Humans of Biology: Dr. Anne Simon

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Q: Can you tell us a little bit about the social paradigms you developed for Drosophila?

A: Ah yes, so I tried to develop two of them. What I wanted were simple assays that could be easily mastered by students. I was working a lot with undergrad students. I wanted a quick readout. So what was done when I started looking at those different assays were studies of courtship. But that’s a very complex process that requires a lot of sensory modalities, many steps and a lot of video taping, not necessarily, but a lot of, more involved and it’s a lot more complex process. Other studies were about aggression which does not happen so much in flies, you need to starve them, you need to really make them really unhappy, so they start becoming territorial. So, I wanted something simpler that was linked to the observations I had made doing other behaviour – I have been doing fly behaviour for a long time – and I wanted to look at some simple response to others.

One of the assays I had developed, the first one, was how flies avoid locations where other flies have been stressed, so I had to observe that phenomenon during my other behaviour – basic locomotion and response to light and stuff. The other one I wanted really to look at was social interaction at a really simple and basic level. So, I tried a different type of assays, seeing how two flies respond to one another and similar type of experiments. But kind of by serendipity, I noticed that I had three different lines of flies and in their steady state in their bottles, they were really aggregated all along one side of the bottle, but they were forming different groups. In one case, I had a very tight group, in the other case, a middle-sized group and the other one sparse. So, the interesting thing there was that they were all from the same genetic background and two of the mutations were known to be opposite of each other. And so, I said, “I might be onto something there.” So, that’s when I started looking at social space and trying to figure out, so that was in a bottle, I was trying to figure out how to find a proper container. It was a side project so I actually had an undergrad spending two years trying to figure out how to measure that.

Q: So that was your motivation for investigating social bubbles?

A: That’s how it started! I decided that looking at social space, or social bubbles, was an easy readout. And, actually, once I observed that, by training them and looking at the development of the brain – I’m a neuro-developmental person, doing genetics, using genetics to understand that. So, I have not done ecology. I have not taken an ecology class, so to figure out whether that was a relevant behaviour, I was in the Brain Institute at UCLA at that point, and I crossed the yard to see the life science researchers, specifically the ecologists. I said, “okay here’s what I see, does that mean something to you?” They said, “Oh yes, it’s aggregation, it’s local enhancement, it’s social distance that’s measured in body length. I said, “Okay, now I have new words to do my pubmed searches and learn more about the natural behaviour and the fact that what I as looking at was not a complete lab artifact.”

Q: What are your thoughts on the importance of Drosophila in biological studies?

A: That’s going to be very quick. [Pulls out PowerPoint on computer]. Ground breaking work in Drosophila has been recognized by 6 Nobel prizes. It started in the early 20th century with Morgan here in 1933, he found that genes were carried by chromosomes – he used the fruit fly. Then Muller here found that X-rays were damaging DNA, so that was in ’46. These three were working together and they found through independent work around the same time – Lewis was in the US, and Nusslein-Volhard and Wischaus were working together in Germany – to identify genes that were important to determine the development  the different parts of the body. Those same genes are helping to organize bodies from the fly to humans, so the colours here, those are the genes – the homeotic genes. Then Richard Axel here made in the fruit fly interesting observations and discoveries about how odors were perceived, and about the odor preceptors and their pathways. Jules Hofmann here is a French person and a French researcher, he found how the innate immune system was functioning and how we have the same innate immune system. The inflammatory response you’re having is the pathways. And this is in 2017! Those researchers here deciphered the molecular basis of the circadian clock of the fly. Actually, that started in a lab, the first mutant was identified in the lab at Caltech, in Seymour Benzer’s lab. Contrary to the others, that was the first Nobel prize on behavioural genetics, and that got me very excited because that’s what I’m working on – behavioural genetics.

