We self-published a history of biochemistry book. The Molecule Hunters is 133 profiles of the people who decoded life, from a physician weighing a willow tree in the 1640s to structural biologists predicting protein folds with AI. 190 scientists, eleven parts, four centuries. Here is how it got made. Last spring I gave my biochemistry students an AI assisted extra-credit project: pick a scientist, do the deep research, write a profile. Then about six months of editing from Abbie and I. More than 500 students are co-authors. This is something that didn't exist, and now it exists (with lots of help from Claude et al). This is a book I wanted to read and I'm happy with how it turned out. I love thinking about science through the personalities of the discoverers. It's free. The full PDF and EPUB are on our site, and the audiobook, about eleven hours, is free on Spotify. It will be free in most outlets. Amazon charges $3 for the Kindle right now and I'm working on getting that to zero as well. Read, download, or listen: deppmannlab.com/book Hope you enjoy it.

The 1947 Nobel Prize in Physiology or Medicine was announced on this day. It went to two labs that had each been told to stop. Half went to Carl and Gerty Cori, for working out how the body stores sugar as glycogen and spends it again. In Buffalo she was told to stop publishing with her husband or leave, and at a later job interview she was told it was "un-American" for a married couple to work together. She didn't stop. When Washington University hired Carl, nepotism rules meant Gerty came on as a research associate at about a tenth of his salary. She wasn't made a full professor until 1947, sixteen years later. With this prize she became the first American woman to win a science Nobel, and only the third woman to win any science Nobel. A few months earlier, on a climbing trip in the Rockies, she had learned she had myelofibrosis, the bone-marrow disease that killed her ten years later. She worked through nearly all of it. The other half went to Bernardo Houssay in Buenos Aires, who showed that the pituitary pushes blood sugar up, against insulin. In 1943 Argentina's military government fired him for calling for democratic elections. He had offers from abroad and stayed, keeping his lab going on private money, and that's where the Nobel news found him. He was the first Latin American scientist to win. Luis Leloir, whose Nobel anniversary is Tuesday, trained with Houssay and also passed through the Coris' lab. All three are in The Molecule Hunters: deppmannlab.com/book

Last week in Berlin I got to stand outside Otto Warburg’s lab. The Otto-Warburg-Haus in Dahlem is now home to the Max Planck Society archives, and I spent some time talking with one of the archivists there. Down the road at the Harnack-Haus, the old Kaiser Wilhelm Society guest house, there’s a wall of portraits of the people who came through between 1929 and 1953. Thirty-five of them were Nobel laureates. Warburg is up there with his poodle. So is Hans Krebs, who visited in 1932 as a young researcher, years before his own Nobel. Warburg’s science is the reason any of this matters, so start there. His main tool was the manometer: a sealed glass flask holding a thin slice of living tissue, with a fluid column that moved as the tissue used oxygen. That let you measure a living tissue’s chemistry directly, in milligram amounts. Nearly every metabolism lab from the 1930s to the 1950s ran on Warburg’s flasks. He used them to find the iron-containing enzyme that hands electrons to oxygen at the end of respiration. The clever part is that he never purified it. Carbon monoxide blocks respiration by binding iron, and light reverses the block. By measuring which wavelengths of light restored respiration best, he read off the enzyme’s absorption spectrum. It matched an iron-porphyrin. That earned him the 1931 Nobel Prize. In 1924 he saw that tumor slices burn glucose many times faster than normal tissue and turn it into lactate even when oxygen is plentiful. He spent the rest of his career arguing that damaged respiration causes cancer. He was wrong about the cause, but the observation held up. It’s called the Warburg effect, and it’s the reason a PET scan lights up a tumor. The lineage is what I keep coming back to. Warburg did his chemistry PhD under Emil Fischer in 1906. Krebs then trained in Warburg’s lab and learned the manometer there. Warburg wasn’t an encouraging mentor. He told Krebs the method was for respiration, not for the slower chemistry of metabolism. In 1930 he told Krebs it was time to go. In 1933 the Nazis dismissed Krebs, and he left for England with 24 Warburg manometers packed in 16 crates. He used them to find the urea cycle and then the citric acid cycle: the work Warburg had waved off. The archivist and I spent a lot of our conversation on how Warburg held onto his institute at all. His father was born Jewish. The Nuremberg Laws classified Otto as half-Jewish, and in 1941 Göring had him reclassified as one-quarter. He never married, and for decades he lived with his secretary, Jacob Heiss. Either fact should have ended his career in Nazi Berlin. Instead he ran his lab straight through the war while Krebs and so many others were pushed out. The regime wanted his cancer research. My guess is that Hitler feared cancer more than he cared about Warburg’s background. Fischer to Warburg to Krebs: three generations, and a big piece of how we understand metabolism. Warburg’s profile in The Molecule Hunters: deppmannlab.com/book

