Carolyn Bertozzi, currently Anne T. And Robert M. Bass Professor at Stanford University, CA. USA, was awarded one of the three Nobel Prizes in Chemistry 2022.
The other two Laureates, Morten Meldal of Denmark and K. Barry Sharpless of the U.S., laid the foundations for what today is known as click chemistry, a functional form of chemistry in which molecular building blocks snap together quickly and efficiently; think Lego for chemists. Carolyn Bertozzi took click chemistry to a new dimension when she started to utilize it in living organisms to map cells. This class of chemical reactions is called bioorthogonal chemistry and before Bertozzi’s development of them 22 years ago, researchers risked disturbing natural processes when observing molecules and their interactions in living beings.
“I have a longstanding interest in glycoscience, and unmet needs in that field motivated my lab to invent bioorthogonal chemistries,” Bertozzi explained to NLS.
The problem when working with living cells is that copper, used by Meldal and Sharpless in the click chemistry, is toxic. However Bertozzi found that it had been shown in 1961 that azides and alkynes can react in an almost explosive manner, without the help of copper, if the alkyne is forced into a ring-shaped chemical structure.
The strain creates so much energy that the reaction runs smoothly. It worked, and in 2004 she published her copper-free click reaction, called the strain-promoted alkyne-azide cycloaddition. “In vivo imaging of cell surface glycans was the original application that drove the invention of bioorthogonal chemistry,” describes Bertozzi.
Other labs have since used the technique to image proteins, lipids, nucleic acids and many other biomolecules and post translational modifications.
Targeting treatments within molecules
Bioorthogonal reactions allow researchers and clinicians to work without disrupting a molecular reaction’s normal routine or nearby healthy cells, creating opportunities for targeting treatments within molecules. Gunnar C. Hansson, Professor at the Department of Medical Biochemistry and Cell Biology, says that his research group at the University of Gothenburg, as well as others involved in medical research have made great use of Bertozzi’s discovery.
“We have for example learned that the some tenths of a millimeter thick protective mucus layer in the large intestine that keeps bacteria away from us is renewed within one hour. Incredibly, much faster than we could imagine,” he explains to NLS.
“Bioorthogonal chemistry has found many applications in basic biomedical research, by enabling researchers to attach tiny chemical handles onto their favorite molecules, be it carbohydrates (sugars), lipids or proteins. These handles can be utilized in the living cell to attach fluorescent dyes or other kinds of probes, or to fish the tagged biomolecule out of the complex mixture of molecules within a cell,” says Simon Elsässer, Group Leader at Science for Life Laboratory and Associate Professor at the Department of Medicinal Biochemistry and Biophysics at Karolinska Institutet.
He and his research colleagues are using chemical biology to probe and manipulate proteins in the living cell and bioorthogonal chemistry is their go-to technology to label proteins that cannot otherwise be labeled, for example because they are processed or modified in complex ways. “Using this technology, we have been able to visualize tiny proteins in mitochondria, study the processing of APP, a protein involved in Alzheimer’s disease, or illuminate membrane receptors,” he says.
Carolyn Bertozzi’s own research group for example develops chemical tools to study the glycobiology underlying diseases such as cancer, inflammation, tuberculosis and most recently COVID-19.
I fell in love with organic chemistry
Bertozzi’s fascination with organic chemistry took hold when she was an undergraduate at Harvard University, she says. “I fell in love with organic chemistry when I took the course in college as a premed requirement. After that course, I changed my major to chemistry and the rest is history.”
I fell in love with organic chemistry when I took the course in college as a premed requirement. After that course, I changed my major to chemistry and the rest is history.”
She didn’t develop career goals until she was a young adult, she says. “Growing up, I was mostly interested in sports and music as hobbies. My seriousness about a career didn’t start until I was a Ph.D. student.”
Bertozzi received her PhD from UC Berkeley in 1993 and in 1996 she launched a lab of her own at the University of California at Berkeley. At her own lab she began researching bioorthogonal reactions.
