How Haifan Lin pushes the envelope on stem cell research

When Haifan Lin, Ph.D., the Eugene Higgins Professor of Cell Biology and founding director of the Yale Stem Cell Center, arrived in New Haven in 2006, Dean Robert J. Alpern, M.D., Ensign Professor of Medicine, gave him a straightforward albeit Herculean mission: Build a top-notch stem cell research center. Lin took note of School of Medicine researchers whose experiments had already delved deep into stem cells, and asked them to join the center as affiliates.

Over the next decade, Lin established training platforms and programs to help more than 40 labs launch research projects on human embryonic stem cells and induced pluri-potent stem cells (iPSCs). He also recruited a handful of fast-rising stars to the center and recruited others to Yale. Now, Yale’s 91 stem cell researchers collaborate, troubleshoot, and problem solve across the campus—not just within the brick walls of the center on Amistad Street. The center acts as a hub rather than a hierarchy, and that has encouraged spontaneity and creativity within research experiments, Lin said.

As Lin recalled the center’s contributions to stem cell science, he highlighted its breakthroughs in basic biology and innovations in translational science. In 2010, Time magazine featured lab-grown lungs created by Laura Niklason, Ph.D., M.D., the Nicholas Greene Professor of Anesthesiology and Biomedical Engineering, as No. 12 out of 50 important inventions that year. (Apple’s iPad was No. 34 that year.) For Lin, who began researching stem cells in fruit flies as a postdoc at the Department of Embryology at the Carnegie Institution for Science in Baltimore Md., in the 1990s, the field has advanced at warp speed. “Using stem cells to cure diseases is not a promise of tomorrow, it has begun as a reality of today,” he said.

What aspect of stem cell basic science research excites you most right now? We are exploring new territory within the molecular mechanisms that govern stem cell division. For example, Andrew Zhuo Xiao, Ph.D., assistant professor of genetics, recently discovered a new modification of the DNA structure as a mechanism of gene regulation. DNA carries genetic information, but there are molecules modifying DNA to determine which genes are active or inactive. Xiao found this new kind of modification to be important for embryonic stem cells. He also discovered a specific protein responsible for regulating this modification of DNA. If a stem cell lacks the modification, then its fate will change. Researchers didn’t know this form of gene regulation existed in stem cells or any mammalian cells. This is one example of how we are pushing the envelope of knowledge not only on stem cells, but also on basic biology.

Tell us about your own research. In one area of my research, I focus on understanding a new class of genes that produce tiny RNAs instead of proteins. In my lab, we have cloned over 10 million tiny RNAs, a number that is about 400 times more than the total known number of genes. Imagine that the nucleotides that make up a gene are beads on a necklace. Most genes make RNAs that are 1,000 beads (nucleotides) or longer. But these genes make tiny RNAs that have only 24 to 31. These genes are located in the part of the genome that used to be called junk DNA. People thought they had no purpose, but I believed they existed for a reason. The latest research from my lab suggests that these RNA-making genes could be closely related to cancer. Normally, these genes are expressed only in reproductive cells (egg or sperm). But we found that regular cells in the body, called somatic cells, become cancerous when some of these genes are expressed. We have preliminary evidence to show that if you remove the expression of these genes, then it may be possible to slow down cancer development.

Many universities and colleges have stem cell research centers. How is Yale’s different? Many stem cell centers are heavily focused on the translational side. This strategy has its reasons and strengths. However, we started by exploring the basic science to better understand what is going on behind the development and biology of stem cells because the inner working mechanisms of stem cells are still poorly understood. Our strategy is to start by discovering more about the fundamental principles and theories around stem cells, and then apply this new knowledge to translational and clinical research.

Bone marrow transplants were for a long time the only stem cell therapy approved by the Food and Drug Administration. Why don’t we have more approved therapies? Several other stem cell-related therapies have recently been approved by the FDA for clinical trial. For example, Yale New Haven Hospital has the first FDA-approved clinical trial for a bone marrow cell-based therapy for congenital heart defects, which has been very successful. These new approvals reflect the rapid progress of the field. We are still working on the best and most reliable methods for growing millions of stem cells outside the body for therapeutic purposes. A stem cell transplant requires many cells—just isolating the cells is not enough. We also need to find a way to amplify stem cells without changing their properties.

Why was Shinya Yamanaka’s discovery of induced pluripotent stem (iPS) cells in Japan in 2006 so important? It offered three huge advantages. The first is ethical. Even a person who favors a conservative approach to stem cell research does not have a problem turning his or her own ordinary cells, such as skin cells, into stem cells for treatment. The second advantage is that iPS cells from a person’s body can become various types of tissue cells that will be recognized by our immune system as our own cells, and so you do not have to worry about our bodies rejecting them after transplantation. The third is that we can now obtain all types of cells from our iPS cells instead of directly from our body, which is often impossible. This way we can study the causes of diseases in our tissue cells and try out different treatments without using or hurting our bodies.

Stem cells exist throughout the human body in all organs and tissue, but are rare and difficult to find. Why is that? Because they are the most important cells, so they exist in extremely small numbers and often hide in the most protected locales. Like on a battlefield, the soldiers, or regular cells, are on the frontline. But the commander, or stem cell, is hiding, usually toward the back, in a fortified shelter. That’s why we’ve had to use special methods in the lab to identify stem cells.