Developmental biologist Alexandra Joyner discusses the embryonic development of her interest in science, her pioneering work with mouse genetics, and her current research goals.
Like many people, my interest in science began with my love of nature. As an elementary student in Toronto, we had a wonderful science teacher, Miss Wansborough, who would take us on field trips to a marsh near our school. Our affectionate nickname for her was "Swamp." She eventually ran an Outdoor Education School, where fifth-graders would spend a whole week studying some aspect of the ecosystem. My friends and I were able to participate in the program in high school, during the month of June, after our classes ended. These experiences peaked my interest in how the diversity of organisms is determined and how the fine balance needed to maintain complex systems is attained.
A Calling is Found
When it was time to begin college at the University of Toronto, I took a number of courses to prepare for a major in animal behavior. In my third year, however, I took courses in both genetics and developmental biology, and that was it for me. I had found my calling.
While an undergraduate, I worked with a wonderful mentor, Ellie Larsen, who was studying developmental genetics in Drosophila. I found it exciting to study genetics in a living organism, though I wasn't thoroughly satisfied working with flies. In my mind, I wanted to do the same type of genetics but in mice -- which became my goal for both my doctoral and postdoctoral research.
Knowing I wanted to pursue a PhD, in 1979, I entered the doctoral program at the Ontario Cancer Institute, which is part of the University of Toronto. The Institute's research was on the cutting edge of the new wave of molecular genetics. It was also an interesting time for cancer research in general. Scientists were just beginning to learn that some of the genes that are normally involved in development might also be responsible for some cancers. This meant that you had to understand their normal developmental role to understand why and how they caused cancer.
At the institute, I trained with Alan Bernstein, who today is the director of the Canadian Institutes of Health Research. Working with Alan, I began to realize that we would need to develop new technologies in order to use genetics to its fullest potential in mice. As a result, my doctoral research involved making some of the first retroviral vectors, and using these to introduce genes into cells. It was an exciting time because a lot of disparate strands were coming together into a new understanding of cancer. A collaboration I had with a postdoc in the program, Gordon Keller, was particularly satisfying -- we were the first to infect mouse bone marrow cells and return them into a mouse, showing that efficient gene transfer into mouse somatic cells was possible.
No Second Thoughts About Science
When it came time to decide what to do after my PhD, my reflex inclination was to go for a postdoctoral fellowship. To be honest, I never really considered doing anything else. For me, it was the natural thing to do, since I liked science and seemed to be successful at it. When I had applied for my PhD, a number of faculty advised me not to go into research because there were no jobs. But I am one of those people who follow their interests, trusting that there will eventually be a position to support my efforts.
At the time of my postdoc, there were only a few labs working on making what were the first transgenic mice, meaning there were very few places I could go to combine molecular biology and traditional mouse genetics. One of the few people offering the potential was developmental biologist Gail Martin of the University of California, San Francisco (UCSF). Gail was famous for being one of the first scientists to discover embryonic stem cells in mice. My idea at the time was to use embryonic stem cells as a vector for potentially manipulating the mouse genome. Back then, it was not yet known that these cells would eventually be used for gene targeting.
Working in Gail's lab in 1983, I tested if we could develop methods for introducing DNA into embryonic stem cells, with the ultimate aim of changing gene expression. At the same time it became apparent that a number of key developmental fly genes had something now known as a homeobox domain, which is a sequence in transcription factor proteins that binds DNA. A number of people began to wonder if we could use these sequences as probes to find similar genes in mice. (At the time, no development genes had been cloned in mice.) There were suggestions that some of the cancer genes might also be involved in development, but that was the only available window into mouse developmental genetics, and a rudimentary one at that.
Pioneering Mouse Genetics
I began to test the general idea that developmental genes are conserved between fly and mouse by using a fly gene thought not to have a standard homeobox (the Engrailed gene). With the help of Thomas Kornberg, a fly developmental biologist, I was able to locate the equivalent genes in mice. Now that I had these genes that we thought were probably important for mouse development, we needed to have a tool to study what role they actually play in mice. To do this, we required a method to induce mutations in particular genes and to observe the resulting effects on embryonic development.