So, the first mutant isolated was called period, it has a different periodicity than 24 hours. So, you could have mutants that had shorter periodicity and mutants that had longer periodicity. The gene was cloned, I would say around 10 years later. Then in the 90’s, they found a family – a human family – that was a little bit off in terms of their circadian rhythms. They were unable to go to bed before three a.m. if I remember correctly, and they could not wake up early and the whole family was like that. They had to find jobs that would accommodate their odd cycles. When they were studied more in detail, it was found that they had a different variant of the human period gene. So, although at the beginning when they first studied the fly circadian rhythm, there was not clear indication that anything would be conserved, it was found that it was; there was a lot of basic mechanisms that were conserved. But basically, through the years, there has been pioneering work on very basic research that was found to be extremely relevant in humans. 75% of the genes that are involved in diseases that are found in humans have a similar gene with a similar function in Drosophila. Studying those can help us understand basic mechanisms that are conserved. Not all of them are conserved but before we study them, we don’t know.

The basis at the molecular level of learning and memory was also elucidated using the fruit fly. Basically, we’re looking at behaviour, and the fly has a much simpler brain, well studied so we know the structure very well. We have some similar neurotransmitters that are very nicely mapped. So, here’s the dopaminergic system for example. We know exactly what is projecting where. We need to understand the function now, but we can study that well. We are using Drosophila as a model for behaviour for a long time, because they share some very basic behaviours. Those that are shared are important for survival – basic needs – and that seems to involve similar genes. The same conservation of the molecular pathways, but the structure of the brain is different. They do sleep, they court, they respond to drugs in a similar way as other animals do, as mammals do. If you feed them cocaine, it would go through the same dopaminergic pathways, the same targets in the cells – the dopamine transporter, the vesicular monoamine transporter, the same targets. They also respond to alcohol. So, a study a few years ago, maybe ten years ago, found that males that have been rejected during courtship would prefer drinking alcohol more than males that were not rejected. Cool huh? They also have different social behaviours, I spoke about courtship, aggression – here we see that one is fighting with another – and the learning and memory aspect that I just mentioned. We’re looking at social spacing as one of the assay.

One of the advantages is that they are cheap. They have a rapid life cycle. They’ve been used a model for a hundred years, so there are a lot of genetic tools. The genome has been sequenced, and it allows us to very easily map mutations. More and more tools are available to manipulate gene expression. So, it’s a good model if you want to study phenomenon in development, behaviour through manipulations of the genes. It’s not the best behavioural model. You would have other animals that probably would have behaviours more similar to humans, but they might be harder to manipulate. A lot of basic work could be done here and then confirmed in higher organisms.

Q: What does the genome size of the Drosophila look like?

A: It has a smaller genome size and it’s much less complex. It has around 13,000 genes when humans have around 20,000 genes. It has a lot of genes too. There has been duplications of the whole genome at some point during evolution. So, often times when you have one gene in the fly, you might have two to four similar genes in humans. It’s much less complex, what’s different in humans is that you have a lot of regions that are important for regulation. Apparently, that’s what’s going on, a lot of genetic splicing and a lot more complexity at the level of the proteins than what the flies have. The size of the human genome is 3 billion base pairs and Drosophila melanogaster has 122 million base pairs. So, it’s quite smaller, however, the number of genes are only around half.

Q: Is that easier to work with?

A: No, in fact, it has a lot of genes compared to its size. What makes it easier is that it only has four chromosomes. So, it has more than half the number of genes, but it was easy to map them at the beginning. It has (1) a big X chromosome, then (2) and (3) and a tiny fourth chromosome that’s very compacted with a few genes present there and a Y chromosome that is not very big and not carrying many genes either. Basically, you would map most of the mutations on one of the three chromosomes. It was easy to start mapping the genes and understanding their function, figuring out where the mutations were on the same genes or not.

Q: Having worked with incredible scientists such as Thomas Préat and Seymour Benzer, how have they influenced the path you’ve taken?

A: That’s a tricky question, they were very smart people but difficult mentors? So, being in their labs I was exposed to very exciting research. Both of them had good means. I also had access to a lot of tools, technologies and questions. I went to grad school 20 years ago, in France at that time, there was not much oversight of the grad students in the lab and Thomas Préat was an awful supervisor. Not only to me, I learned afterwards. He would close the door and yell, and then I would yell back because I was 24 and I did not like that. So, it was very tense. The problem was that he was bringing money and was a good researcher. I have no problem saying that because other people have been through the same path. I think he has been better now. He was also very tense because I was his first grad student and he was in a competitive position with his own postdoc advisor. So, that was not the best place to be nurtured but I learned a lot in term of the science. I started networking a lot with people doing behaviour. So, my project was working on the development of the brain structure involved with learning and memory, but during the lab meetings I would listen to the projects that were on behaviour per se.

