The new director of the Center for Genetic Diseases, molecular biologist Weihang “Valerie” Chai, PhD, wants to establish the center as a hub for innovative research in the fields of genomics, genetic diseases and cancer genetics.

“Our research is aimed at understanding the very complex mechanism underlying these diseases and developing personalized treatment strategies,” said Dr. Chai, who joined the university on Jan. 31 from the Department of Cancer Biology at Loyola University Chicago Stritch School of Medicine. “There are so many wonderful advanced technologies that we can exploit to achieve our goals.”

“Targeting replication processes in tumor cells is a promising therapeutic approach for cancer treatment.”

Dr. Chai leads a nine-member team that takes a multidisciplinary approach, integrating next-generation sequencing, molecular biology techniques and cellular imaging methods.

Genetic diseases, caused by alterations in DNA sequences that can be acquired during the lifespan, affect one in 10 people in the United States. Cancer, which will kill more than 611,000 people in 2024, is triggered by changes to a cell’s DNA. These mutations may be inherited, or instigated by viruses, environmental toxins, metabolic products from our cells or copying errors in dividing cells.

Dr. Chai’s integration of the study of genetic diseases and the genetic targeting of cancer is a good fit for RFU, which is expanding its investigation of cancer across its specialized research centers. RFU’s strong research infrastructure and strengths in immunology, bioinformatics and proteomics will help expand her research and support her vision for the center. She was also drawn by the university’s collaborative research environment. Projects with cancer cell biology and immunology are already underway.

Dr. Chai with some of her lab members, from left: Rishi Jaiswal, PhD; Vikas Gaur, PhD; Kevin Shane, BS; Manobendro Ray, PhD; Zhenguo Wang, PhD; and lab manager Sara Knowles.

“Dr. Chai’s science is outstanding,” said Ronald Kaplan, PhD, executive vice president for research. “She can help us adopt a multi-center approach to cancer research, like we have for neuroscience. The time is ripe for fundamental discoveries that have important clinical applications to combat this devastating disease.”

The Chai Lab works to understand the mechanism for maintaining genome stability, which is a hallmark of cancer. Mutations in genes that help maintain genome stability cause genetic alterations that can lead to diseases that attack multiple organs and harm child development. Mutated genes can also fuel tumor formation.

“Targeting replication processes in tumor cells is a promising therapeutic approach for cancer treatment,” Dr. Chai said. “Selectively disrupting or impairing the replication processes within cancer cells can induce damage to their DNA and inhibit their growth and proliferation.”

Emerging Therapeutic Strategies

The Chai Lab is working on multiple genes, trying to understand the genes that perform critical functions in regulating genome maintenance and damage repair. It’s looking at how cancer cells shield their genome from damage by chemotherapeutic drugs. RNA therapeutics — a rapidly advancing field — is a potential counteragent.

“We could also develop small molecule-based therapies,” said Dr. Chai, whose research has been continuously funded by NIH R01 grants. “While RNA therapeutics is a very promising area, small molecules have their advantages — especially the FDA already-approved drugs, which means no toxicity issue. Those you can repurpose.”

“The question for us is: Can we facilitate the immune response in the patients who have a poor response?”

Dr. Chai is intrigued by immunotherapy and targeted therapy like PARP inhibitors. The latter have been extremely effective in treating breast, ovarian and cervical cancers that contain BRCA mutations.

“We’re working to understand whether PARP inhibitors can be used to treat cancers that have other genetic mutations,” she said. “We’re also trying to understand the resistance to these drugs that will eventually develop and how to overcome that resistance in treatment.”

The big question on immunotherapy, Dr. Chai said, is why certain patients respond so well to the treatment, while others have either no response or a very poor one.

“The question for us is: Can we facilitate the immune response in the patients who have a poor response? How do we make them responsive to immunotherapy? The field has obtained enough findings suggesting that if you damage the genome in the cancer cells, that will help the efficacy of the immunotherapy response in patients. There are a lot of pathways and genes to investigate. For example, we already have data in one of the genes we’re working on showing that if we remove that gene, the cells change the immune response. So, we could inhibit the gene in the cancer cells to alter its response to immunotherapy, making it more responsive to immunotherapeutic treatment.”

Advancements Driven by Technology

Sweeping transformation in the life sciences has been the backdrop to Dr. Chai’s career. She earned her PhD from Cornell University in 1999, shortly after the discovery of human embryonic stem cells. In 2003, midway through her postdoctoral fellowship at the University of Texas Southwestern Medical Center in Dallas, the Human Genome Project was completed. A vital resource for biomedical research, the mapping of the human genome led to the ability to rapidly sequence large amounts of DNA or RNA.

“We were very, very excited,” Dr. Chai said. “Once that genome sequence became available, it was followed by next-generation sequencing — now a common technique. You prepare and submit your samples to the next-generation sequencing facility, obtain the sequence, then align the sequence to the human genome and get information that can provide new leads for your research. Just to say that — it’s almost unimaginable.”

New tools and technology drive biomedical research forward. CRISPR, for targeted genome editing. Nucleic acid-based approaches, to modulate gene expression. AI, to mine vast amounts of data, identifying trends and patterns. The Chai Lab either uses them already or intends to use them all.

Continual advancements in cutting-edge tools help scientists analyze, predict and see ever more accurately, ever more clearly. In structural biology, cryo-electron microscopy (cryo-EM) has emerged as the go-to method to solve the structures of large protein complexes, which the two conventional technologies, nuclear magnetic resonance (NMR) and X-ray crystallography — used to luminous effect by Dr. ˮ������Ƶ Franklin to capture the first image of the “B” form of DNA — cannot do.

“I’m not a structural biologist, and I cannot do cryo-EM,” Dr. Chai said. “While we wait for our collaborator to do the work, which takes time, we are also using AI to predict the structure of our protein of interest.”

“It’s amazing how technology is changing the research.”

Dr. Chai’s lab is using AlphaFold, a free program by Google DeepMind that accurately predicts 3D models of protein structures. Another algorithm, Rosetta, developed by computational biologist David Baker, PhD, does the same thing.

“We’re already using AI in scientific research,” Dr. Chai said. “Now people are talking about using AI not only for diagnosis, but to read images. You can feed X-ray or MRI images into an AI program, and it can identify the pathology of the patient. Researchers are using AI to design drugs and to predict which drug may be more effective. It’s amazing how technology is changing the research.”

Dr. Chai uses fluorescence microscopy as a proxy to visualize proteins inside cells. But images obtained through super resolution microscopy — with the help of Mirek Dundr, PhD, in the Center for Cancer Cell Biology, Immunology, and Infection — are offering unprecedented resolution in nanometers.

“They’re revealing information we were never able to observe,” Dr. Chai said. “When you can visualize the small molecules in nanometer resolution, suddenly they are different. You get different conclusions, and that leads to new directions for the research. It means we’re being challenged by new findings.”

While technological advances are accelerating the pace of scientific discovery, they’re not replacing the scientific method, which begins with a question — and in Dr. Chai, unflagging optimism.

“You search and search,” she said. “It’s unrealistic to expect the answer to your question the first time you try. You’ve got to conduct research, apply innovation, be creative. Our research evolves over time. As we get new leads and based on new tools and discoveries, we open new lines of inquiry — and ask new questions.”

Judy Masterson is a staff writer with RFU’s Division of Marketing and Brand Management.