Last week in Berlin I spent a morning walking past places from The Molecule Hunters. Outside Humboldt University, a bronze Emil Fischer sits in a heavy academic robe, one hand on his knee. He faces Robert Koch’s statue in the neighboring park, and that seems right. Koch showed that a specific germ causes a specific disease. Fischer showed that the molecules of life obey the same chemistry as everything else. Around the corner is the building on Hessische Straße that housed his lab. It opened in 1900, and it’s where he coupled amino acids one bond at a time. By 1907 he had an 18-residue chain that digestive enzymes cut just as they cut a real protein. Before that he had worked out the shapes of the sugars, which is why every student still draws Fischer projections. And in 1894 he gave us “lock and key” for how an enzyme picks its target, then hedged it right away, as if embarrassed to be caught speaking in pictures. One more Berlin thread: Otto Warburg did his chemistry PhD under Fischer, finishing in 1906. More to come on Warburg later. Fischer’s profile in The Molecule Hunters: deppmannlab.com/book

On this day in 1987, Merck announced it would give a drug away. Mectizan treats river blindness, a parasitic disease spread by black flies that had blinded people across Africa and parts of Latin America for generations. The people who needed it couldn’t pay, and no government stepped up to buy it. So Roy Vagelos, Merck’s CEO, announced the company would donate it to anyone who needed it, for as long as it was needed. Vagelos grew up working the counter at his Greek immigrant parents’ luncheonette in Rahway, New Jersey, a few blocks from Merck. Merck chemists ate there and noticed the kid who was good at math. He became a physician, then a biochemist at NIH, where he helped show that cells build fatty acids on a small carrier protein that shuttles the growing chain from one enzyme to the next. Later, after chairing biochemistry at Washington University, he went back to Rahway, this time inside Merck. In 1980, with Merck’s first statin in trials, a report of tumors in animal studies came out of Japan. He halted the trials until the drug was proven safe. That drug, lovastatin, reached patients in 1987, the same year as the Mectizan pledge. Billions of doses of Mectizan later, river blindness is being eliminated country by country. His profile in The Molecule Hunters: deppmannlab.com/book

I spent part of today wandering around Berlin, looking for the places where modern biochemistry and experimental medicine were born. One of my favorite discoveries was an inscription on the back of Robert Kochs statue, unveiled in 1916. The inscription comes from a speech Koch gave at the International Medical Congress in 1890: "I hope that, in the war against the smallest but most dangerous enemies of humanity, nations will continually strive to surpass one another." Koch, who identified the bacteria responsible for tuberculosis and helped establish the experimental foundations of infectious disease research, understood that nations could compete through scientific discovery rather than military conquest. Theres a painful irony in the dates. Koch said this in 1890. His monument was unveiled in 1916, in the middle of World War I (notice the bullet holes). And less than two decades later, Germany would begin driving some of its greatest scientists out of the country because of their ancestry, religion, or political convictions. The United States and Britain would benefit enormously from that exodus, while Germany dismantled much of the scientific culture that had made it an international leader. Koch's own legacy is complicated, particularly his ethically troubling research in colonial Africa. But I find the aspiration expressed in this inscription remarkably powerful. Imagine what science might accomplish if countries competed as fiercely to cure disease as they In other less productive endeavors. Robert-Koch-Platz (outside of Humboldt University), Berlin.

