Lily Jan

Call it intuition, instinct, beginner’s luck, or, as Lily Jan put it, a “vague sense.” However it shows up, Lily Jan has applied it again and again over the last five decades to dig into some of the field’s most fundamental mysteries: probing how ion channels work, identifying their molecular subunits and studying how they regulate nerve cell communication. These insights have paved the way for greater understanding of cellular function and dysfunction.

Jan grew up in Taiwan, where prestige and achievement exert outsized influence over career choices, and spots in undergraduate STEM programs can hinge on a single exam. Medicine ranks high among esteemed majors and would have been a first choice for exceptional high school students such as Jan. However, in the 1960s, Jan attended a fascinating lecture by a visiting physicist who described experiments confirming key ideas of Chinese theorists who had won a Nobel Prize several years earlier. Jan chose to major in physics, earning a bachelor’s degree at National Taiwan University in 1968. The year prior, on a hiking trip with other students in the department, she met a man named Yuh Nung Jan whose life soon became intertwined with hers—inside and outside of the lab.

Both Lily and Yuh Nung attended Caltech for graduate work in physics. Two years into their PhDs, they exchanged wedding vows in a simple courthouse ceremony. Before saying “I do,” the pair made another important choice: they shifted from physics to biology.

The decision emerged from a shared perception that biology was entering an era where “everything becomes really exciting and possible,” says Lily Jan, whose calm demeanor belies her doggedness in the lab.

When Yuh Nung decided to join Max Delbrück’s group, Lily initially looked for a different thesis lab. She knocked on the door of every biology professor, asking what they worked on. Ultimately, Lily chose Delbrück’s lab, too; she could not pass up the chance to work with a Nobel laureate probing the underpinnings of inheritance and development—themes that guided her foray into neuroscience and continue to shape her research today.

The Jans stayed at Caltech for postdoctoral work in Seymour Benzer’s lab, pivoting to a new model system: fruit flies. Taking a page from earlier researchers who saw promise in simpler systems—using bacterial genetics to work out biosynthetic pathways—Lily Jan wondered if Drosophila genetics could help identify molecules that regulate signaling between neurons.

Working with Yuh Nung, Lily developed a technique for recording nerve impulses at the neuromuscular junction where a motor neuron meets the leg muscles. They meticulously screened and recorded from mutant Drosophila larvae, looking for abnormal synaptic transmission. They traced the curious leg-rattling behavior of one mutant, known as Shaker, to a defective potassium channel.

At this stage in their careers, Lily and Yuh Nung decided that if they were going to pursue neuroscience, they better learn how to record from what Lily called “tiny little normal-sized neurons” rather than the relatively large muscle cells found in the fruit fly. They opted for a second postdoctoral stint. This time with Steve Kuffler at Harvard Medical School. While there, they made their first big discovery: that molecules known as peptides can act as neurotransmitters, transferring messages from one neuron to another.

In 1979, they set up their own laboratory at the University of California, San Francisco. They continued their work on neurotransmitters, demonstrating that a peptide can transmit messages to relatively distant neurons without synaptic contact. They also restarted their study of the Shaker fly mutant.

It had been a combination of intuition and careful electrophysiology that demonstrated a potassium channel defect led to the Shaker fly’s overactive legs. But to have a definitive answer, they needed to clone the gene. Cloning techniques were in their infancy, and the Jans lacked training in molecular biology. They began with positional cloning, attempting to clone the gene using its physical location on the chromosome.

“We went through not just ‘chromosome walking’ but we had ‘chromosome sitting,’ ‘chromosome crawling’ and ‘chromosome falling off,’” quips Jan.

It took six years to isolate and clone the fly Shaker gene—the first known potassium channel gene. The discovery led to a slew of high impact papers, including the discovery, a year later, of the mammalian ortholog.

Looking back, Jan says that pursuing that line of research shortly after starting their lab at UCSF was “pretty naïve.” Few researchers at the time were thinking about applying molecular biology techniques toward studies of neurons, which at the time were regarded as primarily electrical. “Your tenure clock is ticking, and you take on this thing where you have absolutely no experience,” Yuh Nung agrees. “It was “very risky.”

The Jans have gone on to study whole families of potassium and other types of channels, defining their roles in disorders as varied as epilepsy and diabetes. They were among the first to recognize that the cell biology, not just the neurophysiology, of channels is important—describing processes like channel localization to different domains of the cell.

On a weekend in 1980, Lily and Yuh Nung pulled out some fly tissue sections and decided to stain them with various antibodies to see if Drosophila have substance P-like peptides, since at the time they were looking into neuropeptides. “I would call it a Saturday experiment,” Yuh Nung says, “just trying some random stuff, no deep planning.”

Under the microscope, the whole fly nervous system lit up—a shocking result, as peptides typically have restricted distributions. The pair retraced their steps and realized that Lily took a wrong vial: Rather than using a horseradish peroxidase (HRP)-coupled antibody, she used an antibody raised against HRP. As it turns out, this antibody recognizes a sugar on the surface of fly neurons and led to the first pan-neuronal marker in Drosophila—something researchers did not have in the early 1980s. With this antibody, the Jans took the plunge into neurodevelopment—another area in which they had no experience.

This led the Jans to make seminal developmental insights about neurogenesis—the process by which new neurons are formed—and neuronal cell fate determination—how a cell develops into its specific identity. Using the pan-neuron fly antibody and other neuronal markers that emerged along the way, the Jans did mutant screens to look for genes that affect the development of the fly nervous system. Their discoveries include atonal, a transcription factor that regulates development of neurons for hearing and vision, and numb, which encodes a protein that unequally segregates during asymmetric cell division in the early stages of sensory organ formation—and which sparked the discovery of other molecules in this developmental process. Other genes included cut, which is important for external sensory and chordotonal organ specification and dendrite morphology, and daughterless, which governs the development of the peripheral nervous system.

The Jans excel as well in another domain, the training of successful scientists. Over 100 of their students and postdocs now lead their own research groups at universities around the world.

The Jans have had an incredibly productive collaboration, spanning hundreds of papers, students, and postdocs, decades of late nights, two children, and one laboratory. Their strengths and their scientific interests complement each other. Yuh Nung is said to be adept at asking the question; Lily good at identifying the best tool to answer it.

His take: “I tend to get bored much more easily.” Hers: “He’s really good at picking the question. I tend to stay with the question. I’m more into the nitty gritty.”

What drives Lily Jan is also one of the most fundamental expressions of curiosity: how does it work. She has pursued scientific answers with a sense of freedom and fearlessness. Her guiding philosophy: “Experiments are hard enough, no matter what question you are trying to answer. So you might as well go after a question that you believe is really interesting.”