Hitler’s gift: Hans Krebs—a man of cycle

Frederick Sanger was awarded the Nobel Prize (chemistry) in 1958 for his work on protein structure and a way to figure out the sequence of amino acids in protein (insulin in his work).  He got his second Nobel Prize (again in chemistry) in 1980 for devising a way to sequence the bases in nucleic acids, such as DNA.  He is indeed the “man of sequence” (also a man of consequence).

Hans Krebs

If Sanger is a “man of sequence”, then Hans Krebs (see photo) is a “man of cycle”.  Krebs discovered the urea cycle (converting the toxic ammonia to the harmless urea) and citric acid cycle or tricarboxylic acid (TCA) cycle now bears his name—Krebs cycle.

Krebs was a physician by training (his father was a German surgeon).  Being a Jewish, he was fired from his medical research job at the University of Freiberg in 1933 when the Nazi took over the government.  And this happened even after he achieved the international fame for discovering the urea cycle in 1932.  With their policy of expelling all Jewish scientists from German and Austria, Hitler’s Nazi was either too ignorant or too arrogant about the supremacy of the “Aryan race”.

He fled to Gowland Hopkins Lab at Cambridge University in June 1933, thanks to a Rockefeller Foundation grant, which interrupted for one year.  In 1935 he moved to Sheffield University where he stayed for nearly 20 years with the continuing support of Rockefeller grants.

It was at Sheffield University where he worked out the TCA cycle, work of which was sent to and rejected by Nature and was later published at a Dutch journal called Enzymologia. Rejecting an earth-moving (驚天動地) discovery article must have been a life long regret for the Nature editors.

Simply put, Krebs cycle is the furnace to burn the fuel of life producing energy to keep us going.  In his Nobel Lecture (citric acid cycle), Krebs thanked Fritz Lipmann, who shared the 1953 Nobel Prize with him, for the discovery of the 2-carbon acetyl coenzyme A, without which the concept of a cycle is incomplete, if not impossible.  Recall the 4-C oxaloacetate must combine/react with the 2-C acetyl coenzyme A to make 6-C citrate/citric acid, thus named citric acid cycle.

It was initially thought this was just the burning of carbohydrate, but it was later confirmed that protein and fat also enter this furnace of life.  In fact, all carbon atoms of fatty acid enter the cycle as the form of acetyl coenzyme A.

Fritz Lipmann is another Jewish scientist who fled the Nazi German in 1932 and settled at Massachusetts General Hospital (MGH), where, I believe, the acetyl coenzyme A was discovered.

This following diagram is taken from Krebs Nobel Lecture of the citric acid cycle.

Hitler’s gift: Max Perutz, Lord Haemoglobin—a devoted scientist to the end

Max Perutz’s name spells hemoglobin (Hb or haemoglobin for British).  He spent twenty some years working on the structure of Hb or thirty some years if one adds the deciphering of its function.  I cannot overemphasize the enormous contribution to the advance in medicine of his work.  A modest person he was, he refused any honor that would give him a title, although he quipped on a gathering at Cambridge U to celebrate his 80th birthday,

“I used to tease my son when he was little and when peerages were still hereditary that one day I would become Lord Haemoglobin, and he would inherit the title whether he wants or not.” (Perutz in in 1990, photo credit to Hitler's Gift)

He left Austria for England as a postgraduate student in 1936.  His parents were prosperous textile manufacturers in Vienna, but being Jewish they fled to Switzerland penniless when Hitler marched into Austria in March 1938.

It was Lawrence Bragg, who was then the director of the Cavendish Lab, applied to the Rockefeller Foundation for a grant to cover Perutz’s research that began in 1/1939 and lasted for thirty some years with few interruptions.  James Watson and Francis Crick worked at Perutz’s Lab when they arrived in 1951.

In his letter written to James Watson on January 14, 2002—just three weeks before his death, Max Perutz wrote,

“My days are numbered, and just wanted to let you know how much fun dealing with you gave me in the early days. . . . I was sorry not to appear at your launching party at Clare the other day, but I had a very good excuse.  I had been working on Huntington’s Disease for some years which also got me interested in the amyloid structure, because fibers of poly-L-glutamine with the same cross beta X-ray pattern has amyloid.  That pattern was first seen by Bill Astbury in 1935 and has been a riddle ever since.  Last September I had an idea what the structure responsible for it might be.  The more I thought about it, the more apparent did it become, that it was the only possible solution, so I dropped everything else, replied no letters, went to no meetings and concentrated on that one problem.  I finished two papers about the structure of amyloid at 12.50 on 20th December, and Alan Fersht, now an editor, sent them straight to PNAS.  At 13.00 I had to be admitted to hospital for an operation on my bile duct which was blocked by a tumor of a cancer that started with a pimple under my nose last January, and is now out of control.  I have enjoyed 65 years of productive research here at Cambridge and what more can anyone expect of life?  Please give my regards to Liz [Watson’s wife] and tell her that I am sorry I never got to know her better.”

This is unbelievable, a super human; three weeks left in life and moment before entering the hospital for operation for an end-stage cancer and yet he was talking about his beloved research in frontier medicine in great details.

Students of medicine would know Huntington disease (HD) is caused by expansion of the cytosine-adenine-guanine (CAG) trinucleotide repeats in a gene now known as HD gene. There are normally 15 to 32 CAG repeats, and more than 37 CAG repeats are usually seen in the victims of HD.  The issue of amyloid proteins in HD hasn’t got into clinical medicine yet.  But, it hasn’t escaped my notice that there is an Alzheimer amyloid precursor protein (APP) gene located in chromosome 21, and both Alzheimer disease and Huntington disease lead to dementia.  (This is interesting, but not the topic of interest for this post.)

Hitler’s Gift

Reading science/medicine or about scientists was my first love and the passion never faded.  I’ll write a series of articles calling Hitler’s Gift mostly about the stories of great scientists, many of them happened to be ours, thanks to Hitler’s madness.  I’ll also talk about their sciences so you can appreciate the impact of their work on advancing the modern science.

In the first 32 years of the Nobel Prizes (1901-1932, the year before Hitler came to power, Germany--Germans or scientists working on Germany) won one third of all the prizes in science (33 out of 100), Britain 18, USA 6.  Among German scientists about a quarter was Jewish descent, with Jewish population made up no more than 1% of the population at the time.  Thanks to Hitler’s madness the American and British scientists have since dominated as the Nobel laureates in science after WWII.

At the conclusion of this series we may say “Hail Hitler!” as Sigmund Freud did when he fled the Nazi in 1938 and saw the luxurious villa north to London ready as his new home.

I’ll begin with Max Perutz who wrote a Foreword for the book (Hitler’s Gift—see photo) written by Jean Medawar and David Pyke.

You’ll notice that I’ll mention Rockefeller Foundation every so often as it played a very crucial role in saving over one thousand scientists.  I always lament that the public was not more aware for this humanistic and visionary deed.

In fact, scientists were not the only Hitler’s gifts; great minds in humanity or artists were also among the refugees.  The other day I paid $4.98 for Artists in Exile (see photo) at Half-Price Books.

I often go to Half-Price Books for treasure hunt.  Last month I spotted Alan Lightman’s The Discoveries (see photo below) for bargain $9.98.  I have checked it out from library before, and now I do not have to return it.  Janice first introduced Alan Lightman to me a few years ago when she gave me Lightman's A Sense of Mysteries: Science and the Human Spirit.