Looking Back, Looking Ahead With MSK Developmental Biologist Alexandra Joyner

Alexandra Joyner, PhD, a member of the Developmental Biology Program in the Sloan Kettering Institute of Memorial Sloan Kettering Cancer Center (MSK), is retiring this year, following an illustrious 40-plus-year career. An expert in mammalian (mouse) developmental genetics, Dr. Joyner has made significant contributions to our understanding of how organs are shaped during development and what goes wrong in disease states and following injury.

An overarching question she has pursued for 30 years is: How does the cerebellum get its folds? That quest has led her down additional paths, including asking which motor and nonmotor behaviors are regulated by particular folds. To what extent can the cerebellum be coaxed to regenerate after injury? And how can the growth of cerebellar tumors be curtailed?

“Dr. Joyner is a great example of a scientist trained in a fundamental discipline — developmental biology — who, like many others at the Sloan Kettering Institute, embraced putting that focus in service of improving outcomes in patients with cancer, while gaining fundamental insights into biology through the study of cancer,” says Joan Massagué, PhD, Director of the Sloan Kettering Institute and Chief Scientific Officer for MSK.

According to Developmental Biology Program Chair Kat Hadjantonakis, PhD, Dr. Joyner “pioneered the use of pluripotent stem cells as a platform for generating genetically engineered mouse models” — a technology that has transformed research possibilities in biomedicine.

Before coming to MSK, Dr. Joyner held academic positions at leading institutions around the world, including the Samuel Lunenfeld (now Lunenfeld-Tanenbaum) Research Institute in Canada and the Skirball Institute of Biomolecular Medicine at New York University.

She is an elected member of the National Academy of Medicine, a fellow of the American Academy of Arts and Sciences, and a fellow of the American Association for the Advancement of Science. She has served on numerous journal editorial boards and is currently a deputy editor for the journal Science Advances. She is also a former Howard Hughes Medical Institute Investigator.

We recently spoke with Dr. Joyner, who reflected on her career and talked about the new passions she looks forward to pursuing.

When you think back on your career, what’s something that stands out as a key inflection point?

For the first third of my career, including as a graduate student and a postdoc, and then the first eight years of running a lab, I was focused on technology development — making tools to allow us to ask new and deeper questions. We work on development in mice. Back in the early 1980s, when I started my career, we were very limited in terms of what we could do with the genetics in mice. So technology development took up a large part of my time.

Then, around the time I moved to New York, in 1994, to head the Developmental Genetics Program at the Skirball Institute at NYU, I decided: That’s enough development of techniques. Now I want to see if I’m really a biologist. So I decided to slowly focus more on the questions and take advantage of all the tools we had developed over that time. That is one inflection point.

Did you start out thinking: “I am going to be a technologist”?

No, it just sort of happened. As an undergrad, I was very excited by courses I took in developmental biology and genetics. At that time, the most exciting work was going on in the fruit fly. But I knew I didn’t want to work in the fly. I wanted to work in the mouse or an organism closer to humans.

Some people began using embryonic stem cells, but I really wanted to work in vivo, in the organism. So, I think it was the biology that I was always interested in, but we needed the technology first.

The project I ended up choosing for my PhD was to develop retroviral vectors — a virus used to introduce genetic material into the DNA of a cell — so that we could change the gene expression of cells, for example, to test what makes progenitors differentiate into a particular cell type. I did my PhD at Ontario Cancer Institute, which had just started undertaking gene cloning and all the molecular biology experiments that in the early 1980s were the hot thing.

So it wasn’t so much that I was interested in the technology actually at all. It was more that it gave me a chance to learn how to do cloning, learn some molecular biology and tissue culture. And then for my postdoc, I went to a lab that had just discovered mouse embryonic stem cells. And that got me into mouse genetics work.

This was Gail Martin’s lab at University of California, San Francisco?

Yes, Gail and a few other scientists had just discovered mouse embryonic stem cells. So it was exciting to have that model system. But even at that point, we weren’t focusing on making chimeras (an organism with cells from two sources) or knocking out genes. We didn’t know the full potential of the stem cells at that point.

On the side, I started trying to transfect stem cells using the tools I had developed for my PhD. And then also in parallel, I decided I wanted to try to clone a developmental gene based on homology to the fly. A couple of the HOX genes had just been cloned that way. So I was looking for a gene that wasn’t a HOX gene, and Tom Kornberg down the hallway had just cloned the fly engrailed gene. This is a gene that helps determine the anterior-posterior axis of segments of the developing fly embryo. So we talked to him and asked, “Can you give us a DNA probe that I can use to see if I can find the equivalent gene in mice?” And that’s how I cloned the mammalian versions of the engrailed gene, En1 and En2. This was one of the first times that anyone had identified a gene that shapes organ development in a mammal.

