At this writing three Nobel Prizes of 2026 have been awarded, so this is a good time to think about those who did not win a Nobel Prize but should have. Science has done this in Six biology breakthroughs that should have won a Nobel Prize – but didn’t (archived link). The list of misses in Physics is here (no archive yet); it left out Jocelyn Bell.
Watson and Crick are often mentioned as the discoverers of DNA. No, actually. That was the physician and scientist Friedrich Miescher, who is said to have used bandages filled with pus as his starting material in his early experiments. Watson and Crick proposed the correct structure of DNA as a double helix in 1952. Their Nobel Prize came ten years later, to be shared with Maurice Wilkins. The most important property of DNA, of course, is that it is the genetic material. A hundred years ago the first biochemists knew that proteins were complex and that DNA was composed primarily of a phosphate, a sugar, and four nucleotides. Thus, DNA was unlikely to be the material that could specify the complexity of any living organism. No.
Ostwald Avery, a microbiologist, studied the bacterium Streptococcus pneumoniae hoping to find a treatment for pneumonia. Previous research had shown virulent bacteria could confer their traits onto nonvirulent ones through the passage of some “transforming” material, and Avery wanted to know what it was.
With Colin MacLeod and Maclyn McCarty at the Rockefeller Institute in New York City, he refined a method to study these transformations in vitro. The group treated bacterial extracts to destroy the DNA, RNA, or protein, then dosed other bacteria with the extracts to see whether transformation was still possible. In a paper published in 1944, they showed the transforming material was bacterial DNA.
Avery continued his microbiological research rather than switching to the study of DNA. “One step at a time and the first step is, what is the chemical nature of the transforming principle? Someone else can work out the rest,” he wrote to his brother during the study. “Of course the problem bristles with implications.”
The Avery-MacLeod-McCarty Experiment is described here, along with commentary on its significance as perceived at the time. My older teachers seemed to have known exactly what it meant. But proteins were still considered to be the likely biological molecule capable of being the transforming material, and the discovery didn’t take. About ten years later, the Hershey-Chase Experiment proved without a doubt that DNA is the transforming material when they showed that DNA labeled with radioactive phosphate was internalized when a bacterial virus transformed its host cell, leaving the protein labeled with radioactive sulfur on the outside. It will surprise no one that the Nobel Committee sometimes misses something. In 1949, while Avery, MacLeod, and McCarty were being ignored, António Egaz Moniz won the Nobel Prize in Physiology or Medicine for pioneering the prefrontal lobotomy. Yes, everyone in the room just shivered.
Stem cells have made a revolution in biology and biomedical science, with details still to be worked out for many therapeutic uses that are coming. They were discovered more than sixty years ago in a series of ingenious experiments by James Till and Ernest McCulloch:
In the 1950s, hints that many types of blood cells have a common origin were accumulating. Although the concept of “stem cells” had been around for decades, there was no proof they existed; marking and tracking individual cells was not possible yet. But then a flurry of research into the biological effects of the two atomic bombs dropped on Japan in 1945 showed radiation breaks the backbone of DNA.
Inspired by that discovery, biophysicist James Till and hematologist Ernest McCulloch of the Ontario Cancer Institute irradiated mouse bone marrow cells, already considered the source of blood, so each cell had “its own little pattern of breakages” visible under a microscope, explains David Kent, a stem cell biologist at the University of York. Transplanting these uniquely damaged cells into the spleen of another mouse that had been irradiated to kill its own bone marrow caused nodules consisting of multiple blood cell types to appear in the organ.
It didn’t earn them a Nobel. Later work on culturing stem cells by Donald Metcalf and Leo Sachs was also critical for the field, and some Nobel watchers have speculated that the rule of three long made it impossible to award a stem cell prize.
John Gurdon and Shinya Yamanaka eventually won a Nobel Prize in Physiology or Medicine in 2012 for their work on stem cells, but McCulloch and Till remain the field’s founding fathers, Kent says: “I think it’s rare for an entire field to be able to point to papers from the same individuals and say they started it all.”
Till, McCulloch, and Becker deserved that Nobel Prize. Gurdon and Yamanaka deserved theirs, too, for showing that stem cells can be tuned to develop into differentiated cells (blood, bone, muscle). But Till, McCulloch, and Becker got there first.
Another scientist, from my time in biomedical science, who was missed by the Nobel Committee is Tony Pawson of the University of Toronto. It is difficult to get current students to understand how exciting the first years of the elucidation of signal transduction pathways. Every issue of Cell, Nature, and Science seemed to contain a new discovery. Tony Pawson blazed the widest path through that wilderness:
The cells in our bodies don’t act alone. They are bombarded by signals from other cells, influencing everything from which genes are turned on to when the cells divide.
To receive these signals, the surfaces of cells are peppered with receptors, each shaped just right for a specific molecule. When a signal molecule latches on, the interaction changes the receptor in some way—altering its shape, for example—that sets off a domino effect of activity among other proteins inside the cell.
How exactly this cascade starts inside the cell, however, was a mystery well into the 1980s. Then, Tony Pawson, a cell biologist at the University of Toronto, discovered that a structural feature in certain proteins played a key role.
