A Discussion With Linheng Li, PhD

By Cathy Yarbrough

For Stowers Investigator Linheng Li, PhD, a lifelong passion for science was sparked by a book series he read during his childhood in China. The books, titled Ten Thousand Unknown Questions, “raised so many questions, but offered no answers.” says Li. “It opened my mind and got me thinking about mysteries and how to solve them.”

With his curiosity piqued, Li went on to study biology and genetics at Fudan University in Shanghai. After receiving his BS degree at Fudan, Li moved to New York for his MS and PhD at New York University under the guidance of Edward Ziff, PhD, an international leader in gene regulation. “Dr. Ziff taught me how to ask a research question, how to analyze data, how to think in alternative ways, and how to design experiments to test a hypothesis,” Li says.

In Ziff’s lab, Li investigated the mysterious Myc gene, which is mutated in about 20 percent of human cancers and a prime target in anticancer drug development. At the time, Myc was known to play a role in promoting cell proliferation. Li discovered another function of Myc - to repress genes that instruct cells to specialize and halt their growth. NYU awarded Li a PhD degree in molecular and cellular biology in 1995, based on these and other studies he performed.

Among the first scientists appointed to the Stowers faculty, Li today is an internationally recognized authority on the biology of adult stem cells and the specialized niches that harbor these self-renewing cells in many organs and tissues of humans and other mammals. Adult stem cells are genetically programmed to develop into cells with specialized functions. They provide the replacements for the worn-out or damaged cells of the skin, blood, liver, gut, and other organs and tissues of the body.

Understanding the molecular signals that promote self-renewal of hematopoietic (blood-forming) stem cells (HSCs) could enable clinicians to generate ample supplies of adult bone marrow stem cells. The survival of many patients with leukemia, lymphoma, and other blood cancers depends on these transplants. Insights into adult stem cell behavior can also help explain cancer stem cell behavior which, Li points out, is a newly emerging approach to understand cancer better. Many tumors contain a small population of cancer stem cells, which may underlie the development of resistance to chemotherapy agents that had been effective in the primary treatment. “Cancer stem cells also may play a role in the cancer subsequently spreading from primary to secondary tissues and organs in the body,” Li adds.

Li’s focus on adult stem cells began during his postdoctoral studies with the legendary scientific pioneer Leroy (Lee) Hood, MD, PhD, co-founder and director of Seattle-based Institute for Systems Biology (ISB) and an early scientific advisor to the fledgling Stowers Institute. “Lee told me that if I wanted to be at the forefront of discovery, I should address only the most leading research questions in biology,” explains Li. “He also said that to be on the cutting edge of science, I should identify the technologies that would help me get there. If they were not available, I should obtain them.”

You obviously followed Hood’s advice. After joining the institute in 2000, you spearheaded the development of the technology known as ex vivo imaging of stem cells (EVISC), which has allowed you and your team to monitor in real time the dynamic behavior of adult stem cells. What have you learned by using EVISC technology?

EVISC allowed us to follow the homing of hematopoietic stem cells (HSCs), which are bone marrow-derived adult stem cells, after they were transplanted into laboratory mice. For the first time, we could study the real-time interaction between HSCs and their niches in bone marrow. We were the first to identify an adult stem cell niche at the cellular level and to determine that there are distinct molecular signals that control the size of the HSC niche and thereby the number of HSCs produced in the niche.

What is the potential relevance of your lab’s identification of these molecular signals?

Physicians’ ability to expand, or grow, sufficient numbers of HSCs in the lab for their patients’ bone marrow transplants is limited. If we understand how HSCs normally expand in the mammalian body, perhaps we can improve the expansion of these cells in the lab.

In our lab at the Institute, John Perry, a senior postdoctoral fellow, used three small molecules to mimic self-renewal signals to increase by a hundredfold the number of HSCs generated from mouse bone marrow tissue. Recently, John has been able to achieve the goal of expanding human HSCs in the lab.

Why do you investigate the adult stem cells of two systems–bone marrow and the intestines?

We study the hematopoietic system because it is the original and now well-established system for researchers to understand adult stem cells. It’s the system I learned from Irving Weissman, MD, the head of Stanford University’s Institute for Stem Cell Biology and Regenerative Medicine in Palo Alto, CA. Dr. Weissman was the first scientist to isolate HSCs in both laboratory mice and humans.

Like blood cells, the cells of the mammalian intestinal epithelium are frequently replaced by new cells from their adult stem cell niches. However, unlike the hematopoietic system, the intestines are a solid organ. We want to determine whether our findings with HSCs apply to at least one solid organ system. Although the two systems differ in their developmental origin and anatomic organization, we have found that they share many principles.

Your lab discovered that there are two coexisting, disparate subtypes of HSCs, ‘quiescent’ and ‘active.’ Why do humans and other mammals have two subtypes of these cells?

Our lab and other researchers have found both subsets in the hematopoietic and intestinal systems. Quiescent HSCs are the body’s strategic reserve of hematopoietic adult stem cells. They proliferate only when needed to maintain the supply of active adult stem cells in the niche, or in case of an emergency such as massive blood loss in the body. In contrast, active HSCs continually proliferate because the body’s supply of blood and immune cells must be replenished continually.

If all adult stem cells in the bone marrow were active, there might not be an adequate supply of these cells in case of emergency. That’s why quiescent cells are referred to as the strategic reserve.

Does the coexistence of quiescent and active stem cells have any possible relevance to cancer?

Yes. We and other scientists propose that active cancer stem cells in a tumor support its rapid growth, while quiescent cancer stem cells in the tumor maintain the seed of malignancy, and thus are the basis of a tumor developing resistance to drugs. We propose that to treat cancer efficiently, a new method should focus on targeting both the active and quiescent cancer stem cells. And currently, we are actively testing this hypothesis in both bone marrow and intestinal systems.

Did you and your family celebrate the 2015 Lunar New Year on February 19?

We did, but not at the level that it’s celebrated in China! My family and I observed the Lunar New Year in Kansas City with other members of the local Chinese-American community here. The community is not large, compared to New York, Seattle, and of course China. Celebrating the Lunar New Year is a way my wife, CiCi, and I remind our son and daughter of their Chinese heritage.

How do you relax and have fun in Kansas City?

I play tennis with my teenage son or with colleagues at the KC Racquet Club. It’s one of the few times I’m not thinking about science. I only think about the game when I play. I also enjoy hiking and spending time with my family. We visit local art exhibits and sometimes the City Market.

In Kansas City, it’s so easy to drive from one place to another without the stress of frequent traffic congestion. As a result, I can spend more time on my work and with my family. We really like living here.