Chapter 3: Squiggles and Gold

3

Squiggles and Gold

Hans Krebs and Fritz Lipmann shared the 1953 Nobel Prize in Medicine for their separate but related discoveries about basic metabolism.

Hans Adolf Krebs was born in 1900 in Germany. He made his first important discovery by sorting out exactly how the body neutralizes the toxic ammonia that is left over from the metabolism of protein.1 In 1932 the dean of the medical faculty at the University of Freiburg, surgeon E. Rehn, praised Krebs as an outstanding scientist whom the university should regard with pride. Krebs’s work was abruptly interrupted in 1933 when Germany’s National Socialist government passed the Law for the Restoration of the Professional Civil Service, which scrubbed all public institutions of Jews and anti-Nazis.2 On April 12, 1933, the same Dean Rehn called for Krebs’s immediate suspension. A letter from the minister of education explained the termination: “The

1 H. Krebs and K. “Henseleit, Untersuchungen über die Harnstoffbildung im

Tierkörper” [Studies on urea formation in the animal body], Hoppe-Seyler’s

Zeitschift für physiologische 210 (1932): 33–66. 2 The legal document describing Law for the Restoration of the Professional

Civil Service can be seen on the website of the United States Memorial

Holocaust Museum, section “Timeline of Events 1933–1938,” at ushmm.org/ learn/timeline-of-events/1933-1938/law-for-the-restoration-of-the-professional -civil-service.

Minister of the Interior has decided that all members of the Jewish race (regardless of their religion) who are employed in the civil service or educational facilities will be suspended until a further decision is made. All academic instructors and assistants in this category are to be informed that they are immediately suspended.”3 Krebs was fired from his academic post and became a scientific refugee. The Academic Assistance Council (AAC) came to his aid. The AAC was founded in May 1933 by William Beveridge, then the director of the London School of Economics. Beveridge formed the organization as a response to the Nazi decree, with initial support and funding coming from British academics. With help from the AAC, Krebs was invited to Cambridge.4 Krebs’s laboratory equipment had been seized when he was fired, but in June the entire contents of his old lab were acquired with funds from the Emergency Association of the German Sciences and the Rockefeller Foundation. His loyal former coworkers packed his instruments for export to Cambridge. On his travel papers, Krebs indicated his religion as “non-denominational,” and he officially carried only the allowed ten marks in cash, but hid another five hundred marks within his books.

By 1936, it became clear that the need for ongoing assistance was not temporary, and the AAC joined the Swiss-based Emergency Association of German Scientists Abroad to become a new larger organization called the Society for the Protection of Science and Learning (SPSL).5 Its stated goal was “the brotherhood of scientific endeavour, regardless of race and creed and politics: and it stands for it, not by passing pious resolutions or by putting out disguised political propaganda,

3 Roth, Klaus, “Sir Hans Adolf Krebs (1900–1981), Part 2.” Chemie in unserer

Zeit [Chemistry In Our Time] (Wiley-VCH, December 1, 2020. DOI: 10.1002/ chemv.202000121). 4 For more detailed information on the role of Cambridge as an academic refuge, see, “Keynote: Sir Hans Krebs and the Sir Hans Krebs Trust. Introduced By

Stephen Wordsworth,” Trinity College, Cambridge, May 7, 2020, youtube.com/ watch?v=QYoFCHD8_pc&feature=emb_logo. 5 E. Rutherford, “The Society for the Protection of Science and Learning,” Science,

April 17, 1936, 372.

but by trying to help colleagues in their need.”6 In the early years, some two thousand people were saved, sixteen of whom would become Nobel Prize winners.

