish her findings until 1962, confirming Skou’s work and quoting his articles from 1957 and 1960 (3). Furthermore, in 1960 Robert Post published a paper on the ATPase and its role in active transport of Na+ and K+ in erythrocytes (4).

Second, Skou had chosen a rather bland title: ‘The Influence of Some Cations on an Adenosine Triphosphatase from Peripheral Nerves’ of his article in 1957, since he thought that it would be too provocative to mention active transport or even ‘sodium pump’. Consequently, there was little response to his first article. In the three following papers and the review from 1965 active transport of Na+ and K+ was included in the titles in order to strengthen the message.

Third, he realized that the confidence in his colleagues had limitations, and might not be mutual and requited. Skou had worked with Robert Post at Woods Hole during the Summer 1953, and Post visited Skou in Aarhus in 1958, where he became convinced that the ATP-ase was implicated in the active transport of ions. Nevertheless, in Post’s publication on the Na,K-ATPase in 1960 he failed to mention that Skou in his 1957 article proposed that the ATPase could be the ion pump in the cell membrane, only mentioning the enzyme in crab nerve membrane in the introduction (4). Skou concluded that the scientific community is very sensitive to such omissions, and that it is not conductive to a good reputation.

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Figure 2. Travel to Teotihuancan, the Mayan City of Gods and Mexico City 1962. Mural by Juan O'Gorman on the outside of the Central Library on the Ciudad Universitaria Campus of the National Autonomous University of Mexico in Coyoacán, Mexico city. Photo: Hanneke Luijting/Getty Images.

International interest, skepticism and recognition

Ten years after Skou initiated his experiments on the crab nerve enzyme in 1954, and proposed its putative role as an ion pump in cell membranes, his work had obtained national as well as international recognition in the field of membrane transport. He was invited to give lectures at congresses and universities around the world, and traveling became a regular activity along with the experiments at home. However, it resulted in meeting other scientists in the field, spreading the word about his ground-breaking research, and building contacts and networks.

Skou concluded that if you want the scientific world to know your views, it is not enough to publish your work in journals; you must also visit scientific communities around the world and sell your ideas. It should be emphasized that the scientific community in basic science in the 1950-1960s was much smaller than today.

In 1959 the International Congress of Physiology in Buenos Aires gathered all the important scientists in membrane transport. After his lecture on the crab nerve enzyme Skou was invited to lunch with Professors Alan Hodgkin, Andrew Huxley and Richard Keynes, who studied the electrical charges in the large nerve fiber from the squid and were able to show how nerve impulses are exchanged between cells. Alan Hodgkin and Andrew Huxley were awarded the Nobel Prize in 1963 for their work. Skou notes that he was surprised, that three world-renowned scientists from Cambridge were interested in what he had been doing in Aarhus. It gave him the feeling that his findings were more important than he had imagined.

Others were skeptical to the idea that the transport of Na+ and K+ was driven by ATP, and expressed resistance to Skou’s theory that the enzyme was the pump. They held the views that the cell membrane did not contain any proteins, and that enzymes were catalytic proteins which did not convert energy to work. Skou felt humbly that he was an intruder in the field of membrane transport compared with the established researchers, who had studied the active transport of the two ions for a number of years, and deserved to make the discovery.

However, his review article in Physiological Reviews in 1965 succeeded in convincing the scientific community that the Na,K-ATPase was the pump that transported ions into and out of the cell membranes. His prominence became cemented when the Na,K-ATPase was described in Biochemistry: The Molecular Basis of Cell Structure and Function, the widely used and recognized biochemical textbook in 1970 (5). The author Albert L. Lehninger had covered the work on the enzyme by Skou and others in detail in his textbook.

Travel deligths

During his busy traveling schedule to meetings and universities Skou made several detours for sight-seeing. He was driven his by his inborn curiosity and sense from adventure, which had characterized his childhood in Lemvig and early medical and scientific career. After the visit to Woods Hole in 1953 he spent a month at Columbia University in New York, where he was fascinated by the city’s multiculturalism and architecture. He made the most of ballet, opera, and concerts as well as the many excellent museums.

On his way home from the International Congress of Physiology in Buenos Aires in 1959 he made stops in Lima and Cuzco in Peru, where he visited the Inca ruins, and continued to St. Thomas in the West Indies, once a Danish colony. During an International Symposium on Membrane Transport and Metabolism in Prague, in 1960, Skou enjoyed the old city together with his wife Ellen-Margrethe in between the papers and dicussions.

In 1962 he received invitations from 10 physiology departments at American universities to lecture on the crab nerve enzyme. In Houston he took a detour to the Mexico to see the excavated Mayan cities on the Yucatan peninsula as well as Teotihuancan, the City of Gods, outside Mexico City (Figure 2). Skou was invited to give a lecture at the International Congress of Physiology in Tokyo, in 1965, and decided to travel via Moscow and the Trans-Siberian railway to the Pacific ocean and then sail to Yokohama. After the meeting he continued to Kyoto, Hong Kong and Bangkok, but plans to visit Cambodia and Nepal were abondoned due to political unrest. In the years that followed Skou travelled even more to teach, lecture and participate in conferences all over the World giving him a continuous and concentrated overview of the field and any recent developments.

Childhood and education

In the first chapter of the memoirs Skou recalls his birthplace and childhood in the small town of Lemvig in West Jutland on the coast of Limfjorden, where his father ran a timber and fuel business. The family lived in a big house overlooking the town and harbour surrounded by high hills and a lake. In a beautiful pastorale Skou tells about his favorite playground, the timber yard with warehouses, where he and his brothers would meet friends and develop their skills as architects and builders of cabins, sledges, rafts for sailing and a replica U-boat. In the winter they were skating on the most glorious ice rink of the lake, skiing in the hills and sledging on a windy road. The family spent the summer holiday in a cottage in the dunes of the North Sea coast at Vejlby. They would drive from home in a horse-drawn carriage, and later in an open Chevrolet or on bicycles. He and his brother acquired a yacht and sailed on the fjord, and Skou continued sailing in the Danish seas throughout his life.

However, Skou’s carefree, joyful and relaxed childhood reminiscent of Arcadia was abruptly interrupted when his father developed a fatal pneumonia. He was only 12 years old and the following year he moved to Haslev on Zealand to attend high school. Skou was enrolled as medical student at the University of Copenhagen and moved to a guesthouse in the city where he became attracted by the cultural life with art museums, exhibitions, theatre and concerts, initiating a life-long interest in culture and art.

References

 

  1. Skou JC.The influence of some cations on an adenosine triphosphatase from peripheral nerves. Biochim Biophys Acta. 1957;23:394-401.
  2. Skou JC. Enzymatic basis for active transport of Na+ and K+ across cell membrane. Physiol Rev. 1965;45:596-617.
  3. Hess HH. Effect of Na ions and K ions on Mg ion-stimulated adenosinetriphosphatase activity of brain. J Neurochem. 1962;9:613-21
  4. Post RL, Merritt CR, Kinsolving CR, Albright CD. Membrane adenosine triphosphatase as a participant in the active transport of sodium and potassium in the human erythrocyte. J Biol Chem. 1960;235:1796-802.
  5. Lehninger, AL. Biochemistry: The Molecular Basis of Cell Structure and Function. Johns Hopkins University, Baltimore. Worth Publishers, Inc., New York, 1970.