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Most chemistry happens in clean flasks. A living cell is the opposite: water, salts, thousands of proteins and other molecules, all reacting. Carolyn Bertozzi wanted to run a reaction inside that mess that would touch only the molecule she chose. This post explains why she needed it, how she built it step by step, and what students can learn from her method.
Who is Carolyn Bertozzi?
Her Nobel facts page gives her birth date as 10 October 1966 in Boston, USA. At the time of the award she was at Stanford University and the Howard Hughes Medical Institute. The 2022 Nobel press release adds that she earned her PhD in 1993 at UC Berkeley. She shared the 2022 Nobel Prize in Chemistry with Morten Meldal and K. Barry Sharpless "for the development of click chemistry and bioorthogonal chemistry".
What problem was she trying to solve?
The Nobel Committee's popular science background for 2022 tells the story. In the 1990s, biologists were mapping genes and proteins quickly, but glycans got little attention. Glycans are complex carbohydrates built from sugars, often sitting on the surface of proteins and cells. They matter when viruses infect cells and when the immune system is activated, but the new molecular biology tools could not be used on them.
In the early 1990s, Bertozzi began studying a glycan that attracts immune cells to lymph nodes. With the tools available, it took four years to understand how it worked. She wanted something faster.
What was her idea?
At a seminar she heard how cells had been made to produce an unnatural version of sialic acid, one of the sugars in glycans. She wondered: if cells could build a sialic acid carrying a chemical handle, she could later attach a fluorescent tag to that handle and see where the glycans were.
The handle had to react with the tag and with nothing else in the cell. She named that requirement bioorthogonal: a reaction that runs inside a living system without interfering with its normal chemistry.
How did the method develop?
There were three main steps, each in a paper you can still read:
1997, a ketone handle. In Mahal, Yarema and Bertozzi in Science, cells were fed an unnatural relative of N-acetylmannosamine carrying a ketone group. The cells turned it into sialic acid and displayed the ketone on their surface, where it could be linked to molecules carrying a hydrazide group.
2000, an azide handle. In Saxon and Bertozzi in Science, the handle was an azide, installed in cell-surface glycans through a synthetic azidosugar. A modified Staudinger reaction joined it to a specially designed phosphine. The abstract notes that both partners are "abiotic", meaning not found in living things, and do not react with the cell's own components.
2004, copper-free click. Sharpless and Meldal had shown that azides click onto alkynes with a copper catalyst, but copper is toxic to cells. Agard, Prescher and Bertozzi in JACS used an alkyne held inside an eight-membered ring, a cyclooctyne. The abstract reports that this strain-promoted reaction ran under physiological conditions with no catalyst and no apparent toxicity to living cells.
Why does a ring make the alkyne react?
An alkyne's carbon-carbon triple bond prefers a straight line. Forcing it into a small ring bends it, and that strain stores energy. The popular background explains that a 1961 study had already shown strained ring alkynes react with azides almost explosively without copper. Releasing the strain drives the reaction.
You can count the atoms in the product. An azide brings three nitrogen atoms in a row; the alkyne brings two carbon atoms. They join into a five-membered ring of 3 N + 2 C atoms, called a triazole. That ring is the stable link between the tag and the glycan.
What is it used for?
According to the popular background, these reactions are now used worldwide to explore cells and track biological processes. Bertozzi's own work on glycans on tumour cells suggested some glycans help tumours hide from the immune system. Her team built a drug joining a glycan-targeting antibody to enzymes that remove those glycans, and it entered clinical trials in people with advanced cancer. The cell surface she was studying is the same membrane you meet in our guide to cell membrane transport.
What can a student take from her way of working?
Let frustration define the tool. Four slow years on one glycan made her imagine a better method. Notice what wastes your time and fix that, not just the topic.
Borrow across fields. She took an idea from a seminar, an old reaction from the literature, and copper-free chemistry from a 1961 paper. Reading outside your chapter pays off.
Improve in steps. Ketone, then azide with phosphine, then a strained alkyne. Each version fixed a weakness of the last.
Name the rule. Coining "bioorthogonal" made the goal clear to everyone. Writing your own one-line rule for a topic helps you apply it.
For another chemist who borrowed nature's methods, read our post on Frances Arnold and directed evolution. If functional groups like azides, alkynes and ketones still feel shaky, the Fermi Concept Library has every concept in physics, chemistry, biology, mathematics and computing, so you can review them one at a time.
Next step: draw an azide and a cyclooctyne, then sketch the five-membered triazole ring that joins them.