At Cambridge, Krebs studied how cells convert fuel to energy. He discovered that after food gets broken down into sugars, fats, and proteins, these components use oxygen in a multistep chain reaction. The process converts the biochemicals into energy-providing molecules (ATP), with leftover carbon dioxide and water. This became known as the Krebs cycle. The ATP supplies the power for all the work of the body, such as muscle movement, breathing, and cell function. In 1937, Krebs submitted a report on his discovery to the editors of Nature, the world’s premier scientific journal, but it was rejected.7 He managed to get his work published in a small Dutch biochemistry journal, and it was soon recognized the world over as groundbreaking.8 Krebs soon became a naturalized British citizen, and he served on the faculty of the University of Sheffield for many years. In 1970, there was much debate about cutbacks to the US federal budget for scientific research. Dr. Krebs was reported to have told a meeting of the American Philosophical Society that, among other things, the government should eliminate wasteful and unproductive research, which he characterized as “occupational therapy for the university staff.”9 The last part of his career was at Oxford, where Krebs remained highly active with the publication of hundreds of scientific articles and contributions to textbooks. Hans Krebs died in 1981 at the age of eighty-one.

6 “Science and Learning in Distress,” Nature (1938): 1051–52. 7 F. MacDonald, “8 Scientific Papers That Were Rejected before Going on to Win a

Nobel Prize,” Science Alert, August 19, 2016, sciencealert.com/these-8-papers-wer e-rejected-before-going-on-to-win-the-nobel-prize. 8 H. A. Krebs and W. A. Johnson, “The Role of Citric Acid in Intermediate Metabolism in Animal Tissues,” Enzymologia 4 (1937): 148. 9 As quoted in “Sir Hans Krebs, Winner of Nobel for Research on Food Cycles, Dies,”

New York Times, December 9, 1981.

The work of the organization that had assisted Krebs to flee to England did not end after the second world war. The SPSL assisted academic

refuges from Stalin’s regimes in the USSR and Eastern Europe, and in later years it assisted academics threatened by military juntas in Chile and Argentina or apartheid in South Africa and those who were persecuted for religious, racist, or political reasons in other African countries as well as in Syria and Iraq. In 1999, the SPSL changed its name to the Council for Assisting Refugee Academics (CARA). This name was modified again in 2014 to become the Council for At-Risk Academics. In 2015, Krebs’s descendants arranged for Sotheby’s to auction his Nobel medal. It was made of 23-karat gold, measured 6.5 centimeters in diameter, weighed 196 grams, and was inscribed, “Inventas vitam juvat excoluisse per artes” (the word-for-word translation is “inventions enhance life which is beautified through art”). Krebs’s medal was sold to an anonymous collector for $275,000.10 The money went toward the Sir Hans Krebs Trust, which supported young biomedical scientists working in the UK who have been forced to leave their own country because of conflict, discrimination, or danger. The trust subsequently partnered with the Council for At-Risk Academics to administer scholarships for refugees.11 When it was revealed that the buyer of the medal was planning to take his purchase out of the country, England’s Reviewing Committee on the Export of Works of Art and Objects of Cultural Interest (RCEWA) managed to get a temporary stay on the movement of the medal. RCEWA felt the object should remain in the UK as a testament to the contribution of scientific refugees to the war effort. They got a two-month hold while an English buyer was sought. In 2016, the medal went on the auction block at Nate D. Sanders, where it sold for $269,000.

10A. B. Kenner, “Krebs Nobel Auctioned,” Scientist, July 16, 2015. 11“Who We Are,” Council for at Risk Academics, cara.ngo/who-we-are/our-history/.

Nobel Gold

Krebs’s medal was 23-karat gold, but since 1980 the medals have been made of an 18-karat green-gold core, which is an alloy of gold and silver with trace amounts of copper, then plated with 24-karat gold. Nobel Prize medals have fetched a variety of amounts on the auction block. In 2008 the Nobel Peace Prize medal won by Aristide Briand in 1926 was sold for $14,000. The medal awarded in 1962 to Francis Crick for his DNA discoveries sold in 2013 for $2.27 million. The proceeds went to the Francis Crick Institute for medical research in London. The medal of his cowinner, James Watson, sold the following year for $4.1 million. The Russian billionaire who bought it, Alisher Usmanov, gave it back to Watson. In 2015, Leon Lederman, physics winner from 1988, sold his medal to pay mounting medical bills, fetching $765,000. He died the following year. That same year, the medal for the 1963 medicine prize awarded to Alan Lloyd Hodgkin sold for $795,614. Also in 2015, the medal for the 1971 economics prize (not strictly a Nobel Prize) awarded to Simon Kuznets brought in $390,848. The medal for the 1994 Nobel Prize in economics awarded to John Nash sold for $735,000 in 2016, a year after he’d died in a car accident. The medal of the 1965 physics prizewinner Richard Feynman sold for almost $1 million in 2018.

