Dr. Nick Barker is a Principal Investigator (PI) at the Institute of Medical Biology (IMB), A*STAR, Singapore. Currently, Nick also holds a visiting professorship at the University of Edinburgh’s MRC Centre for Regenerative Medicine and is an associate Principal Investigator with the EC-funded research consortium EuroSyStem. Nick’s studies focus on tissue (adult) stem cells, particularly in the intestine, skin and stomach. He is also interested in the role of these stem cells in cancer.
Giuseppe Diafera interviewed Nick for EuroStemCell in September 2011, at Hydra VII: The European Summer School on Stem Cells and Regenerative Medicine.
What is your research about and how will it impact on the general population?
Some parts of our body, like the intestine or skin, are constantly regenerating – new cells are made to replace dead or damaged ones. These regenerative properties rely on tissue stem cells to make the new cells the body needs. In my lab we are investigating how this process works, but unless we have a way of specifically identifying the stem cells in an organ, it is very difficult to make progress. We discovered that a protein called Lgr5 is produced specifically by tissue stem cells in the intestine and this gave us a way to identify the cells we want to study. We then developed a method of using these cells to grow something in the lab that resembles the human intestine – an artificial structure we call an organoid. The organoid can be transplanted into a mouse to replace damaged parts of the intestine. These discoveries open up many new avenues of research and give us the opportunity to develop methods for growing stem cells in the lab for potential applications in regenerative medicine.
What got you interested in stem cells and the intestine?
It was a bit of serendipity: I joined the Hans Clevers’ lab at 24 years old, straight from my PhD in Immunology in Reading, UK. At the time, the lab was studying key factors involved in immune system development. Those studies led to the identification of a mechanism particularly important in colorectal cancer. So the research naturally translated from immunology to colorectal cancer and normal intestinal biology. The intestine is a beautiful system to study stem cell biology: it renews itself every 3 to 5 days so we can quickly monitor stem cell ability to regenerate these cells every day.
What kinds of diseases might your research help with?
Understanding how stem cells enable a normal tissue to regenerate can help us to understand what drives cancer formation in that tissue, so that new therapies can be developed. In cancer, cells divide in an uncontrolled way, eventually forming a tumour. Different cancers are caused and grow in different ways, but we now know that most tumours contain a subpopulation of malignant cells with stem cell properties (read more in our Factsheet on cancer and stem cells). If we could identify a way to discriminate reliably between ’cancer stem cells‘ and ’normal stem cells‘, we could develop a new cancer treatment to destroy the problematic cells.
Unfortunately, we’re still just at the beginning of this kind of research. The identification of unique cell features that we can use to target cancer cells, and the subsequent development of anticancer agents, first requires a more complete understanding of normal stem cells. To study these cells, we use ‘lineage tracing’, a technique that allows us to follow Lgr5 in animal models and look closely at what the cells with Lgr5 – the stem cells – are doing. We showed that these cells, in opportune conditions, can escape from the normal controls of the body and start a tumor. Now we need to show that the same cells are also responsible for driving tumor growth during cancer progression, before we can think about developing more general cancer therapeutics. Obese people, who are at significantly increased risk of developing bowel cancer, would be the first patients to benefit from this research. However, I think we are still a decade off seeing any drugs targeting Lgr5 cells within tumors.
"You don’t really need access to large numbers of cells from the body to do something useful"
It sounds like Lgr5 cells could be important for some future cancer therapies. Are they only found in the intestine?
No. They are not present in every tissue in the body, but they are generally found in tissues with a rapid turnover of cells, such as the stomach, intestine and the hair follicles in the skin. And you don’t really need access to large numbers of cells from the body to do something useful. We have shown that you can start from a single cell isolated from a small biopsy of the intestine and grow organoids in the lab that contain stem cells able to generate new cells. In this way you can rapidly and exponentially amplify the cells and generate a fair amount of biological material.
Could organoids grown in the lab really give us ’spare parts‘ for the intestine? Do you think this technique can be applied to any other organs?
We still need to do more research on the organoid technique. One of the problems with trying to identify and use tissue stem cells is that they all exist in very defined regions of our body that we call ’niches‘. The niche dictates to the stem cells that it should generate only those cell types needed for the tissue it is in. So we first need to identify which signals drive this mechanism and then build up a defined recipe to force the stem cells to make the specific cell type we need. We have identified some of these key signals and this allowed us to grow our organoid structures in the lab from mouse tissue stem cells. We can grow mouse organoids that appear to closely resemble the stomach, small intestine, colon and pancreas, but further studies are needed to generate fully functional human cells.
What would be the next obvious step to move into the clinic?
