Stowers assistant investigator Ho Yi Mak, Ph.D., thinks that factors contributing to obesity can be understood through assessment of some unlikely waistlines—those of the roundworm C. elegans.
“The genes that control fat metabolism are well conserved between worms and humans,” says Mak. “And, worms are transparent so we can use imaging techniques to actually look at subcellular structures like lipid droplets directly right through the animal.”
Worm intestinal cells containing lipid droplets (shown in red.) The endoplasmic reticulum in shown in green.
Image: Mak lab.
Mak’s interest in fat metabolism was sparked in part by a choice he made at the end of graduate studies in MalcolmParker’s labat the Imperial Cancer Research Fund (now Cancer Research UK). Although he had done thesis work onregulation of gene expression by nuclear receptors, Mak decided he must master genetics before launching an independent career.
To get that training he applied only to fly and worm labs. “My advisor said, ‘If you’re going to the states and like living in London, you should apply only to labs in Boston.’” Heeding that advice, Mak, who is originally from Hong Kong, headed to Harvard Medical School for postdoctoral training with C. elegans geneticist Gary Ruvkun in 2000.
Mak eased himself into C. elegans biology by working briefly on factors that function with a nuclear receptor in worms, work published in 2004 in Development. But when Ruvkun suggested he develop a “side project”, Mak set up a screen for factors enhancing mutations in a worm gene called tub-1, which when mutant in mice produces fat storage anomalies manifested by a “tubby” phenotype.
That study culminated with a 2006 Nature Genetics paper showing that tub-1 and another protein called bbs-1 comprise a neuroendocrine signaling pathway regulating fatty acid metabolism-related genes. When that pathway is perturbed, abnormal lipid accumulation ensues in the worm gut. Interestingly, human genes encoding BBS proteins are mutant in Bardet-Beidl syndrome, marked by obesity and mental retardation.
Arriving at Stowers in 2006, Mak extended his investigations to factors governing lipid droplet size. In a 2009 PNAS study his group showed that mutations that perturb organelles called peroxisomes block fat breakdown and enlarge lipid droplets in the worm intestine. These defects could be reversed by a change in the worms’ diet. Mutations in similar human genes perturb the peroxisome’s capacity to metabolize fat and are associated with neurodegeneration and neonatal death.
“Lipid droplets, which are conserved from yeast to humans, are not passive like an oil droplet in a bowl of soup,” says Mak. “Instead, they are coated by proteins sitting on top of them that move fat into and out of the droplets. Our long term goal is to explore how these processes are coordinated.”
Mak has also combined proteomic with genetic approaches to identify components of a cGMP signal transduction pathway. In a 2011 PLoS Genetics study he and his colleagues showed that activation of the worm version of the cGMP dependent kinase, which regulates cardiovascular, neuronal and intestinal functions in mouse and human, stimulates transcriptional changes in genes governing behaviors like food foraging, egg-laying and potentially metabolism.
In recognition of the relevance of these studies to human health, Mak received the 2008 Basil O’Connor Starter Scholar award for research into birth defects. Obesity is a leading cause of type-2 diabetes and in pregnant women can promote miscarriage or abnormal fetal development.
Mak credits his mentors for teaching him self-reliance. Parker, he says, never gave explicit directions but rather posed questions that fostered independent thinking, while Ruvkun’s open-mindedness encouraged creativity. “No idea was too wacky for him if you worked hard and your science was rigorous,” Mak says of Ruvkun. As evidence, the Ruvkun website describes ongoing projects related to miRNA and insulin signaling as well as a joint effort with MIT to send PCR machines to Mars to look for microbial life.
Although thus far confining his efforts to terra firma, Mak tries to instill adventurousness and camaraderie in his students. “I want them to be self-motivated—I give them projects designed to make them ask questions,” he says, adding that he works at the bench to “test-drive” new ideas. “Once a project is promising I give it to my students so they don’t waste time.”
Some time-wasting is, however, mandatory: every Wednesday afternoon at 3 o’clock the Mak lab holds afternoon tea, where the boss makes the tea and the lab socializes (although some science talk is OK) and marks milestones.
These occasions may evoke what are to Mak happy memories of his days in London and Boston, where afternoon tea breaks were great opportunities to exchange scientific ideas and life lessons with folks from around the world. “It reinforced the idea that science can bring people together.”
© Stowers Institute for Medical Research