On the third floor of Sinsheimer Labs, straight across from the stairs, an open door leads to Professor Lee’s office. It’s a small, compact space, fitted with a white board adorned with molecular sketches and a bike leaned against one end of a desk. The bike, though unassuming, marks an important continuity in Professor Lee’s life—and a catalyst to his professional career.

As a child, Lee had always enjoyed the outdoors. He was an avid hiker, backpacker, and biker—nowadays, he professes to a long-running, ample appreciation for the “natural world.” Though a proposed math major at UC Davis, his exploration of lower division courses, alongside his love of the natural world, deepened his interest in an entirely different field. 

“I always liked science and, honestly, did well in science, so [my interests] evolved that way. I don’t think it was even until my third year that I decided on a biology major,” Lee recalls. 

Now, as a professor and researcher in UCSC’s Molecular Cellular and Developmental (MCD) Biology Department, Lee focuses on the pathology of Alzheimer’s disease, studying regulators of the amyloid precursor protein (APP). When cleaved, APP yields amyloid beta (Aβ) peptide; elevated Aβ levels then lead to amyloid plaques, a “hallmark” of dementia. In his lab, Professor Lee aims to identify genes affecting Aβ-induced neurodegeneration. This is done through the use of Drosophila—or fruit fly—models. 

“One of the advantages [of Drosophila models] is being able to make transgenic organisms relatively easily—it’s not simple, but compared to, say, mice, it’s easier in flies,” says Lee.

Beyond transgenic flies, employment of the GAL4/UAS system allows for the expression of transgenes in very controlled ways—such as in specific tissues, specific stages of development, or at specific levels. In this way, researchers in Lee’s lab can make flies that express Alzheimer’s-associated human peptides (i.e. Aβ) in any desired domain. Coupled with rapid generation times and genetic manipulations less acceptably performed on vertebrate animals, Drosophila models present unique experimental advantages that, as Lee summarizes, are “part simplicity, part genetics.” 

“On the other hand, [Drosophila models are] not so simple that the experiments [we perform] have no relevance for understanding humans,” Lee adds. 

Methods performed in the lab revolve around standard molecular techniques to generate flies and assess expression. Though PCR, reverse transcription PCR, western blots, and DNA cloning are most commonly used, the lab has recently engaged with co-immunoprecipitation, a technique that determines protein-protein interactions. 

These protein-protein interactions—specifically, the binding of antimicrobial peptide LL-37 with Aβ in vitro—are a central question in the lab’s ongoing collaboration with Stanford Professor Annelise Barron. While Aβ-expressing flies live significantly shorter than wild-type flies, adding in LL-37 appears to partially ameliorate the behavioral defects of Aβ gene expression. This has potential implications for a neurodegenerative treatment, though additional experiments are being performed to determine more comprehensive results.

A second collaboration with UCSC Professor Raskatov involves P3, a shorter version of Aβ present on the brains of Alzheimer’s patients but with little known of its effects. Through observation of P3-expressing flies, recent data suggests that P3 shares adverse characteristics with Aβ and possibly contributes to Alzheimer’s pathology—shedding light on both the underlying causes of Alzheimer’s as well as possible therapeutic interventions.

 “This is all very early days, though. I don’t want to make more of it than it is. But both of these [projects] are suggestive, and might help us understand a bit more about [the underlying causes of] Alzheimer’s and how to deal with them,” Lee asserts.

Potential is a defining characteristic of Lee’s research lab, which is composed entirely of undergraduates. His decision to build a lab centered around undergraduate education stems from a number of factors—including his unique teaching philosophy.

In 2018, Professor Lee designed and taught (BIO 20L) . At the end of the class, students were tasked with reading and presenting a research paper focusing on the effectiveness of human iPS cell-derived dopaminergic neurons as a cell-based therapy for Parkinson’s Disease. The paper—a challenging, technical piece, especially as a first exposure to scientific literature—was chosen specifically to encourage significant academic effort.

Looking back on the experience, Lee remembers being “pleasantly surprised” by the presentations.

 “When I first chose it, I thought: this is going to be really hard, and it’s probably going to be a total disaster. But [the paper] sort of exemplifies how I think about teaching—to provide the [guidance] that will allow [students] to understand, but to not make it so easy that they don’t get enough out of it—you know, make it challenging,” Lee declares.

Another idea central to Lee’s teaching philosophy and support of undergraduate research is the importance of hands-on experience. Though labs in the MCD Biology Department are heavily comprised of graduate students, Lee emphasizes how the mere act of “trying” research is crucial to a student’s academic path. Simply put: “I think that a lot can be gained by giving as many undergraduates an opportunity to work in a lab as possible.”

When asked about his proudest accomplishment during his time as at UCSC, Professor Lee lights up. “Probably what I’m most proud of is that I’ve helped guide a lot of students to do the things they want to do,” Lee says. “That’s both in my lab and, hopefully, in my courses as well. That’s what I get the most satisfaction out of—having an influence on students in such a way that it enables them to pursue the things they’re really interested in doing in this world.”