FAST FACTS
Stage: Scientists have developed a chemical recipe for observing the molecules of living things
Date: October 23, 2007
Where: UC Berkeley and other laboratories
WHO: A team of scientists led by Carolyn Bertozzi
In 2007, scientists published paper who laid out the recipe for a new type of biochemistry. The method will allow scientists to see what is happening in organisms in real time.
Glycans are one of the three main classes of biomolecules (along with proteins and nucleic acids). involved in inflammation and diseasebut scientists have had difficulty visualizing them. To do this, Bertozzi relied on a chemical approach pioneered by biochemists C. Barry Sharpless of Scripps Research and Morten Meldahl of the University of Copenhagen.
Sharpless outlined vision of “click chemistry”“—a way to quickly create complex biological molecules by combining smaller subunits.
Biological molecules often have skeletons connected carbon atoms, but carbon atoms do not tend to combine. This meant that historically chemists had to use laborious, multi-step processes that used many enzymes and left behind unwanted byproducts. This was good for the laboratory, but bad for mass production of biomolecules for pharmaceuticals.
Sharpless realized that the process could be simplified and scaled up if he could connect simple molecules that already had a complete carbon framework. They just needed a fast, powerful and reliable connector.
Separately, Sharpless and Meldahl stumbled upon a crucial connector: a chemical reaction between azide and alkyne compounds. The trick was to add copper as a catalyst.
reaction was extremely powerful and fast, and it happened more than 99.9% time without producing any by-products.
But Bertozzi had a problem: copper is very toxic to cells.
So Bertozzi analyzed the literature to develop click chemistry that was safe for living cells. She found the answer in work decades ago: the azide and alkyne would react “explosively” without the need for a catalyst if the alkyne assumed a ring shape.
In 2004, her team demonstrated that this reaction can be used to attach azide molecules to living cells. without harming them. And in 2007, Bertozzi and his colleagues used her method to visualize glycans in living hamster cells.
Her process involved incorporating an azide-modified carbohydrate molecule into the glycans of living cells. When they added a ring-shaped alkyne molecule linked to a green fluorescent protein, the azide and alkyne bonded and the glowing green protein revealed where the glycans were in the cell.
Bertozzi called this process “bioorthogonal” click chemistry—so named because it was orthogonal to the biological processes occurring in the cell, that is, it did not interfere with them. Her work has been pivotal in understanding how small molecules move through living cells. It was used for tracking glycans in zebrafish embryos to see how Cancer cells protect themselves from immune attack using sugar moleculesand develop radioactive “tracers” for biomedical imaging. And click chemistry in a broader sense accelerated the process drug discovery.
In 2022 Sharpless, Meldal and Bertozzi received the Nobel Prize in Chemistry for their work on the chemistry of clicks.