Pawson focused on cell surface receptors called tyrosine kinases, whose structures extend into cells. When activated by an external signal, these receptors “phosphorylate” themselves: A chemical group called phosphate floating inside the cells attaches to a tyrosine, an amino acid within the receptor. When Pawson studied the proteins within the cell involved in the receptors’ domino effects, he discovered that many had one domain in common, which he called Src homology 2, or SH2.
Pawson found SH2 was like a magnet for phosphorylated tyrosine. His research revealed that an army of proteins, bumbling around inside the cell, get pulled toward the activated receptor after a signal arrives, allowing the chain of interactions known as signal transduction to begin.
Many anti-cancer drugs target the pathways that were described based on Tony Pawson’s work and the research he stimulated. The drug imatinib comes immediately to mind. Also known as Gleevec, it was the first inhibitor of phosphorylation to “cure” cancer, although in many cases the tumor cells eventually develop resistance to the drug and the patient will require new therapies. Perhaps if he had not died young the Nobel Committee would have made that very early morning phone call to Tony Pawson.
Craig Venter, who was the prime mover in genome sequencing did not die young, but he never won the Nobel Prize he should have. That he didn’t is almost certainly due to his “outsider” status. The prospect of a human genome sequence reached critical mass in the late-1990s when I was a postdoctoral fellow. It was clear that the technology would soon be mature enough to work in real time. Then, there were two approaches to the problem:
In 1990, an international scientific consortium embarked on a gargantuan task: sequencing the estimated 3 billion base pairs in the human genome. Some scientists believed it wouldn’t be possible. Others said it would be a waste of time and money, because large parts of the genome consist of “junk DNA.”
Action kicked off at the U.S. National Human Genome Research Institute, initially led by (James) Watson, who said the project’s goal was “to find out what being human is” (that would have been his attitude). The Wellcome Sanger Institute in the United Kingdom played a leading part as well, and groups in Japan, China, France, and Germany were also involved. “The Human Genome Project was exceptionally special because people came from around the world and worked towards one project,” says genomicist Muzlifah Haniffa, deputy director of Wellcome, noting it laid the blueprint for large collaborative projects in biology.
Along the way, the team developed new, faster sequencing methods, for example by breaking DNA into smaller pieces and sequencing them in parallel, then using computers to reassemble them.
In 1998, geneticist Craig Venter announced a private effort to sequence the human genome, using an even faster technique he had developed with colleague Hamilton Smith (Nobel Prize in 1978 and someone who later helped me with my first project as a postdoc), and the race was on. Venter’s company, Celera Genomics, had plans to sell human genome data to pharmaceutical companies (after Bayh-Dole, why not).
Bitter acrimony broke out between the public and private teams, but they reached a truce in June 2000 and announced at a White House press conference that both had produced a “working draft” of the genome, which they published in 2001—the Human Genome Project (HGP) in Nature, and Celera in Science. (HGP reported a more finished genome in 2004 but gaps continue to be filled to this day.)
“Bitter acrimony” is an understatement. But Venter’s technique was the better idea, and it has made the science of genomics what it is today. As an aside, the shotgun sequencing technique developed by Venter and Smith was the basis of an NIH grant they submitted. It was rejected because it their technique “wasn’t feasible” or something like that. At about the time the grant was rejected, Venter and Smith and many others published the entire genome sequence of the bacterium Haemophilus influenzae using their shotgun method. Oops.
Ben Barres discovered that glial cells are essential for brain development and remodeling. He could have gotten that call from Stockholm. He also died young, of pancreatic cancer at the age of 63, and he left with this statement:
I lived life on my terms: I wanted to switch genders, and I did. I wanted to be a scientist, and I was. I wanted to study glia, and I did that too. I stood up for what I believed in and I like to think I made an impact, or at least opened the door for the impact to occur. I have zero regrets and I’m ready to die. I’ve truly had a great life.
That he did…
And finally we come to Brenda Milner (b. 1918; yes, she is currently 108 years old), who first proved the biological basis of memory:
There was a time when people pursued psychology without even mentioning the brain. Brenda Milner, born in 1918, changed that. “She established this whole field of brain-based psychology,” says Alan Evans, a neurologist at McGill University, where Milner worked for 6 decades.
In 1957, Milner published her first work on an epilepsy patient known as H.M. (His real name, Henry Molaison, became public in 2008, following his death.) To treat his severe and frequent seizures, H.M. underwent a risky operation in which part of his hippocampus was removed. Afterward, he couldn’t recall any new experiences.
When Milner started to study H.M.’s memory systematically, she found that although his ability to perform a drawing task improved over a few days of practice, he could not recall the practice sessions. She reasoned that remembering events must rely on the hippocampus but that “procedural memory,” needed to learn a physical task, must be distinct, relying on another brain system.
The Nobel Committee still has time, but the clock is ticking. Oh, and Brenda Milner is further evidence of why McGill University is a special place.
Thank you for reading! Apologies for this somewhat unconventional Coffee Break, but recovery from oral surgery is proceeding at a snail’s pace and I may be out of internet range when this appears. See you next week, when I hope to discuss this Nobel Prize business further. It is a fertile ground. Stay safe out there! For those of us in the Grand Ol’ US of A, Election Day is less than a month away. Almost anything can be endured for another four weeks. My mostly air gapped television is turned off for the duration.
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