Was cloning mammalian genes at the time a big deal for a postdoc to do?

Yes, I think so, in terms of using homology to an invertebrate. We had several high-profile papers. Those are still some of my most highly cited papers.

It was a really exciting time in my career after I started my own lab at the Samuel Lunenfeld Research Institute in Canada. All the people who were there with me, including my colleague Janet Rossant and my postdoc at the time, Wolfgang Wurst, agree now that it was an exciting time. Because we had the genes, we had cloned them, and then we quickly got the technology going for knocking them out, making mutations in mice to determine their functions in vivo. It was very collaborative and interactive, science-wise. And also socially, there was a lot going on after hours. So it was a really fun and life-changing time.

When you think back on your career, what two or three things are you most proud of?

I think what’s given me the most pleasure for that whole time is the mentoring. You’re a part of this group, which is always turning over because students and postdocs stay around for five to seven years and then move on. But there usually are phases where a group of them are stably there together at the same time and working on one focus or helping each other reach their goals. And then it morphs into a new focus with a new group of people. So that really keeps it exciting.

Also, when grad students come in, they don’t usually know much about how science is done. But by the end, after good mentoring from faculty and other trainees, they emerge as rigorous scientists who have made an interesting discovery. That’s really satisfying to see.

I’ve also had two career technicians now since around 2000 who have just been unbelievable — Daniel Stephen and Zhimin (Jimmy) Lao. They’ve provided the backbone of the lab the whole time. They’re the memory of things that I can’t always remember.

And you edited a textbook — how did that come about?

Yes, this was back in the early 1990s. We had just developed this technology for gene targeting in mice in our group, and everybody wanted to use it. We were being asked all the time to knock out somebody’s favorite gene and train them. And it was quite a bit of work. So I was approached about putting a methods book together, and I thought, “This is going to be a lot of work, but in the long run it’s going to be less work because at least we have a manual to give everybody.” And I guess for a time it was the go-to source for mouse embryonic stem cell techniques, for about 20 years.

You moved from NYU to MSK back in 2007. What was the draw of the Sloan Kettering Institute?

Each of the programs here is bigger than at the Skirball, and MSK had more developmental biologists than most other institutions. So you have a nice broad group of people studying different areas, using a variety of systems and organisms. And importantly for me, there were more people working on mice.

We have outstanding facilities here for doing mouse work, which I realized was critical. Also, the developmental biology group that Kathryn Anderson had set up was just fantastic. And I didn’t want to do administration anymore. I just wanted to focus on doing science.

Also it’s very easy to interact with people in all the other programs. They’re happy to help or interact if your project happens to have some link to theirs. It’s also really unusual here, with The Rockefeller University and Weill Cornell Medicine right across the road — The Tri-I. The number of scientists you can easily interact with here is amazing.

As you’re winding down your lab and your research, I’m curious what you see as the next big challenges in your field. Where do you see things going?

Probably the most impactful work done now is when scientists with different expertise come together and are able to tackle new problems. It’s kind of rare to see a project that uses just one technology and becomes a high-profile paper. Usually, the high-profile papers require expertise in three or four areas, which is hard for one lab to have. On the flip side, it can be challenging to get such collaborations going because of the reward system in science, and the need for publications — for promotions and to obtain funding to keep going.

For large projects, companies often have an advantage because people aren’t worrying as much about the publication. They can freely pursue a goal. But on the other side, a problem with companies is you don’t have a lot of freedom to choose the problem to study, and importantly, they don’t usually do curiosity-driven science — which in the end is often the most important research that starts a new field and can be the most exciting.

What advice do you have for scientists who are going to be entering this new world?

A lot of people my age are thinking, “I am glad we’re not trying to set up a lab now.” It seemed easier in the 80s and 90s, because the fields were narrower and the system was simpler, however the career opportunities are much greater now.

I think in the end — and this is true of any career — you have to decide: Why are you going into this career? And then you have to stay true to that. So for me, it was the curiosity-driven science, the discovery, and the mentoring. Those are the things that make me want to come to work every day. And those are the people who I still see are the ones that go into this academic career and are successful. We get paid less compared to what we could if we went into nonacademic fields. So you have to be in it because you just love it.

What do you plan to do when you officially hang up your lab coat?

I’m going to spend the summer in the garden, and we hope to be raising a new puppy. We just built a house back in Canada. My family had a property on Lake Huron. My sister and I inherited it, so we both built houses there. They already retired there a few years ago. The nicest months up there are June to September — thus we want to be there this year.

Then I’ll probably do something in the climate advocacy area, supporting nature in some way. There’s lots of things I’m considering, but I haven’t decided what exactly I want to spend my time doing yet. We’re also likely going to keep a place in New York, so we’ll be back here too to visit family and friends and do a little science.