Dr. Xinhong Lim
Junior Principal Investigator, Institute of Medical Biology, A*STAR, Singapore.
Dr. Xinhong Lim is a recipient of an A*STAR National Science Scholarship, and the IMB Investigatorship in Skin Biology. He joined Institute of Medical Biology (IMB) as a Junior PI in 2013 and works on understanding skin cell fates and signals that pattern the skin tissue.
We sent over a few questions pertinent to stem cells and his current work on skin and he was happy to reply to them as seen in the piece below.
The buzz word is ‘stem cells’ nowadays. What do you think is the value that stem cells hold for a common man?
I think stem cells have captured the popular imagination for their enormous potential in regenerative medicine applications. I myself got interested in stem cells because the idea of being able to use multipotent cells to grow complex organs for transplantation seemed really cool. For stem cells to really become a mainstream therapy however, we still have to solve many problems regarding supply, scale, safety and efficacy. However, many of the current advances are really promising. For instance, researchers have shown that stem cell injections can result in moderate improvement in mobility and feeling for animals with spinal cord injury. Also, the supply of stem cells harvested from tissues is necessarily limited, but researchers have recently been able to convert mature cells into stem cells using a simple and scalable method of genetic manipulation, opening the door to large-scale production of these cells for therapy.
However, there is a lot of hype surrounding the use of stem cells for therapy. Unscrupulous people prey on patients’ hope and bank on this hype by injecting these cells for all sorts of applications that are not supported by any reliable data. The only well-validated therapies currently available involving stem cells are bone marrow, skin and corneal transplantation, where the stem cells present in these bulk or purified tissues can engraft and replace recipient tissue. I refer the discerning reader to the ISSCR resource on stem cell therapies (http://www.isscr.org/home/publications/patient-handbook) for more information and advice.
While it might still be some time before we can regrow organs, stem cell research has already yielded many benefits in the nearer term, for instance in the development of new diseased tissues-in-a-dish to screen for therapeutic drugs. These new stem cell-based disease models hold great promise in expanding our understanding of how diseases develop and improving our ability to identify targeted and effective drugs.
Using skin as a model system for understanding stem cell fates and development of tissues is highly impressive. What made you think of this and how did you go about implementing this in your primary research?
I got into skin research rather serendipitously. I have always been interested in tissue regeneration/development and understanding how it is controlled. The lab that I joined was interested in how extrinsic signals can control stem cell behaviors. To study this, they had recently developed a reporter mouse where lung cells producing an injury-responsive signaling protein would turn fluorescent green. I decided to look at where else in the body this fluorescent reporter might be expressed under non-injury conditions, and I found very interesting patterns in the skin. The more I worked on it, the more I realized that skin was an ideal experimental model for studying stem cell fate decisions because:
- It turns over rapidly and thus requires constant stem cell activity,
- Its stereotypical architecture allows rapid identification of stem and differentiated cells,
- Being on the body surface, there is a lot of it and it is very accessible,and
- Many genetic tools are already available.
In another serendipitous development, another colleague then developed a genetic lineage-tracing mouse that would allow us track the fates of stem cells in intact tissue, which is the gold-standard way for assessing stem cell potential. Combined with the previous reporter mouse, we now had a way of studying niche and stem cells in vivo. I looked in the skins of these mice and found very interesting behaviors that were different from the dogma in the field. These and further investigations led me to formulate my current research questions on stem cell fate control using mammalian skin as a model system.
The most ‘happening’ thing in the field of research now is imaging. Everyone is excited about something that can be visualized and actually seen by eye (even if it through a microscope!). How has imaging impacted the outcome of your research?
3D-imaging is fundamental to my work and has yielded profound insights into how cells behave in their native environments. By visualizing where RNA transcripts are relative to their proteins, I can see which cells are making the signal and which cells are responding to it. By counting how labeled cells in the various strata of epidermal cells change over time, I’m able to chart the fate of stem cells and calculate the probability of various fate decisions. These approaches have yielded insights that have overturned many assumptions in the skin stem cell field. Many tools are now being developed for live imaging deep into the body, and I believe that these will yield even greater biological insights that may overturned even more of scientific dogma.
Stem cell banking is gaining popularity world over. What would you suggest to be the best/economic way and/or the best source for human stem cell banking?