Gertrude Elion's Nobel Prize was announced on this day in 1988, shared with George Hitchings and James Black, "for their discoveries of important principles for drug treatment." It was a prize for a way of thinking, and it went to someone who never earned a PhD. She was 15 when her grandfather died of cancer, and she decided that was the disease she would work against. She graduated from Hunter College in chemistry in 1937, in the middle of the Depression, and no graduate program would fund her. Labs asked why a woman would want to be a chemist. She taught high school, did quality control for a food company, and finished a master's degree at NYU at night. In 1944 Hitchings hired her at Burroughs Wellcome. His idea, considered naive at the time, was to stop screening compounds at random, figure out what a diseased cell needs, and build a molecule to block it. Dividing cells need DNA bases, so Elion built fake ones, close enough to be taken up and wrong enough to jam the works. What came out of that lab: 6-mercaptopurine, one of the first drugs to put childhood leukemia into remission. Azathioprine, which made organ transplants practical. Allopurinol for gout. And acyclovir, a decoy that only a herpesvirus can switch on. After she retired, the program she built produced AZT, the first HIV drug. She worked into her eighties. Her story is in Part 10 of The Molecule Hunters: deppmannlab.com/book

Rosalyn Yalow's Nobel Prize was announced on this day in 1977, for radioimmunoassay. She was the second woman ever to win in Medicine. Her partner of 22 years, Solomon Berson, had died in 1972 and couldn't share it, so she renamed their lab the Solomon A. Berson Research Laboratory. His name stayed on every paper she published after that. They met in 1950 in a converted janitor's closet at the Bronx VA hospital: a nuclear physicist and a medical resident who played blindfold chess. In 1955 they showed that diabetics treated with insulin make antibodies against it. The journal rejected the paper because insulin was supposedly too small to provoke antibodies, and they had to call them "insulin binding globulin" to get it published. Years later, Yalow put the rejection letter on a slide in her Nobel lecture. Then they turned those antibodies into a measuring tool. Think musical chairs. There is a fixed number of antibody "chairs," and a known amount of radioactive insulin competes with the patient's own insulin for seats. Count how much radioactive insulin is left standing and you can work out how much insulin was in the blood, at levels no chemical test could reach. The same idea soon spread across endocrinology, blood banking and newborn screening. They refused to patent it and mailed their antibodies to any lab that asked.

The 1992 Nobel Prize in Physiology or Medicine was announced on this day, to Edwin Krebs and Edmond Fischer, for a discovery that started with a piece of filter paper. In 1953, working across a hallway at the University of Washington, they tried to repeat Carl and Gerty Cori's recipe for phosphorylase, the enzyme that breaks down glycogen, and couldn't get active enzyme. The difference looked trivial. The Coris filtered at one step where Krebs and Fischer had been centrifuging. They switched to filtering, and the enzyme came out active. Wash the filter paper first, and it didn't. The secret ingredient was calcium leaching out of the paper. Calcium was needed to turn on a second enzyme, which clipped a phosphate from ATP onto phosphorylase and switched it on. Another enzyme took the phosphate back off and switched it off. That reversible phosphate switch turned out to run almost everything. The human genome has hundreds of kinases and phosphatases, controlling cell division, immunity and how neurons answer signals. My own lab studies the Trks, a family of receptor kinases, so all of our work sits downstream of the switch that filter paper revealed. Two things I love about these two. They traded first authorship from paper to paper and never cared who went first. And Krebs spent his career being congratulated for the Krebs cycle, which was a different Krebs. Once a department chair assumed he was that Krebs, and he didn't correct him. Their profile in The Molecule Hunters was researched by UVA undergraduate Emily Bloom. The enzyme regulation lesson at Biochemistrypedia covers the switch: biochemistrypedia.com

The 1994 Nobel Prize in Physiology or Medicine was announced on this day, to Martin Rodbell and Alfred Gilman, for G proteins: the switches that carry a hormone's message from a receptor on the outside of a cell to the machinery inside. Rodbell drew the idea first, on a tablecloth in a Washington bar: a receptor, a hidden relay, then the enzyme that makes cyclic AMP. At NIH in 1970 he found that a trace of GTP switched the system on. As a grad student he had once been fooled by a contaminated batch of ATP, so this time he made ultra-pure ATP to prove the effect really came from GTP. So, the relay was inferred. Gilman Gilman figured it out.. He liked to say he was "named after a textbook," since his father co-wrote Goodman & Gilman, the pharmacology bible. Here at the University of Virginia in the 1970s, he and his postdoc Elliott Ross took a mutant cancer cell line that couldn't respond to hormones, added back an extract from normal cells, and restored the response, but only with GTP present. His UVA lab then purified the protein, Gs, before he moved to UT Southwestern in 1981. That's the second Nobel story from Charlottesville this fall, after Ferid Murad and nitric oxide. Eighteen years later to the day, Robert Lefkowitz and Brian Kobilka won chemistry for the receptors that hand the signal to G proteins. Both men are in The Molecule Hunters, and the signaling lessons at Biochemistrypedia walk through the G-protein on/off cycle: biochemistrypedia.com

