Michelle Chang: A catalyst for change

© Eric Millette

As a child, Michelle Chang would sit listlessly in a University of California, San Diego, lab while her mother, a geneticist, ran experiments. As hours ticked by on the lab clock, the young Chang made a decision: she would not grow up to be a researcher.

But after only a handful of introductory science classes her freshman year at UCSD, Chang became so excited about chemistry and molecular biology that she couldn't resist science. The following summer she began working in a lab that studied how mobile genetic elements contribute to microbial community adaptation and the consequences for bioremediation in contaminated environments. Chang says "the experience of connecting science to real world problems through research" sealed her fate: she would be a researcher after all.

With degrees in chemistry and French literature from UCSD, the native Californian traveled to the Massachusetts Institute of Technology for graduate school to study ribonucleotide reductase (RNR), an enzyme that catalyzes the conversion of nucleotides to deoxynucleotides, the building blocks of DNA, and acts as the gatekeeper for DNA replication and repair.

At the time, working RNR models suggested that the two-subunit enzyme functioned by the movement of protons and electrons from one subunit to the other-a path of 35 Å in distance-called proton-coupled electron transfer (PCET). But there was no direct evidence for the reaction.

Chang used two different chemical approaches to study the mechanism of PCET. First, she showed she could replace one of two subunits of RNR with a synthetic peptide that, in the presence of light, initiated the electron transfer mid-reaction without disrupting the ability of the enzyme to produce dexoynucleotide. ¹ Later, she inserted a synthetic amino acid into RNR to disentangle individual proton and electron transfer steps along the pathway. ²

Chang's work not only provided the first evidence to support the long-range PCET in RNR, but also showed that interference with PCET could inhibit RNR, which potentially could be developed into new anticancer agents.

For her postdoc, Chang says she wanted to "continue studying enzyme-catalyzed reactions, but expand [the focus of her research] from the test tube into a cellular context." She settled on the lab of UC, Berkeley, chemical engineer Jay Keasling (see "Energy from E. coli "). In 2007, Chang was able to express the plant enzyme P450 in Escherichia coli successfully, demonstrating that E. coli could be engineered to produce semi-synthetic precursors to drugs, including artemisinic acid, the precursor to artemisinin-an antimalaria drug-at high yields, potentially slashing the cost of the drug in the future. ³

"Dr. Chang has an interesting mix of a chemistry and biology background that is often difficult to find in others," Keasling says by email. "In addition, she is extremely smart, works hard, and is incredibly creative."

Now the head of her own lab at UC, Berkeley, Chang is working to genetically engineer new biosynthetic pathways in microbial hosts to develop biofuels and new drugs. Her group is busy coaxing microbes to do the dirty work of converting lignin, an agricultural waste product, into carbon sources to make fuels.

It's exciting to "take the unusual chemical reactions out there in nature, understand how they work, and use these processes," says Chang.

Correction (posted February 18): When originally posted, Chang's affiliation was listed incorrectly. The Scientist regrets the error.