The professor who taught that organic chemistry class at Harvard, David Evans, was a strong influence on Bertozzi, as was her father, a retired Massachusetts Institute of Technology physics professor. Her doctorate advisor, Mark Bednarski, also helped launch her career.
“He gave me a big break as a practicing organic chemist at a time when women had difficulty breaking into the field,” Bertozzi says.
She is only the eighth woman to have been awarded the Nobel Chemistry Prize. “We all wish the numbers were higher,” she says. “As for why the number isn’t higher, this is a question that more men should be thinking about.”
Bertozzi also said in an interview with Nobel Media right after the announcement that the numbers of women who receive these kinds of awards ticks up. “I’m sure there’ll be many more in the future. I mean, there’s so many amazing women scientists and I think we’ll see them coming up more and more,” she said.
Seven companies in twelve years
Carolyn Bertozzi’s goals include seeing some of the inovations from her academic lab translated into therapeutics and diagnostics tools that improve human health, she says to NLS.
These goals are well on the way. Several of the technologies developed in her lab have been adapted for commercial use and she has launched seven companies in 12 years, all rooted in her extensive knowledge of modifying sugar structures. Actively engaged with several biotechnology startups, Bertozzi co-founded Redwood Bioscience, Enable Biosciences, Palleon Pharmaceuticals, InterVenn Bio, OliLux Bio, Grace Science LLC and Lycia Therapeutics.
I am especially excited about a company called Shasqi Pharmaceuticals that is performing bioorthogonal chemical reactions inside the bodies of cancer patients as a means for delivery of chemotherapy drugs to tumor tissues.”
“People also use bioorthogonal chemistry for drug target identification, chemoproteomics and for constructing complex biologic therapeutics. I am especially excited about a company called Shasqi Pharmaceuticals that is performing bioorthogonal chemical reactions inside the bodies of cancer patients as a means for delivery of chemotherapy drugs to tumor tissues,” she says.
In 2020 California-based biotech Shasqi initiated this first human use of bioorthogonal chemistry, starting a Phase 1/2 clinical trial of a doxorubicin prodrug that exploits the tetrazine–TCO chemistry. The treatment is based on the pre-injection of a tetrazine-loaded hydrogel into the tumor site, followed by infusions of the doxorubicin prodrug. Only where the two components meet, at the tumor site, is the drug unleashed.
For the future, Carolyn Bertozzi envisions the number of bioorthogonal reaction applications multiplying.
Our technologies can lift people out of poverty, increase scare resources and access to them, mitigate disease and climate change. All of this can contribute to peace if we execute well.”
“There are many ongoing efforts focusing on new reaction development and applications in biomedicine and other sectors like materials science,” she says.
Scientists have many important roles in improving the human condition and in turn global stability. “Our technologies can lift people out of poverty, increase scare resources and access to them, mitigate disease and climate change,” she says. “All of this can contribute to peace if we execute well.”
My path was unique
Her advice to young women entering the science field is “Don’t take others’ advice too seriously.”
“Most of the “advice” I was given as a young scientist, while maybe good for other people, was not good advice for me,” says Bertozzi.
“I had to figure out what worked for me as an individual – what path of study would best capture my interest and stoke my passions, who might be my most effective role models and advisors, who and what to steer clear of. My path was unique to me, and I would expect others, including young women scientists, to follow their own path to success,” she adds.
“All of us need advocates and sponsors – that is universal for all professional people. So choose them wisely and build relationships and friendships that last a life-time. People and your relationships with them are more important than any traditional metrics of success, as I see it. So make the investments in those relationships first and foremost,” Carolyn Bertozzi concludes.
Featured photo of Bertozzi: Christopher Michel
Facts: Carolyn Bertozzi
Award: Nobel Prize in Chemistry 2022
Place of birth: Boston, MA, USA
Education: M.Sc, PhD, University of California at Berkeley, B.A. at Harvard University
Current position: Stanford University, Stanford, CA, USA, Howard Hughes Medical Institute, USA
Personal: Enjoys sports and music and is learning to play the electric bass.