G. N. Ramachandran was born on this day in 1922, on the Kerala coast. In 1963, at the University of Madras, he and two colleagues asked a question nobody had put so precisely: of all the ways a protein backbone could twist, which ones are physically possible? Each amino acid in a chain has two bonds that can rotate. For every pair of angles, they calculated whether atoms would run into each other. With no computer available to them, a student spent a full year doing the calculations on a mechanical desk calculator, copying trig values out of printed tables. When they plotted what survived, nearly the whole map was forbidden except a few compact islands, chiefly one for the alpha helix and one for the beta sheet. Sixty years later, every protein structure, from crystals, NMR or cryo-EM, gets laid against that plot before anyone believes it. The Nobel committee never called. A busy birthday, too. Jens Skou (1918), who found the sodium-potassium pump in crab nerves, and Roy Vagelos (1929) were born on October 8, and the 2003 Nobel to Peter Agre and Roderick MacKinnon for membrane channels was announced on this date. Agre found the water channel at Johns Hopkins, where I trained, by injecting its RNA into frog eggs and watching them swell until they burst. Ramachandran's story is in The Molecule Hunters: deppmannlab.com/book

The 2004 Nobel Prize in Chemistry was announced on this day, to Aaron Ciechanover, Avram Hershko and Irwin Rose, for working out how a cell decides which of its proteins to destroy. The puzzle was ATP. Breaking a peptide bond releases energy, so why does a cell spend ATP to break down its own proteins? Hershko had chosen to study protein destruction when the subject was, in his words, "distinctly unfashionable." A visiting biochemist once told him he shouldn't have most of his lab working on a hopeless problem. In 1978, at the Technion in Haifa, Hershko and Ciechanover split an extract of immature red blood cells into two fractions. The protein-destroying activity died in both. Put them back together with ATP, and it returned. One fraction, red with hemoglobin, held a small factor that survived boiling, which one expert told them proved it couldn't be a protein. It was a protein. They called it APF-1. The work soon had a second home in Irwin Rose's lab at Fox Chase in Philadelphia, where Hershko spent sabbaticals, and Keith Wilkinson in Rose's lab showed that APF-1 was ubiquitin, a small protein already known from other tissues whose purpose nobody understood. Its purpose is a tag. The cell spends ATP to stitch chains of ubiquitin onto proteins it wants gone, and the proteasome destroys whatever carries the tag. The ATP pays for choosing and tagging, not for breaking the bond. That one system turned out to drive the cell cycle, the response to low oxygen, and which protein fragments the immune system gets to see. None of them treated the prize as the point. Rose went back to enzyme mechanisms three days a week. Hershko was still at the bench at the Technion into his late eighties. Their story is in The Molecule Hunters, free to read or listen to: deppmannlab.com/book

Louis Pasteur died on this day in 1895, at Villeneuve-l'Étang outside Paris, in a plain room above stables where his institute was making diphtheria antiserum. The work went on below him to the last. He started as a chemist. At 25 he sorted tartrate crystals by hand under a microscope and found they came in mirror-image forms, which was the discovery of molecular handedness. He turned to wine and beer and showed that fermentation is the work of living yeast, not a spontaneous chemical breakdown, winning a long fight with Justus von Liebig. His swan-neck flasks finished off spontaneous generation, and gently heating wine to stop spoilage gave us pasteurization. Then came the leap: if specific microbes cause fermentation, specific microbes cause disease. That logic ran through silkworms, chicken cholera, anthrax (the public sheep trial at Pouilly-le-Fort in 1881) and, finally, rabies. Here is where biochemistry comes in. Pasteur held one of vitalism's last lines: some chemistry, fermentation above all, needed an intact living cell. Two years after his death, Eduard Buchner ground yeast with sand, filtered out every cell, and the juice still turned sugar into alcohol. Enzymes, not life itself, were doing the work. Pasteur had been right against Liebig and wrong about the cell, and modern enzymology grew out of both. France gave him a state funeral at Notre-Dame and wanted him in the Panthéon. Marie Pasteur said no, and he lies in a crypt at the Institut Pasteur. His profile in The Molecule Hunters can be found here: deppmannlab.com/book