Possibly the easiest way for now by which this is currently being done is by harvesting cells from skin biopsies. These mature fibroblast cells can be converted into stem cells via the simple genetic manipulation method I mentioned previously. We have a skin bank here at IMB, where both keratinocytes and fibroblasts are derived from donated skin and banked. However, the caveat with this approach is that adult fibroblast–derived pluripotent stem cells have been shown somewhat deficient when compared embryo-derived pluripotent stem cells, though the extent to which this deficiency is functionally important for stem cell therapy is unclear.
In line with the previous question, stem cell banking is extremely expensive and from personal experiences, most people do not opt for it since it will burn a huge hole in their pocket. Do you think biotech research in anyway can help in cost cutting?
I know that cord blood banking is very expensive, and I honestly think that the expense is rather unjustified. After all, in many of the banking services, they are really just taking a vial of blood and storing it in a liquid nitrogen freezer, without necessarily even purifying stem cells from it! As mentioned earlier, possibly the only established use for cord blood is to treat blood disorders. We have to be clear that cord blood may not help the donor him/herself, since any genetic abnormalities that a donor patient may have will also be present in their cord blood. Cord blood from normal donors would be useful for closely related or matched recipients suffering from blood disorders. I think a better approach is public, non-profit banking of cord blood. The scale would reduce costs, and increase availability, since any donor would automatically have access to the entire repository of donated cord blood.
Certainly, a lot of useful work is also now being done to optimize isolation and storage conditions, culture media, and even methods to direct cell differentiation. These might all mean we need fewer cells to be harvested and stored, and might bring down the overall cost of cell banking.
The recent publication in Science on cancers due to so-called ‘bad luck’-‘Variation in cancer risk among tissues can be explained by the number of stem cell divisions’, what are your thoughts on that?
Seems intuitively correct – tissues with more rapidly dividing cells have a higher chance of errors in DNA replication, predisposing them to accumulating harmful mutations that may lead to cancer.
Coming to your journey in the field of biology, your CV is extremely impressive and you are very successful at such a young age. What career paths/suggestions would you give to early career scientists/post docs as to reaching where they actually want to be?
I think I got extremely lucky that a number of good things happened, the stars aligned and I was able to get a Principal Investigator position pretty early on in my career. I was certainly persistent and worked very hard but I think there is certainly a strong element of luck that the project that I was doing (eventually) worked out, and the results were interesting enough that Science agreed to publish them. As such, I got opportunities to present the work at one of the most prominent international skin basic research conferences and get noticed, and my current Institute director and the selection committee thought that my presentation skills, the work and the proposal that I wrote to extend the work were compelling enough for them to take a chance on me.
Because I recognize that whether or not we reach a desired endpoint can be unpredictable, especially in research, I’ve come to realize that it is really important to enjoy the journey, to do work that you find intellectually satisfying regardless of the outcome. Some things I think helped me along the way were the ability to be creative and open to different ways of thinking and solving problems, which led to a very productive collaboration with a physicist and engineers, and which contributed to the relative novelty of the work that in turn led to its publication in Science. Focus is also important – I started out working on too many projects, and while I learnt a lot, I was much more productive when I focused only on trying to solve a few questions. Also, good presentation skills and networking certainly helped – I got to know of the job opportunity by reaching out to my Institute Director and presenting various talks when I was back in Singapore visiting family. Eventually, I think what really helped was also taking informed risks and just trying or asking for opportunities, even if it may seem like a moonshot.
Singapore is booming with biotech research and in terms of funds/opportunities, it is top notch. What do you think holds in the future for Singapore biotech research and where do you think it is heading to?
I think Singapore, especially A*STAR, is in a unique position to experiment with fundamentally different models of funding and executing science, especially in the space of public-private partnerships. Here, as a PI running a basic research lab, I have had the unique opportunity of getting a large grant to work very closely with a large industrial company. This is not contract research at all; my collaborator and I jointly designed the specific aims of the study to be of mutual interest, many of which are targeted at understanding fundamental biological mechanisms of tissue stem cell biology and disease, as well as drug and product development.
At the same time, I have been able to get the experience of working in an industrial-like setting with milestones and timelines, which one doesn’t usually see in an exploratory basic research setting, and designing experiments with an eye to the company’s bottom line of discovering safe and effective drugs and consumer products. My team works very closely with the company’s scientists, and we share reagents and even lab space. At a time of declining global investment in public and private R&D, with many biotech and pharma companies shutting down entire R&D divisions, my experience with this collaborative co-funded project suggests that this could be a good model for how effective and efficient R&D might be conducted in the future.