Researchers are moving closer to understanding how human sleeping and waking patterns function.
Dr Matthew Tso (Croucher Fellowship 2018) has dedicated his career to understanding the science behind sleep. Born and raised in Hong Kong, Tso moved to Wisconsin to study molecular biology after high school. He was particularly interested in the brain and went on to complete a PhD in neuroscience at Washington University.
As a doctoral student, Tso focused on circadian rhythms, the internal processes that regulate the daily timing of sleep, hormone release, metabolism, and many other bodily functions. Generally, people sleep when the sun has set and wake up as it rises, a biological pattern set in place by the brain’s suprachiasmatic nucleus (SCN). Located in the hypothalamus, the nucleus is a tiny area that directs neural and hormonal activity related to circadian rhythms.
“My graduate research focused on a regulated mechanism of what time of day an animal goes to sleep or wakes up,” Tso said. “As an output and a process, sleep is a proxy that we can use to measure properties of the animal’s internal clock.”
Research into circadian rhythms has already produced findings that have been translated into applications, from helping travellers recover from jet lag to developing treatments for insomnia.
“Jet lag is an example when we can actually feel the biological clock within our bodies being misaligned,” Tso said. To combat the effects of moving across time zones, travellers must reset their circadian rhythms by changing eating and sleeping patterns accordingly.
Now a postdoctoral fellow at the University of California, Berkley, Tso is taking his enquiries into sleep a step further by using optogenetics, a method of manipulating brain cells with light. “We insert light-sensitive bacteria protein called channelrhodopsin (ChR2) into cells that we are interested in and then use laser lights to activate these cells,” he said.
Utilising this technique, researchers can “turn cells on or off” by triggering or blocking them from communicating via electric pulses. The mice used are specifically designed so that ChR2 is present only in cells that the researchers are interested in. “This way we can manipulate a subset of cells while leaving many others unchanged,” he said.
This level of control is a recent development. “Back in the days when you stuck an electrode in a brain area to stimulate it, every single cell in the area ‘turned on’,” Tso explained. “You couldn’t tell which cell was doing what. And in some cases, as we now know through optogenetics, different subsets of cells in the same area have opposing roles. For example, some are sleep-promoting, and some are wake-promoting. If we performed stimulation studies in the old way, the effect from the two group of cells would be offset and we would not be able to tell.”
Tso works with mice brains as they share many similar traits to human ones. “This is especially true in the more primitive brain areas where we think sleep and arousal are controlled, such as the hypothalamus and brainstem,” he explained.
And what the brains of mice lack in size is made up for in research potential. As Tso noted, mice possess a great variety of genetic tools that allow researchers to target many different subsets of cells for experiments such as optogenetic studies.
In assessing the possible outcomes of his research, Tso remains cautious: “For now, we are learning how the brain is organised to give rise to function.” However, he sees two potential ways it could progress.
“Firstly, by identifying which cells are sleep-promoting, there may be opportunities to identify drug targets for a new class of sleep medication. On a separate track, in coming years there may be a demand for a medical device that promotes sleep. Of course, this would require new technology to enable this to happen. It would also rely on advancing our fundamental understanding of how sleep is regulated. The engineering and biology have to go hand-in-hand.”
Dr Matthew Tso is an alumnus of Queen’s College in Hong Kong. He received his BS in Molecular Biology (Honors in Major) from the University of Wisconsin-Madison and PhD in Neuroscience from Washington University in St Louis, where he worked with chronobiologist Professor Erik Herzog. Currently, Tso is a postdoctoral fellow in Professor Yang Dan’s group at the University of California, Berkeley/Howard Hughes Medical Institute (HHMI). He received a Croucher Fellowship in 2018.