
==== Front
Yale J Biol MedYale J Biol MedThe Yale Journal of Biology and Medicine0044-00861551-4056Yale Journal of Biology and Medicine InterviewCancer issueDr. Haifan Lin Lee Han Rosenstein Rachel Yale University School of Medicine10 2007 12 2006 79 3-4 187 191 Copyright ©2006, Yale Journal of Biology and Medicine2006Yale Journal of Biology and MedicineThis is an open access article distributed under the terms of the Creative Commons CC BY-NC license, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited. You may not use the material for commercial purposes.Dr. Haifan Lin is professor of Cell Biology at Yale University, where he studies the mechanism of stem cell self-renewal in fruit flies, mice, and human cancer cells. Recently named director of the Yale Stem Cell Center, Dr. Lin has made seminal contributions to the stem cell field, most notably his demonstration of the stem cell niche theory using the fruit fly model, his discovery of the PIWI/AGO gene family that is essential for stem cell division in diverse organisms, and his recent finding of a group of small RNAs called PIWI-interacting, or piRNAs, which may play a crucial role in stem cell proliferation and germline development. Dr. Lin’s work on piRNAs was recognized by Science Magazine as a top scientific breakthrough of 2006. Recently, the Lin lab has begun exploring the role of these molecules in stem cell division and oncogenesis.
==== Body
What do you foresee as the next big breakthrough in stem cell research that will contribute to our understanding of cancer?

The next big breakthrough will come as researchers recognize and develop the concept of cancer stem cells. Before this, cancer researchers generally treated all cells in cancers as equal. Recently, however, people found in several tissues — especially in the hematopoietic system and now in breast tissue and a few other tissues — that only a small number of cancer cells actually are vivacious and malignant and are able to self-renew, which is the hallmark of stem cells. By saying self-renew, I’m describing the process in which a cell divides into two cells and one of the daughter cells is identical to itself. The mother cell will always keep an exact copy of herself, and therefore, it really is an immortal process. So the identity of that particular mother cell, in this case a cancer cell, will never be lost. And that’s really the defining difference between a stem cell and any other progenitor or precursor cell. A lot of other progenitor cells lose their own identity when they divide. They generate a number of specialized cells called differentiated cells, and they’re done. The cancer stem cell concept, to me, is quite well proven in the hematopoietic system for leukemia. People have found that a very small number of leukemic cells have stem cell-like properties. By saying so, the stem cell-like property is only related to leukemia as a tissue. These cancer stem cells are not equivalent to the real stem cells in the sense that they don’t have the capacity to generate the normal lineages of the hematopoietic cells. However, in cancer tissue, they behave like stem cells. This is important because these cells actually have lots of peculiar features. They are more resistant to irradiation or chemical insult. In fact, there is one kind of cancer stem cell that was just recently discovered at Duke for gliomas, a very vicious type of brain tumor. For that type of cancer stem cell, the more insult you give to it, it improves itself faster and it enhances DNA repair mechanisms to a higher level. It’s almost completely, in a way, working against your treatment. These cells are usually very difficult to get rid of, and, therefore, cancer can reoccur — I think one of the main reasons could be due to the existence of the cancer stem cells, which are never eradicated during the treatment. And now, instead of designing drugs toward generic cancer cells, one should be able to design drugs rationally against these stem cells. Before that breakthrough happens in the clinics, we need to understand what exactly cancer stem cells are, what makes them different from regular cancer cells, and what makes them different from normal stem cells. The next breakthrough from the stem cell perspective and for cancer research is understanding and characterizing cancer stem cells, and based on this knowledge, we then can find the targeted drugs for these cells.

There has been recent research regarding the stem cell niche. For instance, one can insert a perfectly fine donor hematopoietic stem cell back into a patient, but if the niche is messed up, these cells, too, can become cancerous. What do you think of research into the area of the stem cell niche?

