Profile of Nancy Ip

Elected in 2015 as a foreign associate of the National Academy of Sciences, neuroscientist Nancy Ip has made seminal discoveries concerning neurotrophic factors and the molecular mechanisms underlying brain development and synaptic plasticity, as well as their dysregulation in neurodegenerative disorders. Bridging traditional Chinese and modern medicine, Ip, the Morningside Professor of Life Science at The Hong Kong University of Science and Technology, has identified potential treatment strategies for Alzheimer’s disease. The disease is the focus of her Inaugural Article (1), which reports the first whole-genome sequencing study of Alzheimer’s disease in the Chinese population. The article’s publication precedes the planned launch of the China Brain Project, an initiative codeveloped by Ip.

Nancy Ip. Image courtesy of Yu Chen (Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong).

Formative Years

Born in Hong Kong in 1955, Ip is the youngest of six siblings. She and her four sisters attended the prestigious girls school St. Mary’s Canossian College in Kowloon. To support the family, three of her sisters became teachers after they graduated. One of Ip’s first grade teachers was her eldest sister. “In part because of their sacrifice, I was able to continue with my education,” Ip says, adding that curiosity kindled her passion for science that was nurtured by her biology teacher, Mrs. Hung. “My interest in the biological sciences was sparked during high school, when I learned how to dissect a cockroach. I had a strong desire to understand the intricate systems in the body.”

Ip continued her studies in the United States, attending Simmons College in Boston on a full scholarship. The focus of her senior year project, synthesis of the β-lactam ring of penicillin, led her to a realization: “I came to understand how engaging in fundamental research can lead to a positive impact on society and in people’s lives.” She majored in chemistry and biology and earned a bachelor’s degree with distinction in 1977.

Focus on Molecular Neuroscience

Ip’s next stop was Harvard Medical School, where she studied pharmacology and became enamored with neuroscience. “While undergoing lab rotations in different research areas, I became intrigued by the complexity of the brain and how little we knew of its functions,” she says. Ip joined the laboratory of Richard Zigmond, now a Case Western Reserve University professor, to study neurotransmission. She credits Zigmond for teaching her to develop sound experimental protocols and to have patience when striving to achieve research goals.

Upon earning her doctorate in 1983, Ip served for a year as a postdoctoral fellow at the Sloan-Kettering Institute, and then for 2 years as the laboratory head of medical genetics at Lifecodes Corporation. Ip recalls that these early years of her scientific career coincided with important developments in the field of molecular biology, such as the invention of PCR technology in 1983. The following year, Ip and Zigmond also advanced the field with their finding that patterns of presynaptic nerve activity can determine the type of neurotransmitter that regulates postsynaptic events (2).

Biology of Neurotrophic Factors

Before long, Ip was hired by the biotechnology firm Regeneron Pharmaceuticals, Inc., in New York, where she worked as a senior staff scientist. “My experience working at Regeneron was a transformative one, when we made revolutionary contributions to the field of neurotrophic factors,” she says. Ip’s mentor at Regeneron was George Yancopoulos, who is now the company’s chief scientific officer. With Yancopoulos and her colleagues, Ip demonstrated in 1992 that blood and neural cells share receptor components, such that the actions of their key growth factors overlap (3). The research bolstered evidence that the immune and nervous systems are linked.

The following year, Ip, Yancopoulos, and their team demonstrated the binding specificity of different neurotrophins to their cognate receptors that affect neuronal survival and differentiation (4). Because neurotrophins regulate neural development and plasticity, Ip’s work has inspired subsequent efforts by other research teams, including at Regeneron, to identify molecules that can cross the blood–brain barrier and mimic the actions of neurotrophic factors, efforts that could pave the way for the treatment of neurological disorders.