With an interesting research project in hand, it was time to find a place to set up my own lab. At this time, in 1986, I had just had a baby, and my husband and I decided to limit our job search to Toronto, where our families lived. Mt. Sinai Hospital had just created the Samuel Lunenfeld Research Institute, which had recruited Alan Bernstein, Janet Rossant, a developmental biologist making transgenic mice, and Anthony Pawson, a cancer biologist studying intracellular signal transduction.
Collaborative Progress
My lab was one of five at the institute doing mouse developmental genetics. Everyone had different and complementary strengths. One of my aims was to develop new methods to mutate genes. Using embryonic stem cells, my colleague Janet Rossant and I created mice with a mutation in one of the mouse Engrailed genes, hoping to learn its role in development. It was an exciting time to be involved with the development of these and other genetic methods in mice. We could now begin to study mouse genetics with more precision than in the fly.
I function best in a group when there is a real give and take. From 1986 to 1994, the group that we had in Toronto was special. Our collaborative work was natural and very rewarding. By 1994, however, I was ready for a new challenge. Having helped to develop a variety of new technologies, I then decided to determine whether we could apply them to study brain development.
New York University (NYU) had just opened its Skirball Institute of Biomolecular Medicine and I was invited by the director, Lennart Philipson, to create a program in developmental genetics. I liked the idea of having the opportunity to bring together developmental geneticists working in mouse, fly, worm, and fish, and have them all on one floor. One floor up was the neurobiology program, my other great interest, so it seemed like a perfect place for me.
From Simple Embryonic Neural Tube to Complex Adult Structure
I decided that the cerebellum would be an ideal system to study how a region of the brain is transformed from a simple embryonic tube-like structure, to eventually become a complex adult brain structure with billions of cells organized into a foliated structure with many axon connections but only a few cell types. In my 12 years at the Skirlball Institute, we were able to develop the basic ground rules for how we think that developmental system works. We now need to elaborate the molecular details.
In parallel to our work on the cerebellum, we had an ongoing interest in the Sonic hedgehog signaling pathway and its implications for brain development, cancer, and most recently stem cell biology. While we initially studied stem cells in the brain, we now realize that this hedgehog pathway probably regulates stem cells in many different adult tissues.
Next Step - SKI
While trying to decide where next to take my two pronged cerebellum-adult stem cell work, the one institution that continued to rise to the top of the list was Sloan-Kettering Institute (SKI). It is rare in a center's leadership to have someone like Harold Varmus, who truly understands the importance of mouse genetics and mouse in vivo studies. I was starting to wonder if I was going to put myself out of business because the necessary infrastructure and expertise for sophisticated mouse genetics research is rare in academic institutes. The core facilities at SKI are excellent, which made this one of the few places where I could easily expand my research. In addition, I knew that Kathryn Anderson, Chair of the Developmental Biology Program at SKI, was building a very exciting developmental biology group, which had the kind of interactive and complementary feel that my past research environments had offered. She was expanding the program into neurobiology with the hiring of Songhai Shi, and Kathryn and I agreed that I would be a good bridge between the neurobiology and early embryology focus groups.
Looking Ahead - Research Goals
Now that my SKI lab is up and running, my research goals are twofold. First, we will continue to analyze how genetic decisions made in the early embryo impact on the final structure and function of the cerebellum. As one way of helping to understand this process, we are studying a childhood cancer of the cerebellum called medulloblastoma, which several labs at SKI study. We are also beginning to develop new genetic tools to allow us to study the physiology of cells in mice. The second focus will be on adult stem cells, in order to understand how our body's natural stem cells could combat disease or injury. With both goals in mind, I feel this is the perfect place for me to make significant progress. I also am looking forward to having a direct cancer research connection again, which I have missed since leaving Toronto.
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