That is a deeper level of question. When I say cancer stem cells, I just descriptively say: Any of the cells that behave like stem cells in cancer are “cancer stem cells.” However, I didn’t explore the possible causes. There are two possible causes. One is that stem cells themselves go bad and become cancer stem cells. Another possible cause is that the niche becomes malignant. Cells in the niche may send out unnecessary signals that make stem cells overproliferate and not differentiate. As a result, the stem cells and any cells that receive and respond to this kind of malignant niche signal will become cancer stem cells. Lots of people are designing drugs strictly against cancer cells, but now you have to think about the equally important target of niche cells, which we can modulate, too.

What obstacles need to be overcome in basic science research to advance our understanding to the point of improving current therapy? How can stem cells be used to treat non-hematologic malignancies?

The principle for treating any cancer stem cell-derived disease or any disease due to the overproliferation of stem cells is the same. The hematopoietic system, being a relatively easy model, provided the most mature model, the paradigm for which we can develop treatment that can be equally applied to other solid tissues. Then what is the problem, what are the roadblocks for treating solid tissue stem cells and cancer stem cells? Mainly, the problem is identifying them. The field of adult tissue stem cells is still facing a problem, what I call an “identity crisis.” We don’t quite know exactly where the normal stem cells are, and in the case of cancer stem cells, this concept has not been demonstrated in a lot of cancers yet. It’s just beginning to be demonstrated in a few more well-studied or characterized cancers, such as breast cancer, leukemia, and glioma. But for most other types of cancer, we still don’t know whether they are caused by cancer stem cells and, if so, if cancer stem cells are the main cause. These are the roadblocks — this identity crisis and characterizing the key genes and signaling molecules from the niche.

How have the federal rules on stem cell lines affected progression of cancer stem cell research in America? What have research institutions, such as Yale, done to overcome the limitations that labs face with not being able to use federal funds for embryonic stem (ES) cell research (other than the previously flawed ES cell lines approved for federal funds)?

The cell lines are non-ideal because of several reasons.

They were derived earlier, and the technology at that time was not as good as now. The quality of the older cell lines is not ideal.

The cell lines are aged and not much has been done to rejuvenate them.

These cell lines are cultured in a system that is supported by another type of cell called “feeder cells” that are actually from mice. In a way, these cells are contaminated by mouse cells. Therefore, they cannot be used directly for clinical applications.

From these three limitations, you immediately will know the roadblocks. If we don’t have new cell lines, then you cannot do any clinical research with stem cells, period. And that is one of the largest impacts or negative impacts from (President) Bush’s regulations. There are other impacts that manifest from this central core problem; we need better cells that we can use in humans, but we have neither.

How does Yale overcome this problem? We are in a very lucky situation where the state of Connecticut actually initiated a stem cell support program to fund research on non-federally approved stem cells. We don’t suffer as much from the consequences (in reference to Bush’s regulations) like many other institutions in the country, which speaks volumes to the progressive mentality of the people in the state of Connecticut and also the government of Connecticut vs. the one in D.C. Because this money is coming in this month we should be able to go ahead and do stem cell research on non-federally funded embryonic stem cells. Of course, our research has been set back a few years as compared to research in other countries.

What do the states that don’t have state funding do?

Most states do not have state funding. I can tell you the states that do have state funding: California, New Jersey, Maryland, New York (there is a tri-institutional stem cell support consortium started by Harold Varmus), and, of course, Connecticut. A few other states are trying to start funds, but they are not there yet. In states that don’t have funding, you have to find private donations. A small number of researchers have managed to do that. Some stem cell researchers have left for places like Singapore and the United Kingdom.

Is it true that the first grant money that comes from the Connecticut Stem Cell Research Grants will be used for building an infrastructure for stem cell research?

Yes, it is true that the first grant we got for $2.5 million called the Yale Embryonic Core Grant will be used to build a core facility for others at Yale to use. Yale has contributed money to building this facility, which will be housed where the Amistad building is and will be built without using any federal money. So this is where we will be doing stem cell research legally.

Much has been written about the Connecticut Stem Cell Research Grants and other states' funding of stem cell research. How much do these state grants contribute to total funding? What are other possible sources of funding?

