On the Mic with Mike #9: Dr. Michael Hendricks discusses the wonder worm C. elegans

Dr. Mike Strong: Well, welcome to this episode of On the Mic with Mike. Today we're at McGill University here in Montreal, and we're actually in the faculty club. They’ve got some amazing artwork and things on the walls here. The history is just immense. What we're going to be doing today is we're never having a conversation with Michael Hendricks. Michael's a researcher here at McGill. He's been doing some fascinating work on something called C elegans. He's going explain a little about that to what we're actually what he's actually doing with it. But it's just an amazing career and an incredible level of excitement about being a scientist. So please join me. We're about to head into that conversation as we speak.

So welcome to this episode of On the Mic with Mike. I'm here with Michael Hendricks. We're going be talking today a little bit about his career and how it's moved forward. But first we're in this really unique room. It’s the Maude Abbott room here at McGill University. You know a little bit about this.

Dr. Michael Hendricks: Yes. Maude Abbott was a heart disease researcher, and she was one of the first women to get a bachelor's degree from McGill. She was eventually a member of the faculty in medicine. So she was honoured with this room. It has all kinds of moulding.

Dr. Strong: It really is quite impressive. There's a little story about her sneaking into the men's dining area.

Dr. Hendricks: Yes. She was one of the first women to be allowed to become a member of the faculty club. But they were segregated for a long time after that. That was in the 1930’s. It wasn't until the 1970’s when it was actually desegregated that men and women could spend time in the same part of the club together.

Dr. Strong: That's kind of a cool story. Anyway, I'm here to interview you, and have a little bit of a conversation there. So you have a really interesting background history as to how you got into science.

Dr. Hendricks: It’s kind of a torturous route. I grew up interested in science, and with science around me, because my dad was a scientist. He was in psychopharmacology. In a way, I ended up somewhere in the same general vicinity as him, but I was not particularly interested in science starting my undergraduate degree. I particularly didn’t like biology, because I didn't like biology at all in high school.

Dr. Strong: OK - and yet you're dealing with worms.

Dr. Hendricks: I’m dealing with worms now. But biology was not my thing. I liked physics. I liked math. But when I started university, I wanted to be an English major with a music minor.

Dr. Strong: OK.

Dr. Hendricks: It's interesting because I was just thinking about this. My dad passed away a few years ago, and around then a few people said: “your dad is the reason I became a scientist, and I really wanted to get into science after taking a class with him.” I lived with him for 18 years, and I didn't want to be a scientist. So something failed to rub off on me there.

But I took a biology class. You know how you have to pick a class in the sciences? I took a biology class for non-science majors that I really loved because we went on field trips all over Maine, and I was going to school in Maine. We went up the coast and we went into the parks and stuff ,and I decided to give biology a try after that. When I took a class in developmental biology, that really hooked me. I loved it.

Dr. Strong: All right. How so? Was there something seminal in terms of a lecturer? Or was it just the whole field?

Dr. Hendricks: I had a great teacher. I think his name was Keri Phillips. He’s since retired. But it was the field, and it was this idea of the sort of self-generating nature of development and self-organizing principles of the embryo. How do you create these sort of oriented axes and acquire sulfates? Over time and in space, I thought it was a fascinating problem.

Dr. Strong: Now that really sounds like somebody who does work on C. elegans, right?

Dr. Hendricks: Yes.

Dr. Strong: OK - which is worms for those who don't know. It’s one of the most amazing tools that have come along in developmental biology. Were you before or after that discovery?

Dr. Hendricks: I was an undergraduate before the whole RNA revolution. It was more in the late-90’s or right around that time that Victor Ambros and Kerry Rabkin were doing that work. Mike – you do microRNA work. So you know.

Dr. Strong: Right. C. elegans were more important because it actually allowed us to track cell fate.

Dr. Hendricks: Exactly. That led to the hetero chronic genes, which turned out to be some of the first microRNAs. It also to a lot of programmed cell depth pathways, which it became very interesting in terms of immunotherapy and things like that as well.