The first two years were really hard and after that I decided that I just wanted to get my PhD as soon as possible and get out of academia. So, I started to care less about him and I got really into research. Because instead of being very reactive and worried about his reaction, I was more, “Okay, let’s finish, I can do that, let’s wrap it up and get out.” Then I worked for me, and when I started working for me, I got very excited. When he wanted me to stay up until 9 p.m. and I said, “well I have a life.” When I wanted to know what was the result of that cross, where was the antibody expressed, I would stay because I was driven by my own interest. So, I think I started then, when I started working for me instead of for him, to really do good science. I think I was doing good science before, but it was not fun. At that point I was really engaged. That’s fun, you know, you have a rush when you’re testing something and you’re observing a result that might be expected or not. Your hypothesis might be wrong but it’s novel. I really got very excited at that point, when I was able to dissociate from the social difficulties to focus on reading all of the articles and learning about what was known at the time on brain development.

So, I think at that point I decided that I would stay, and I got two papers out of it. Although I had wanted to get out without any papers and just to move on. I was able to publish two papers; one of them, the first one, is still cited now. And so, then at that point I though, “huh, maybe I can do a postdoc and you know what, I’ve never really travelled.” I’m not coming from a super wealthy family, it’s lower-middle class, so during the summer we would go to the grandparents. So, I did not travel and I as thinking, “if I do the PhD, I can travel.” I was working during the summer so during my summers while I was at the university, I would work for a month and do two months of internship that were poorly paid if at all, to get experience. So, then I applied, and I was thinking, “oh where do I want to go?” I applied to positions on the west coast of the U.S. and I got two interviews and ended up at Caltech with Seymour Benzer.

So, again there it was difficult because Seymour Benzer’s approach to science, as in a lot of big labs, is to have a lot of money, try to hire potentially smart people and let them be. The mentoring was very minimum. He was also very critical and very harsh. On one hand, he was extremely astute, he read a lot of literature, he understood your project. When I was there, there were nine postdocs total and I was the only woman. Yet, mostly they were very old school, a lot of brash interaction, it was very unpleasant in the lab. Now, that was part of my life but the whole culture of postdocs at Caltech was pretty friendly. I made a lot of friends that am I still in touch with. Similarly, at Caltech, I had a room big like here, with a desk, a molecular biology bench, a fly bench. I had a half-time technician working for me who I shared with someone else. I had access to excellent undergrads that were coming at Caltech. Either they were working at Caltech or they were coming for summer internship. One of those undergrads is now an excellent faculty at Harvard, Monica Dus. She has her own podcast if you look her up, she’s really cool. So, I needed to be very dependent and to be kind of strong to put up with their harsh comments and internal competition from the guys. But I had so many resources, so again I came with a hypothesis. I got a fellowship to test that hypothesis, so I was financially independent. I got two fellowships during my four years and Benzer was bridging the gaps in between the fellowships. I was working on aging and I made the hypothesis that steroids would be important for aging. I found they were, so I got a Science paper that way. However, Benzer was not interested in that project so he did not want to read the paper. So, I told him when I was three years in, “okay so I’m submitting the paper, if you want to be an author, let me know.” At that point he said, “okay, let’s read that.” It was not nurturing at all.

And so, at that point I was, you know, “okay so I like research, I’m doing a good job at it, but it’s really…unpleasant.” I did not have good mentorship where I had started, but then it kind of trickled. A lot of times, people can lean back on their previous mentors and what I had were more mentoring moments with people I had met at conferences. So, those sustained me. One person that I met in ’94 in my first grad school – whom I’m still friends with – happened to have done his undergrad here at Western, Steven de Belle. He’s a Canadian and I met him when he was a postdoc in Germany when I started grad school. He was working on learning and memory, that was my field in Drosophila. Then he got a job at the University of Las Vegas when I was at Caltech, and so we started seeing each other again at conferences. Then I moved to UCLA and we also kept on interacting. So, he has followed me through my whole career and he gave me good mentorship advice. Those really sustained me, even at Caltech, people that I met at conferences, that were generally interested in the science. They did not care whether I was a woman or not, they did not care about all that. “Wow, what you’re doing is super interesting. It goes along with what I observed.” So, I knew there were good people in the research community.

