Sharpless coined the phrase “click chemistry” about two decades ago, as he and Meldal experimented with how to tie together molecular building blocks quickly and efficiently. Bertozzi built on those advances to develop bioorthogonal chemistry, which allows scientists to modify molecules in living organisms without disrupting processes occurring within the cells — a technique that allows the mapping of molecules within cells and is being tested for targeted cancer therapies, among other uses.
“I’m absolutely stunned,” Bertozzi said early Wednesday morning when awakened at her Palo Alto home by the call from the Nobel committee, a video of which was played during the announcement. “I’m sitting here and can hardly breathe. I’m still not entirely positive that it’s real.”
Later, in an interview with The Washington Post, Bertozzi said that after receiving the initial call from the Nobel committee 50 minutes before the public announcement, she telephoned her father, William Bertozzi, 91, a former physics professor at the Massachusetts Institute of Technology.
“Dad,” she said, “you will not believe this, but I just got a phone call.”
When she paused, he exclaimed, “Oh, my God, you won the Nobel Prize.”
Johan Aqvist, chair of the Nobel chemistry committee, commended the three scientists for making extraordinarily complicated processes simple.
“Click chemistry is almost like it sounds,” he said in the briefing from Stockholm. “It’s all about snapping molecules together. Imagine that you could attach small chemical buckles to different types of building blocks. Then, you could link these buckles together and produce molecules of greater complexity and variation. This was the basic idea that Barry Sharpless had about 20 years ago. The problem was to find good chemical buckles.”
The scientists solved that problem in stages, he said. Sharpless’s and Meldal’s research — done separately — used copper as a catalyst to join molecules, which was effective but toxic in higher concentrations. Bertozzi developed a method that allowed scientists to modify molecules in living organisms without disrupting them.
“It’s a great choice. This is really elegant chemistry,” said former National Institutes of Health director Francis S. Collins. Click chemistry improves the tumor targeting of cancer drugs, he said, some of which are now in clinical trials.
Jon Lorsch, director of the National Institute of General Medical Sciences at NIH, compared Bertozzi’s method to a trap that snaps shut once the animal is inside. “When the partner molecule comes in it snaps shut and it will only act on the partner molecule.”
The work of the award winners has already found “a huge number of applications. It’s used to assemble molecules of different sizes to create huge [chemical] libraries that can be used to screen for drugs,” Lorsch said. The method also allows scientists to attach dye to a molecule and watch where it goes and what it does, for example when a virus infects a cell.
The concept of click chemistry has been “transformative” in many areas of chemistry, materials science, biology and medicine, said Tom Brown, professor of nucleic acid chemistry at the University of Oxford. “It has given rise to new highly functional materials, has catalyzed important pharmaceutical developments and has been influential in many areas of chemical biology.”
The research recognized by the award spans at least two decades, but “in many regards, this is still a technology that is in its infancy,” said Angela K. Wilson, president of the American Chemical Society. “We talk a lot about personalized medicine and I think it’s going to help open the doors to that in the future.”
Wilson said the techniques used to link molecules should also have applications to regrow damaged tissue, and to read the genetic script of humans, animals and plants.
They also have industrial applications, including the development of ways to prevent corrosion and brighteners used to make plastics and other materials appear cleaner, she said
Bertozzi, who also won a MacArthur “genius” award at age 33, is the third woman to win the chemistry prize in as many years. In 2020, the academy recognized Jennifer A. Doudna of the University of California at Berkeley, and Emmanuelle Charpentier of the Max Planck Research Unit for the Science of Pathogens in Berlin for development of the genome-editing tool known as CRISPR/Cas9.
“Chemistry many years ago, like many fields, was male-dominated. There are a lot more women in the field and they’re doing amazing science,” Wilson said, noting that pioneering chemist Marie Curie was the first person to receive two Nobel Prizes.
Sharpless, 81, became the fifth person to win a second prize, joining Curie and Frederick Sanger, the only the other person to win the chemistry prize twice. Sharpless previously won in 2001 “for his work on chirally catalyzed oxidation reactions,” a process that has enabled the manufacture of safer and more effective antibiotics, anti-inflammatory drugs, heart medicines and agricultural chemicals.
“I’m pretty cheeky about thinking my ideas are good ideas,” Sharpless said in a statement to reporters. “It’s how I keep myself motivated when everyone thinks I’m crazy. I thought click chemistry was a good idea, and probably good enough to be worthy of a Nobel Prize. But winning for a second time is absolutely thrilling, and it’s so gratifying that it’s happening in my lifetime. I’ve always been lucky, but right now I think I’m the luckiest person alive!”
He added that he was gratified to share the award with Bertozzi, his friend. “A few years ago, my wife and I decided she’s the person on Earth who’s the single best candidate for being cloned — if only the world had more Carolyn Bertozzis.”
Bertozzi’s commitment to being a mentor as well as a scientific pioneer was lauded by many who worked with her.
Michelle Bond, a program manager at the National Institute of General Medical Sciences, said Bertozzi “is one of the reasons I went to graduate school. She’s not only an excellent chemist but incredibly good at communicating to the public the importance of [her work] and its future potential.”
Bertozzi’s research has advanced the field of glycoscience, which focuses on the carbohydrates on the surface of virtually all cells that are involved in binding to and communicating with other cells.
Those carbohydrates differ when cells are healthy or diseased. Identifying those differences allows researchers to target diseased cells. Glycoscience has proved important to our understanding of cancer, inflammation, diabetes, heart disease and even covid-19.
Bertozzi told The Post that Shasqi, a San Francisco-based biotechnology company, is already conducting a Phase 2 clinical trial using the chemistry she developed to treat patients with solid tumors that have reached an advanced stage in one location or spread to other areas of the body.
“We are encouraged by the promising results,” company CEO José M. Mejía Oneto, said in a news release last month announcing the Phase 2 study.
Bertozzi is also the founder of three companies working on practical applications of her discoveries: Palleon Pharmaceuticals in Waltham, Mass.; Lycia Therapeutics in San Francisco; and Redwood Bioscience in Emeryville, Calif.
Jennifer Kohler, a professor of biochemistry at UT Southwestern Medical Center in Dallas, called Bertozzi “a visionary scientist” who is fearless about tackling difficult scientific problems.
“She would say, ‘That’s so crazy we should do it,’ ” recalled Kohler, who worked as a postdoctoral researcher in Bertozzi’s lab between 2000 and 2004.
“She’s also an amazing mentor. There are scientists all over the world working on research projects that build on her discoveries.”
Frances Stead Sellers contributed to this report.