The next big challenge would be to reproduce what we’ve found in the mouse with human material. A recent publication in the journal Nature Medicine (Nature Medicine 17, 1225–1227, 2011) proved that is possible to grow organoids from a small biopsy of human colonic crypts (a specific region of the intestine), but there’s been no success with human stomach and skin yet. It will also be necessary to improve the techniques to efficiently isolate the stem cells from human samples. Ultimately it will be crucial to get industry to invest: you will never be able to develop a therapy on a scale that can enter the clinic without industry involvement.
"You can have the best biology in the world, but if you are not close enough to a identifying a molecule that could become a new drug you are always going to struggle to get industry on board"
You’re an academic now, but you have worked in industry in the past; how do you rate that experience?
It was very important for me, although I was not “all-the-way” into industry. It was a mixed academic-industrial environment, but it was nice to try and translate our findings in colorectal cancer into the development of a small molecule able to stop growth of this tumour. I also give talks to investors, trying to convince them to put money into the process, which was an eye-opening experience: you need to offer a lot for them to be interested; you can have the best biology in the world, but if you are not close enough to a identifying a molecule that could become a new drug you are always going to struggle to get industry on board.
Once your studies get close to clinical application, do you see yourself going back to industry?
Only if I can start my own company. Gastric cancer is a major health problem in Asia where I’m currently based, and if my studies on Lgr5 lead to potential for developing a realistic treatment of gastric cancer, there will be a lot of opportunity for spin-off companies to emerge.
Do you think that industrial and academic careers are mutually exclusive?
There are no rigid boundries; usually the flow is from academia to industry because people get frustrated with short contracts, the publication review process, funding restrictions and constant pressure to publish decent papers in academia. In industry you can get a permanent contract, more money, job security. On the other hand, working in a big company can be frustrating: projects that you are working on could be cancelled half the way through for reasons that will never be explained. But once you’ve really made the switch to industry you get used to more money, going home at 6pm, having a life in the weekend…it’s a very different lifestyle from academia!
Where do you think stem cell research is going in the near future?
The funding situation is becoming so critical now that research needs to move toward the clinic: it is going to be very difficult to keep doing basic science; at some point the research has to prove itself. Stem cell research has been on such a high for the last 5 or more years and such a lot of money has been going into basic stem cell science that it needs to start to make good on its promise by producing more patents and more clinical applications.
"My motto is work heartily and hard"
What advice would you give to the next generation of scientists, who will be working hard to deliver those stem cell applications?
My motto is work heartily and hard…You should be able to let off steam, go out for lunch, have party at night (sometimes!), but also work hard. It is very important to select where you go for your training and early career. There are a lot of different labs, lots of different kinds of atmospheres and lots of different Principal Investigators (or in other words, bosses). So before you join a lab, go and talk to the people who are already there to get an honest opinion about the atmosphere in the lab and how successful the last PhD students were. You need to get a good grounding in the techniques you are interested in and have the opportunity to publish your work, but you also need to enjoy yourself. Your PhD is both the best and the toughest time of your life, so choose it carefully.
Good researchers need to ask the right questions, as well as looking for answers. How do you learn to ask the right questions?
You need to be inquisitive and curious, always questioning and never take everything you read as fact. There are a lot of dogmas created 20-30 years ago and many of them are not true. So, pick an area that you think is going to make an impact on humankind, keep an open mind, challenge the dogma and go for what you believe.
What do you do to relax and to switch off from the lab?
I used to do a lot of swimming and squash competitions but now I’ve got a young baby so I don’t do that as much. I am trying to start swimming again now I’ve moved to a place with a pool in the building.
Why did you move to Singapore? Not only for the swimming pool?!
No, it was mainly because of funding. I was starting a family and it was very hard to take the decision to move to the other side of the world, but the move has given me a nice opportunity to start a group of my own without the hassle of writing grants every day. It’s also a great research environment to act as a stepping stone to full independence.
What are your next scientific goals?
Definitely a better understanding of gastric development and it will take at least a decade to get a grip on that and arrive at the point we’re now at with the intestine. The stomach is a completely different environment and has different physiology from the intestine, and even the Lgr5 gastric stem cells behave differently from the Lgr5 intestinal stem cells.
Find out more
More about Nick Barker:
Related articles on EuroStemCell:
- Cancer: a disease of stem cells?
- Regeneration: what does it mean and how does it work?
- Meet Cedric Blanpain: stem cell scientist working on skin cancers
Information for cancer patients:
- European Cancer Patient Coalition
- Cancer Research UK
- Macmillan Cancer Support
- American Association for Cancer Research
Scientifc papers (Journal subscriptions may be required):
- Isolation and in vitro expansion of human colonic stem cells, Nature Medicine 17, 1225–1227 (2011); doi:10.1038/nm.2470
Images by Nick Barker.