I also knew I needed to be better at interviewing, I did not only want to be accepted in a lab but checking whether I wanted to be in the lab. I did step out of academia per se after Caltech and I worked for a year in a medical centre in Los Angeles, Cedars-Sinai Medical Centre. That’s when I really started going more into social behaviour. So, it was a lab that was led by a pediatrician. She was specialized in two disorders: Down Syndrome and William Syndrome. I was supposed to be the scientist leading the William Syndrome project, well I did that for a year. The William Syndrome individuals are very interesting because it’s a hemideletion of 21 genes that leads to a flurry of cognitive and psychological problems, one of which was mental retardation. They have problems with abstract thoughts and their visual cortex is not developed very well, so they have a hard time climbing stairs for example and they don’t see as well. However, they are extremely social. They are very empathetic. They are thought to be at the origin of the fairies and elves descriptions in tales because they tend to have more pointed ears and a big space between their nose and their lips. So, they have facial features that make them really look like elves or fairies the way you would think about them. And, to have curly hair regardless of their ethnicity.

In that lab they were trying to figure out, out of those 21 genes, which are responsible for the hyper social behaviour. Then I was excited because that was something I really found very interesting. I found it more interesting to work on engaging social behaviour than on courtship or aggression or fear. That’s something I wanted to read about, whether in human or any animals. That’s something I found fascinating! The problem in that lab was that it was part of a big consortium of five labs that were all working on the same subject. What we’re doing – because I was a geneticist – was to genotype. So, we were taking blood and genotyping, day in and day out. It was boring. What was exciting was that we met every three months with the other PI’s of the other labs. One in San Diego was working on the neurocognition of the same patients, so trying to figure out their cognitive abilities. Another one was doing fMRI to figure out if their brain were functioning the same way. Another one was looking at another aspect at event-related potential to see how their brain was excited. Finally, another one was looking at the brains of individuals that had died, if the family had agreed that we looked at their brains.

I found the subject very interesting but it was so slow and depended on so many other people that I thought I would go back to academia and find a lab that was a good place, a nurturing place, and try to really move to understanding social behaviour. That’s how I ended up as a research scientist at UCLA. It was a non-tenure track faculty position with no teaching, so basically some kind of super postdoc. And I did that. I went online, and I read how to interview, what other questions to ask and I found a lovely place. I spent really four years there and it started to be the best four years in research because I both had an exciting time research-wise, but the place was wonderful. In the laboratory of David Krantz. And that allowed to starting being the job market.

At that time, I was still supervising undergrads, I’ve always done that as soon as I arrived in the U.S. I’ve even supervised a high school student. On my Science paper, I have a science student. Her mom was a secretary in another department, in astronomy, and I had met her at a party at Caltech. And the mom said, “oh, my daughter is finishing school super early and I work up to 6, do you have something for her?” I said, “no,” but I really liked her mom, I really liked Judith, and so I said: “okay, let’s give it a chance.” I told Antha: “you’re just going to shadow the other students here, I have nothing for you.” But then she started coming with excellent questions. She said, “why do you feed the fly that kind of brown pudding? They’re fruit flies, shouldn’t they eat fruit?” I was: “uh, yeah maybe? Come back with a protocol to test that.” And she did! She did test the longevity of flies fed on our “pudding” and banana. It was really good, so I started having her more and more involved in my research and she really played a role working on steroids. We’re still in touch, she’s at Seattle. She stopped doing Biology and she’s working in a web development company, so she went more into computers and stuff like that. I’m keeping in touch with a lot of the students. So, in terms of life story, after that at UCLA, I wanted to look for a faculty job, but I had what was called a “two-body problem.” That’s a term that academics use to discuss the fact that you are two faculty of the job market at the same time and it’s hard to find positions.