The cowinner in 1953 was Fritz Albert Lipmann, who was born in 1899 in Königsberg, then the capital of East Prussia. The region is now called Kaliningrad, and is an outpost of the Russian Federation sandwiched between Poland and Lithuania. Even before getting his medical degree in Berlin, Lipmann was conducting basic research in chemistry. He continued with biochemistry research to earn his PhD at the Kaiser Wilhelm Institute for Biology, and it was there he met Krebs in 1927.

Lipmann subsequently left Germany to work in research labs in New York, Copenhagen, and London.12 Lipmann sought to answer exactly how the metabolic products of glucose were pulled into the Krebs cycle—there was a missing intermediate chemical. He discovered the small linking molecule and named it coenzyme A. The role of a coenzyme is to hold atoms or molecules together to make it possible for enzymes to work. Two years later, biochemist Feodor Lynen detected yet another intermediate substance, but his contribution was not recognized with a Nobel Prize until 1964. These combined discoveries revealed how the body converts chemical energy into physical energy. They are the underpinnings for all subsequent work on metabolism and nutrition, and they also made it possible for others to discover how DNA is made. Lipmann immigrated to America and worked at the Marine Biological Laboratory at Woods Hole on Cape Cod in Massachusetts, Cornell Medical School in New York, and Massachusetts General Hospital in Boston. He did not meet Krebs again until they were receiving their shared prize at the ceremonies in Sweden in 1953. Lipmann subsequently contributed to many biochemical discoveries, but his other claim to fame was the introduction of the squiggle “~” to biochemistry notations, known on the computer keyboard as the tilde. He used the squiggle to denote that a molecule had a high-energy bond. Lipmann used this shorthand for the ATP molecule, AMP~P~P, with the squiggles indicating that when those bonds are broken, they release a lot of energy.13 Chemists pounced on Lipmann’s squiggle as inaccurate and misleading, but it was such a handy way to describe the concept that it was used in textbooks for decades to come. The squiggle is not used anymore, because it is now known that it is neither the ATP molecule

12 W. P. Jenck and R. V. Wolfenden, Fritz Albert Lipmann, 1899–1986: A Biographical

Memoir (Washington, DC: National Academy Of Sciences, 2006). 13 F. Lipmann, “Metabolic Generation and Utilization of Phosphate Bond Energy,”

Advances in Enzymology and Related Areas of Molecular Biology 1 (1941): 99–162.

nor the bonds in the molecule that are high energy. Rather, it is the microenvironment (the system) in which the ATP is operating that makes it “molecular energy currency” for the cells. Most ordinary people understand the idea inherent in the squiggle better than the concept of energy currency, but then again, the job of the scientist is not to make things clear to ordinary folks.14 In 1986, at the age of eighty-seven, Lipmann was notified that his latest research grant application had been successful. He was preparing notes for a scientific conference presentation when he uttered, “I can’t function anymore,” and slipped into a coma, dying shortly thereafter.15

14 H. Kleinkauf, H. Dohren, and L. Jaenicke, The Roots of Modern Biochemistry: Fritz

Lippmann’s Squiggle and Its Consequences (Berlin: De Gruyter, 2011). 15 As quoted in H. Kleinkauf, H. Dohren, and L. Jaenicke, The Roots of Modern

Biochemistry: Fritz Lippmann’s Squiggle and Its Consequences (Berlin: De Gruyter, 2011).