Dr. Strong: I struggle when I'm talking to friends. When I say: “what do you use as an animal model in your lab?”, I talk about flies. That leads to the usual tirade of jokes about how do you feed them and all the rest of that. But then to try and explain to them how such a simple model tells us so much. So when people ask you about C. elegans, they don't say C. elegans. They must say you work with worms. So how do you explain how it is teaching us so much?

Dr. Hendricks: You have to be careful. It's kind of a conversation ender.

Dr. Strong: Yes, it can be.

Dr. Hendricks: I think what has made C. elegans so powerful - and it’s why it was chosen by Sidney Brenner - was this idea that you could enumerate all the parts. You could sequence the genome, and track the entire cell lineage. It’s that stereotype in development and in anatomy that makes it a very powerful system to detect differences in genetic differences or environmental configurations. So if you know that the cells are always supposed to divide in exactly the same pattern and acquire the same fates, you can at very high resolution look for problems when that when that happens. So in terms of developmental genetic control, it's extremely precise.

Dr. Strong: And this can be genetically modified?

Dr. Hendricks: A lot of these developmental genes are involved in the timing of cell divisions or the acquisition of fate in various well-defined tissues. If you look at certain parts of the worm, you know an organ is composed of 18 cells that always originate in the same way, and then you can watch under a light microscope and see when that goes wrong. So that’s incredible.

Dr. Strong: How do you link that to your psychopharmacology interest?

Dr. Hendricks: I came into C. elegans not as a developmental biologist. Actually, what happened was I love the zebrafish. That's what I did my PhD in - axon guidance in zebrafish. It’s a beautiful system because it's a transparent embryo, and you can watch the nerves grow. But what I got interested in doing was the function of the neural circuits and their behaviour. In that case, I thought zebrafish were too complicated. They had too many neurons. They’re too fast, and they twitch around. Worms have 300 neurons, and they’re always connected to each other in the same way. So it’s the only animal where we have the whole wiring diagram of the nervous system. All of its behaviors are slow - it crawls around and it follows suit. So these questions are really tractable. You can go in, associate the activity of individual neurons, and their connections with behavior much more easily than you can in a vertebrate animal.

Dr. Strong: So are worms sentient beings?

Dr. Hendricks: I'm a ‘no’ on that. But I went to a summer school where I gave some lectures a couple of summers ago about animal sentience. The point of the school is to sort of run the whole possible spectrum of views on the subject. There were people there who were arguing for some kind of sentience. But it's an interesting question, because I think what they do have is something that all animals almost have to have to be a behaving organism, which is systems for self-monitoring. I think this is becoming widely viewed as universal. Any kind of perception we do has to be integrated with our ongoing movements and behaviour. We have to know what stimuli that we're sensing are resulting from our own behaviour versus what's coming from the outside world. My favourite example of this is that I can't tickle myself because when I move my hand, I'm already expecting it. But someone else can tickle me. That's the difference between re-afference and ex-afference. What's interesting about that is that people with schizophrenia often can tickle themselves. So this relationship between re-afference and ex-afference seems to be a general symptom of schizophrenia. Auditory hallucinations, dissociation, and delusions of control all fall into this failure to distinguish between self-generated and external stimuli.

Dr. Strong: So how do you apply that then into psychopharmacology?

Dr. Hendricks: It’s a good question because schizophrenia is a really hard nut to crack. It seems to involve so many brain systems and no one knows the way in. My pharmacology bona fides aren't there.

But what we do have in the worm are circuits and systems that do that kind of operation. They keep track of the animal's own movement, and allow it to integrate the way it's moving its head with olfactory input. So we can tell which direction the smell is coming from or something like that.

Dr. Strong: All right.

Dr. Hendricks: We think that these kinds of circuits are so fundamental to being an animal, and the systems that support them are so basal, that they're going to be shared across all animals - just like the cell biology. That's an assertion that remains to be proven.

Dr. Strong: Fair enough. Even just talking with you right now, and I obviously did bit of homework on you beforehand, you're a gifted teacher. It would appear to be the perception. You seem to love the explanation of getting to – “…and here's how you understand that.”