[Noises coming from her computer]

Sorry, so my computer, I asked it to speak French to me, but the whole thing is in English. So, it’s reading that it’s eleven a.m., but it’s reading the English words with a French accent. I find it funny, so I won’t delete it.

So, it was not easy to look for a job at that point in two different fields. I ended up being in a teaching university in the University of New York, we were both in Long Island. Well when we arrived in Long Island, we thought that it would be an easy commute – it was the hardest commute. So, the first year we went back onto the job market that would take both of us on the same campus.

Q: Both of you?

A: Me and my then husband. So, that’s how we arrived at Western. We applied to many different places. Then we got the job here, and then we’re not married anymore. That’s life.

Q: Looking back now, what would you give as advice to your past self so many years ago when you were first working in those labs that you thought was a difficult environment?

A: Maybe to not take their behaviours so personally. It was not about me, the way they were. What I was lacking was a proper support system outside mentoring. I really questioned myself, that’s a lot of what made me unhappy. The moment I began enjoying science in Préat’s lab was when I was thinking, “I don’t care about him.” But, it’s really hard and it was similar with Benzer. Around two years I reached a turning point and I though, “you know what he doesn’t care what I’m doing, he’s not supportive.” But he doesn’t prevent me from doing anything either. It’s just that if I don’t interactive with him, he’s not interacting with me but he’s letting me order things. One of the postdocs gave me exactly that advice. “I speak to Benzer only when I have results. He doesn’t come to me, I don’t go to him.” I think I benefited enough from being there that I’m not sure if I should not have gone there, but I think I would tell myself, “don’t worry, it’s not about you. Keep on doing your job. Don’t be so stressed because of them. Because the science was fun.” But what I tell my students now is to make sure that when you interview, not only to be liked and accepted, but to make sure that it’s the right environment for you. I think what I did not necessarily have at the time was the understanding of what type of supervision I wanted. So, some people want to speak on a daily basis with their supervisor, other want to be left alone. You need to have kind of an understanding of the kind of person you are so that you can either communicate that to the supervisor or find a supervisor that behaves that way. So, in Thomas’ lab, we were four, two guys and two girls. The two guys had a great time, the two girls had a horrible time. As Benzer, he did not know how to interact with women. So, if I had known that before, maybe I would have not gone there? I don’t know.

Q: Do you regret anything?

A: No, not really because I got things out of there, it’s because I was in that lab that I really started understanding how the brain is developing in the fly and how it functions. And being in touch with other researchers doing other aspects of behaviour. That science really fascinates me. In Benzer’s lab it was the same, I collaborated with another lab to look at that avoidance behaviour. I met really fascinating people. If I regret something, it was to not have been more mature at the time. To be stronger and again to not take those things as personally. I got opportunities through going into these labs that I probably would not have had otherwise, and the subject, the science, is really what allowed me to stay. I did not leave those labs. I spent four years at each. No, I did not give up.

Q: If you have not gone into biology, or just genetics, what was your plan B? As a child, did you always want to go into genetics?

A: No, I wanted to be a veterinarian. I was always interested in how animals were working, how things were functioning at a biological level. But then, to be a veterinarian in France you need to go to very competitive prep schools and the way universities work in France fit better with my learning style. I also thought being a veterinarian could be boring on a daily basis because some of the pet owners can be really… a drag. In fact, when I was in high school, I had an excellent biology teacher, who liked genetics, and it was the first time I heard about it. It’s so simple. It’s so logical. There’s something about genetics that is mirrored to math. You don’t need to learn too much, you just need to understand the basis and then there’s a world of possibilities. I really loved the classes in first and second year about gene regulation and developmental biology and how the puzzles were put together to make an organism. As an undergrad, I was not thinking about my career, I really followed my interests.

