Faculty members Mathew Blurton-Jones, PhD, Kim Green, PhD, and Masashi Kitazawa, PhD, are principal investigators (PI) of productive, independent laboratories at UCI MIND all aiming to target the underlying cause of and develop effective treatments for Alzheimer’s disease (AD) and related disorders.
How did they get to where they are now? After graduate school in 2003, they came together from different backgrounds to train with renowned scientist, Frank LaFerla, PhD, who continues to run a successful laboratory of his own at UCI MIND.
Blurton-Jones, Green, and Kitazawa reflect on their training experience and what they believe to be their most important contributions to the field thus far:
Why did you choose LaFerla’s lab at UCI MIND for your postdoctoral training?
Blurton-Jones: As a graduate student at UC San Diego, I had been studying the effects of estrogen on neuroplasticity to try to understand why women are more likely to develop AD than men. Around the same time, my grandfather developed the disease, which naturally reinforced my desire to continue AD research. I knew that UCI MIND had several leading scientists – Carl Cotman, Andrea Tenner, and Charlie Glabe to name a few. I was initially drawn to Carl’s lab because he was using exciting new gene analysis and bioengineering approaches to study AD. While in Carl’s lab, Frank published his first paper on the triple transgenic mouse model. The excitement surrounding this innovative new model led me to begin collaborating with his team and, soon thereafter, to pursue a second postdoc to explore some of my own ideas with this new model. For example, I started to think about how stem cells could potentially be used to model or perhaps even treat AD, and Frank gave me the freedom to pursue this relatively wild new idea.
Green: After my doctoral training at University of Leeds, I decided to spend a year backpacking around the world. As my last two weeks approached, I started thinking about what I wanted to do next and remembered meeting Frank at a conference the year before. He was known in the late 90’s for his work on calcium in AD, which was the focus for my PhD. His team was doing great work. So, during my last stop in LA, I had the opportunity to interview for a postdoc position and got it. And then when I got to UCI, Frank had just made the triple transgenic mice, and my research focus changed at that point.
Kitazawa: I was very interested in how chemical agents affect the nervous system. So, I pursued my PhD in environmental toxicology where my research focused on using cell cultures to examine environmental chemicals, including pesticides in Parkinson’s disease. Then, I wanted to expand my knowledge in toxicology to other neurological diseases, so my mentor recommended AD and mentioned a rising hot shot at UCI, Frank LaFerla. Frank was known for his triple transgenic mice and I wanted to expand my techniques, skills, and knowledge to working with mouse models for my postdoc training. Fortunately, he offered me a position to join his lab.
What were your most important accomplishments as a postdoctoral trainee?
Blurton-Jones: Of course there’s those scientific moments where you see for the first time a really exciting result. When we first got the result that our stem cell transplant was improving behavior and memory impairment in AD mice, that was super exciting.
Green: We were fortunate – we all had a string of discoveries. One of mine, for example, was that nicotinamide (high doses of vitamin B3) restores cognition in mice with AD, which has led to a current clinical trial in people. I view that as good translational science that worked here at UCI MIND. It feels good to have made a discovery that led to a clinical trial that might help people with the disease.
Kitazawa: I was probably the first in the lab to explore the link between inflammation and AD in mice. Obviously there were other investigators in the field studying that, but at the time it wasn’t the main topic. Right now, it is! Another one is the link between muscle disease and AD. Degenerating muscles, like in inclusion body myositis, accumulate amyloid beta just like in the brain, but those people somehow don’t develop AD. I continued to investigate this and published some work on the topic.
What is the focus of your independent lab?
Blurton-Jones: When I started my own lab in 2011, I began to investigate whether we can use induced pluripotent stem cells (iPSCs) to better understand AD. Most recently, we have used iPSCs to generate and study microglia, the immune cells of the brain. Part of what has encouraged us to study microglia are new findings in the field that have shown that many AD risk genes are primarily expressed in microglia. So those are the cells we need to be studying to better understand the disease and develop promising new therapies.
Green: Microglia. When I started my lab in 2011, we looked at a lot of different things, including microglia which people weren’t really interested in at the time. And somewhat through luck, we found a way to get rid of microglia completely, which was unheard of. We published this finding in 2014 and there was originally a lot of disbelief. No one believed we could eliminate an entire tissue from the brain and that the mice would be fine. But now, it’s a widely used, reproduced, and very popular approach.
Kitazawa: After a few years at UC Merced, I came back to UCI in 2016 and launched my lab focusing on environmental risk factors for AD using cell cultures and animal models. Right now, we’re looking at the potential effects of chronic copper exposure in drinking water as well as particulate matter, or air pollution. There is emerging epidemiological evidence that these environmental factors may be associated with cognitive decline, so now the question is, what is the mechanism?
What have been your most important contributions to the field thus far?
Blurton-Jones: Probably two-fold. The first is developing an approach to differentiate iPSCs into human microglia, and now a lot of researchers and biomedical companies are using our approach. This allowed us to ask the next set of questions, which is our second big achievement. We are now using iPSC-derived microglia combined with gene editing tools to try to understand what exactly AD risk genes do to microglial function. Most recently, we’ve taken this to the next step by transplanting those human cells back into mice with AD pathology to see how the genetic mutations change microglial responses to pathology.
Green: Our method to completely eliminate microglia in mice is the most important contribution that I will ever make. It has been a highly influential finding that is now used by more than 200 groups across the world and has led to many important discoveries. It’s hopefully inspiring clinical trials in Europe and the U.S. Because we figured out how to get rid of microglia, it allows us to explore what these cells do in the disease, which was just not possible before.
Kitazawa: We’ve published some important findings on the link between copper and inflammation, as well as the vascular damage caused by copper.
Is there anything you took from LaFerla’s mentorship that you use with your own trainees?
Blurton-Jones: To give my graduate students and postdocs the freedom to pursue what they’re passionate about in their research, with some guidance and advice of course! It’s not an easy career, so I think having that freedom to embrace our intellectual curiosity is critical. Frank also taught me the importance of interpersonal relationships – how to talk confidently about our research and engage people in what we’re doing at both the scientific and lay levels. Frank is an expert at that.
Green: Everything. Frank had a big lab with lots of people, allowing me to take on mentorship roles for other trainees, which gave me the experience and perspective needed to start my own lab. With Frank, we also learned the importance of branding, which you can see in his contributions to UCI MIND and the School of Biological Sciences.
Kitazawa: I appreciate how Frank gave us freedom to research within the capacity of his lab. I feel that works very well for my lab as well. I think it’s good for young postdocs who have lots of ambitions and some crazy ideas (that we may not have anymore) to try to test them. If it works, that’s great. If it doesn’t, we move on to the next idea. It may be a little risky, but it can lead to some surprising results. Especially for the AD field, where we may need to look at the problem from a different point of view to see what we’ve missed. Those ideas are probably going to come from fresh postdocs bringing in new ideas.