Mechanisms Underlying Synaptic Plasticity

Ip brought her expertise on the molecular basis of neurotrophic factors back to her native country in 1993, when she joined the faculty of The Hong Kong University of Science & Technology (HKUST). She currently serves as vice-president for research and graduate studies at the university, where she is also the director of both the State Key Laboratory of Molecular Neuroscience and the Center for Stem Cell Research. The move to Hong Kong—supported by her husband, son, and daughter—was a bold one at the time, given Ip’s status in the burgeoning United States biotechnology industry, Hong Kong’s then-anticipated return to China in 1997, and the fact that HKUST was just 2 years old.

The move also marked Ip’s shift in research focus to investigations of synaptic plasticity. In 2001, her team discovered the involvement of a brain kinase, Cdk5, in the signaling of proteins, known as neuregulins, which are involved in intercellular communication (5). Cdk5-dependent signaling was found to be associated with Parkinson’s disease autophagy, Ip’s team later determined (6). She and her colleagues revealed the importance of Cdk5’s interaction with the neurotropic factor receptor TrkB in synaptic plasticity, critical to spatial memory formation (7). These pioneering studies opened an avenue to explore the importance of Cdk5 in modulating memory and learning.

For her work on Cdk5 and other achievements, Ip was elected as an Academician of the Chinese Academy of Sciences in 2001. Three years later, she became the first Chinese honoree in life sciences to receive the L’Oréal-United Nations Educational, Scientific, and Cultural Organization “For Women in Science” Award. At HKUST, Ip has helped to develop policies that benefit women and families, such as by reducing teaching loads and extending tenure clocks for faculty members who are pregnant or raising young children.

Drug Leads for Treating Alzheimer’s Disease

Ip recalls struggles faced by her mother’s sister, who suffered from Alzheimer’s disease. Ip says, “My mother asked me how much longer it would take for me to discover a cure that could help such patients.” Ip continues to work toward that goal. She and her team elucidated the role of the cell surface receptor protein, EphA4, in synaptic plasticity (8). They demonstrated the protein’s importance in Alzheimer’s disease and its potential as a drug target. The researchers also identified rhynchophylline, derived from the Chinese medicinal herb cat’s claw (Uncaria rhynchophylla), as an effective EphA4 inhibitor (9). This alkaloid was further optimized into potent compounds that are currently in preclinical testing.

Ip’s team additionally investigates the role of innate immunity in Alzheimer’s disease. She found that the function of IL-33, an immune protein, is compromised in individuals with mild cognitive impairment. Ip further demonstrated that injecting IL-33 into a transgenic mouse model rapidly ameliorated the Alzheimer’s-like pathology and cognitive decline (10). IL-33 has also advanced to preclinical development.

Ip’s Inaugural Article (1) reports genetic risk variants and plasma biomarkers for Alzheimer’s disease in a cohort of more than 1,000 Chinese subjects. The groundbreaking project was an international effort, with scientists from the United States and Europe providing advice and guidance. Ip says, “Overall, our findings have suggested an association between the variant-driven risk effects for Alzheimer’s disease and the immune system. In the long term, they may facilitate the development of better diagnostic tools, especially for early diagnosis.”

China Brain Project

In 2013, Ip and other experts in her field met to discuss ways of promoting neuroscience in China. The meeting initiated the China Brain Project, which Ip and her colleagues outlined in an article last year (11). Through the 15-year plan, the project aims to clarify the neural circuit mechanisms of cognition, establish means for early diagnosis and intervention of brain disorders, lend a scientific basis to Chinese traditional medicine practice, conduct related research on nonhuman primates, improve artificial intelligence, and advance the development of cognitive robotics.

As one of the world’s few internationally acclaimed women life scientists, Ip has a frenetic work schedule. Nevertheless, home life remains important. “It is challenging to balance a career and family, but I find great joy in both,” she says, beaming with pride over her children, who lead successful professional careers. Ip offers this advice, which she also shared with them: “Persevere and be prepared to pursue your dreams with focused enthusiasm and drive.”