I did my first two years in my home town, and I knew I wanted to keep on doing molecular genetics. But they were not specialized in that in my home town, so I applied to a lot of places in France and I ended up in Paris to do molecular genetics. Then I was: “okay, what am I going to do with that?” I started knocking at different researchers’ doors and asking, “can I have an internship with you?” I did a lot of different internships, one was programming to model the way odor molecules would be perceived. It was a laboratory working on chemoperception in the bee. I did another internship in a lab that was working on fungi that were living super long, looking at longevity in these fungi. An internship at the institute of Marie-Curie, looking at basic DNA sequences that were involved in colon cancer. That was really enzymatic work. An internship on fatty acid metabolism in yeast. One in developmental genes in the fly. Finally, I settled on the fly model. The first time I encountered the fly model I though, “oh that’s so cool, we can do so many things in one animal.” Then I heard a talk from that young guy who was coming back from a postdoc and I was completely enticed. I was thought, “oh, that’s what I want to do, looking at the brain and how it functions, learning and memory, neurosciences!”

So, because I did not know what I wanted to do for a career, I took every single opportunity that was given to me in grad school, at Caltech, at UCLA, to attend any brown bag lunch, any career oriented stuff – I did not only apply to PhD’s, I also applied to Masters in gerontology, in bioinformatics – I applied to tons of places thinking, “I’ll see once I have a choice, what to do.” I was lucky because I was taken in most of the places I applied to but then I had to figure out, “okay what do I want to do?” During my grad school, my PhD, there was a PhD Graduate students Association, and at some point, I did a workshop of three days to see how I could apply my PhD skills to the industry. I always kept an eye on the alternatives, I never wanted to feel stuck. I always wanted to have a choice, which is why I think that each time I went back to academia to do research – so I went to Cedar-Sinai and then I went back and then I went to a teaching university, and here I’m doing research again – I know it’s a choice, I know it’s a luck, I know there are other options out there for me, so I don’t feel trapped. After Caltech, I applied to that position to be a scientist at Cedar-Sinai, but I also applied to be a Bioinformatician at Wormbase, which is a database of the genome and publications in the worm. I got the job at both places and I was wondering what would be the career options in either places and I went to the medical centre.

Q: Hm, maybe let’s ask some fun questions. What’s something on your bucket list?

A: I’d love to travel to Africa. Part of my family in France lived in Algeria and my mom was born in Brazaville. In France, you have a lot of African culture that’s present because of the French colonies. So, I’ve always been very curious.

Q: Is there anyway you could find a reason to visit Africa?

A: So, there are different ways. I could become a chaperone on some of the trips that some of our faculty are taking in Africa. But I would wait until my kids are older to do that, now they’re young. I could also, I don’t know, think that I need to find an African fly, but the problem is that they can be shipped. I think I’ll have to do it for tourism at some point. I would like to go specifically in West Africa or Northern Africa, so Algeria and going down. Maybe Egypt. Well so that’s one thing, travelling there and that has nothing to do with research.

Q: If you’re not travelling, what’s your favourite place on campus?

A: My office. I find it very calm. I find the campus very pretty. I like walking through, sometimes I come by bus and I stop at Sarnia and Wonderland and I take different paths to come. I like that little garden in front of the police station. Let me show you on the map, it’s very pretty. So, I’ve been there just sitting and eating and laying down on the bench, it’s very pretty. It’s a little garden, I forget its name. It’s very pretty and calm. Now I find it is a very nice campus. There, the “Beryl Ivey Garden.” So that’s a place I like during the summer because it’s so calm. It’s calm during the winter as well but it’s too cold. The bridges are also very nice. In the winter, they are lovely. You see all the snow and frozen part of the river is very pretty.

I like the grad club too. That’s where faculty go. Sometimes you have undergrad, nobody prevents you from going there. It’s in the Middlesex College, in the basement. In the summer, you have a place that’s outside with a little patio. A lot of faculty just go and hangout there. Especially people from Science because all the science buildings are close. You can see your colleagues. I like the coffee there.

Q: So, undergrads can sneak in?

A: Yeah, because I go there sometimes with my team. During the summer, we have our lab meetings there, we have coffee in the morning and anybody can go there. You can’t use your campus card. It’s a club so you can warm up your lunch and you don’t have to buy food there. Just go and put things in the microwave and be with your colleagues and friends. So, there we celebrate when students have graduated. They have the Goblet of Knowledge in which you can have the drink of your choice if you graduate.

 

Dr. Anne Simon studies the genetics of social behaviour at Western University. Read more about her research here.

Interviewers: Dorisa Meng & Tyler Lue