The funding from the state cannot be measured in its absolute dollar amount. We have at least 43 labs that do stem cell-related research, and all these labs are funded by National Institutes of Health (NIH) money. That means all these labs work on stem cells that are allowed by the federal government. These labs either work on approved human ES cell lines or stem cell research, like what my lab does, on model systems like mice, or in flies even, or on human adult stem cells, which the federal government does not put restrictions on. However, every single research activity at Yale that will use the new, better type of human ES cells will be supported by the Connecticut government. This is the unique and important contribution. Eventually, we hope to broaden our scope by approaching private foundations, and we also hope that after the next elections, the federal government will change their minds. Currently, the House and Senate are both in favor of stem cell research. They are just slightly short of the two-thirds vote to override Bush’s veto.

Countries such as Singapore are building huge biology epicenters and are trying to attract the best stem cell researchers from the U.S. with attractive startup packages and funding opportunities. What is your take on this? Is Yale competing with countries like Singapore when trying to recruit faculty members interested in stem cell research here, or is Singapore not considered a major player so institutions like Yale aren’t concerned about it? What about in the future?

Yale does not compete with Singapore for faculty members, but I am happy to see Singapore focus on stem cell research. I was in Singapore a little over a year ago for an international stem cell meeting. The Singapore government has invested a lot of money to attract talented people there. The Biopolis is an impressive place. But overall, Singapore is a small country, it is a city-country. It is wise of them to invest in one area of research, and biomedical research is what they have chosen. I am sure they will make important contributions, but Singapore alone will not solve all the stem cell problems — that I can say with great confidence. If you look at their Biopolis, there are only five institutes there, and even if all five turn into stem cell research centers, it is still not to the scale that is comparable to the activity that is in the States. I am pretty sure they can make breakthroughs; sometimes it just takes a couple good people. My gut feeling is that they can amass about 50 principle investigator-level people doing stem cell research, and that is quite a formidable force. They will take a sector but not the majority of stem cell researchers. Another thing is the clinical system, and Singapore only has a few hospitals. But the competition is not just from Singapore, there is competition from the United Kingdom, Japan, from countries like China; they are all investing a lot in stem cell research. In biomedical research overall, the U.S. is absolutely the leader, but in the stem cell field, if we don’t get our act together, our leading position will quickly be lost.

There are more established stem cell centers at other institutions, such as Harvard, University of Connecticut, Stanford, etc. How does Yale hope to compete with these centers and is there a niche in the stem cell research field that Yale is hoping to fill?

That’s a very good question. I think when I came here to meet with members of the stem cell community at Yale that was the question I kept thinking. Harvard has a really big stem cell institute already, and it started three years ago. Stanford has one from three or four years ago. My friend started one at Johns Hopkins three years ago, and at Duke I started one two years ago. So Yale is kind of late. However, I think Yale has a very important niche to occupy, in that we can focus on the fundamental principles of stem cells. The existing institutes, such as Harvard and other places, emphasize translational and disease-oriented research, which, of course, is a very important part of stem cell research. However, that is not the whole picture. I don’t want the Yale Stem Cell Center to become a “me, too” situation. I want the Yale Stem Cell Center to do something different and important by focusing on the mechanisms that control stem cell regulation. Naturally, these contributions will lead to clinical applications. And that has a few advantages:

We will make a unique and important contribution to the stem cell field.

It dovetails well with the strength of the outstanding biomedical research community at Yale.

It is fitting for a leading institution like Yale to make important discoveries on key mechanisms.

It requires less investment and a smaller operation but will still be productive.

Very often people say that basic research is a long-term investment where you need lots of money and lots of effort with lots of people. That common wisdom is not true for stem cell research. Stem cell research is no different from other types of basic research. Yet, if you do clinical research, you need lots of investments in building infrastructures and identifying viable patients. This could easily take me five years to do, and at the end of five years, I will have a nice stem cell therapy suite but nothing else will be done using the same amount of resources. That’s not very exciting. However, by doing basic research for five years, I am confident we will be able to say, “Look, we recruited these great faculty members and made these great discoveries.” I am very grateful that the Yale community, from the leadership to the faculty, is supportive of this philosophy.

