The theorist turned experimentalist takes a cross-disciplinary perspective
KC Huang, 38
“My motivating questions are about understanding the physical challenges bacterial cells face,” he says. Bacteria are the dominant life-forms on Earth. They affect the health of plants and animals, including humans, for good and bad. Yet scientists know very little about the rules the microbes live by. Even questions as basic as how bacteria determine their shape are still up in the air, says Huang, of Stanford University.
Huang, 38, is out to change that. He and colleagues have determined what gives cholera bacteria their curved shape and whether it matters (a polymer protein, and it does matter; the curve makes it easier for cholera to cause disease), how different wavelengths of light affect movement of photosynthetic bacteria (red and green wavelengths encourage movement; blue light stops the microbes in their tracks), how bacteria coordinate cell division machinery and how photosynthetic bacteria’s growth changes in light and dark.
All four of these findings and more were published in just the first three months of this year.
Huang also looks for ways to use tools and techniques his team develops to solve problems unrelated to bacteria. Computer programs that measure changes in bacterial cell shape can also track cells in plant roots and in developing zebrafish embryos. He’s even helped determine how a protein’s activity and stability contribute to a human genetic disease.
A physicist by training, Huang delves into biology, biochemistry, microbial ecology, genetics, engineering, computer science and more, partnering with a variety of scientists from across those fields. He’s even teamed up with his statistician sister. He’s an “all-in-one scientist,” says longtime collaborator Ned Wingreen, a biophysicist at Princeton University.
When Huang started his lab at Stanford in 2008, after getting his Ph.D. at MIT and spending time at Princeton as a postdoctoral fellow, his background was purely theoretical. He designed and ran the computer simulations and then his collaborators carried out the experiments. But soon, he wanted to do hands-on research too, to learn why cells are the way they are.
Such a leap “is not trivial,” says Christine Jacobs-Wagner, a microbiologist at Yale University who also studies bacterial cell shape. But Huang is “a really, really good experimentalist,” she says.
Jacobs-Wagner was particularly impressed with a “brilliant microfluidics experiment” Huang did to test a well-established truism about how bacteria grow. Researchers used to think that turgor pressure — water pressure inside a cell that pushes the outer membrane against the cell wall — controlled bacterial growth, just like it does in plants. But abolishing turgor pressure didn’t change E. coli’s growth rate, Huang and colleagues reported in 2014 in Proceedings of the National Academy of Sciences. “This result blew my mind away,” Jacobs-Wagner says. The finding “crumbled the foundation” of what scientists thought about bacterial growth.
“He uses clever experiments to challenge old paradigms,” Jacobs-Wagner says. “More than once he has come up with a new trick to address a tough question.”
Where and when are bacteria in the gut growing? No one knows. How can we not know that? It’s totally fundamental.
— KC Huang
Sometimes Huang’s tricks require breaking things. Zemer Gitai, a microbiologist at Princeton, remembers talking with Huang and Wingreen about a question that microbiologists were stuck on: How are molecules oriented in bacterial cell walls? Researchers knew that the walls are made of rigid sugar strands connected by flexible proteins, like a chain link fence held together by rubber bands. What they didn’t know was whether the rubber bands circled the bacteria like the hoops on a wine barrel, ran in stripes down the length of the cell or stuck out like hairs.
If bacteria were put under pressure, the cells would crack along the weak rubber band–like links, Huang and Wingreen reasoned. If the cells split like hot dogs on a grill, it would mean the links ran the length of the cells. If they opened like a Slinky, it would suggest a wine-barrel configuration. The researchers reported the results — opened like a Slinky — in 2008. Another group, using improved microscope techniques, got the same result.
Huang teamed up with other researchers to do microfluidics experiments, growing bacteria in tiny chambers and tracking individual cells to learn how photosynthetic bacteria grow in light and dark.
But in nature, bacteria don’t live alone. So Huang has also worked with Stanford colleague Justin Sonnenburg to answer a basic question: “Where and when are bacteria in the gut growing? No one knows,” Huang says. “How can we not know that? It’s totally fundamental.” Without that information, it’s impossible to know, for example, how antibiotics affect the microbial community in the intestines, he says.
Stripping fiber from a mouse’s diet not only changes the mix of microbes in the gut, it alters where in the intestines the microbes grow, the researchers discovered. Bacteria deprived of fiber’s complex sugars began to munch on the protective mucus lining the intestines, bumping against the intestinal lining and sparking inflammation, Huang, Sonnenburg and colleagues reported in Cell Host & Microbe in 2015.
Huang’s breadth of research — from deciphering the nanoscale twists of proteins to mapping whole microbial communities — is sure to lead to many more discoveries. “He’s capable of making contributions to any field,” Jacobs-Wagner says, “or any research question that he’s interested in.”
F. B. Yu et al. Long-term microfluidic tracking of coccoid cyanobacterial cells reveals robust control of division timing. BMC Biology. Vol. 15, February 14, 2017. doi: 10.1186/s12915-016-0344-4.
K. A. Earle et al. Quantitative imaging of gut microbiota spatial organization. Cell Host & Microbe. Vol. 18, October 14, 2015, p. 478. doi: 10.1016/j.chom.2015.09.002.
E. Rojas, J. A. Theriot and K. C. Huang. Response of Escherichia coli growth rate to osmotic shock. Proceedings of the National Academy of Sciences. Vol. 111, May 27, 2014, p. 7807. doi: 10.1073/pnas.1402591111.
K. C. Huang et al. Cell shape and cell-wall organization in Gram-negative bacteria. Proceedings of the National Academy of Sciences. Vol. 105, December 9, 2008, p. 19282. doi: 10.1073/pnas.0805309105.
R. M. W. Chau, D. Bhaya and K. C. Huang. Emergent phototactic responses of cyanobacteria under complex light regimes. mBio. Vol. 8, March 7, 2017, p. e02330-16. doi: 10.1128/mBio.02330-16.
X. Yang et al. GTPase activity–coupled treadmilling of the bacterial tubulin FtsZ organizes septal cell wall synthesis. Science. Vol. 355, February 17, 2017, p. 744. doi: 10.1126/science.aak9995.
T. M. Bartlett et al. A periplasmic polymer curves Vibrio cholerae and promotes pathogenesis. Cell. Vol. 168, January 12, 2017, p. 172. doi: 10.1016/j.cell.2016.12.019.
A. D. Cunningham et al. Coupling between protein stability and catalytic activity determines pathogenicity of G6PD variants. Cell Reports. Vol. 18, March 14, 2017, p. 2592. doi: 10.1016/j.celrep.2017.02.048.
T. Ursell et al. Rapid, precise quantification of bacterial cellular dimensions across a genomic-scale knockout library. BMC Biology. Vol. 15, February 21, 2017. doi:10.1186/s12915-017-0348-8.
B. Brookshire. Low-fiber diets make gut microbes poop out. Science News Online. January 15, 2016.