Dr. Hendricks: Sure. This is an interesting thing because we always we wring our hands over how we're training graduate students and postdocs and what we're training them for. But we don't train them ever really to teach explicitly. We don't really train them for any part of this job.

Being a PI has nothing to do with being a postdoc or a graduate student. You're just thrown in. I was a little worried because I didn't know if I would like teaching - but I love it. I think part of it is that it keeps you really close to thinking hard about explanations.

Dr. Strong: Do you teach at the undergraduate level or more at the graduate level?

Dr. Hendricks: Mostly undergraduates. I was teaching developmental biology, which I love teaching because it’s my favorite subject. I don't tell people this often, but I've never taken an neuroscience course.

Dr. Strong: The secret is it's pretty easy.

Dr. Hendricks: Yes, but the development is hard. I really love teaching that, but I gave it up to a colleague recently. I teach a couple of neurobiology lab courses where we get study optogenetics and behaviour with fruit fly larvae. There’s an upper level seminar that has graduate students.

Dr. Strong: Do you ever think back to when you did your developmental biology course, and said: “here's something I'm really interested in”? Do you see that amongst individuals in your class?

Dr. Hendricks: I would hope so. I feel like development is such a cool field because it almost encompasses all of biology. Everything that cells can do happens during development – and that also includes our genome. That's what I'm hoping for among students who are interested in med school or physiology. I hope that they can gain an appreciation of development as this unifying biological process. I don't know if I've converted anyone to biology from English or music, but it would be nice.

Dr. Strong: Fair enough. I’ve got to ask you this question because I discovered it in prepping for this chat - you're building your own microscope?

Dr. Hendricks: Yeah - that's my sabbatical project. We do a lot of calcium imaging in worm neurons while they're wiggling their heads around or we’re making them smell things - which is typical stuff. What we want to be able to do is to do it while they’re freely moving, and crawling around. So we're building a little microscope that's small enough that it can sort of track the worm as it moves around on a stage, and image the head so that we get calcium images and stuff like that. It’s been super fun and a lot of learning for me.

For someone like me who's dumb at computers, it used to be that you couldn't do it. But there's so much amazing open source stuff now that allows you to learn how to build an optical train. I built a light source. It’s software that does the closed loop part like sensing the worms movement, and I can use it with my extremely limited coding abilities. It’s really great that all of this stuff exists now.

Dr. Strong: This is a truly nerd question, but I’m going to ask it anyways. So your own light source - how does light influence behaviour?

Dr. Hendricks: That’s a really good question because it's a lot. Two of the biggest tools in neuroscience now our G camp calcium imaging, which is a green fluorescence of blue light, and optic genetics, which is also blue light to depolarize neurons. Worms hate blue light. They can't see, but somehow they hate blue light. This is something that we're not sure why - but it's intrinsically aversive. So we have two kinds of controls. In one we have mutant strains that don't respond to blue light. The other great one is that in some of these optogenetic regions, you have to provide a chemical go factor, all trans-retinal, that's present in mammalian brains but isn't present in vertebrate brains. We have to supplement, and then leave that supplement out. Then any blue light that we see as intrinsic response.

Dr. Strong: That's my nerd question for the day. It sounds like you really love what you do.

Dr. Hendricks: I do - I love worms. I get their limitations, and they're not as pretty as zebrafish.

Dr. Strong: Neither are flies, I can tell you.

Dr. Hendricks: But I think that they have a lot of potential. The history of discovery in that organism is pretty astounding. I think it's because what's true of all animals is true of worms. It's in this simplified package where you can really pick things apart.

Dr. Strong: So if you were sitting here having this conversation with you as an 18-year-old, how would you feel?

Dr. Hendricks: I don't know if I'd be disappointed because I really loved English literature then, and I really loved music. I still love music. But in the first couple of years of undergrad I was taking music theory and history courses, and the English lit canon. I also realized that while I really enjoyed music, and I play music and listen to music, I'm not talented in music. I’m not someone who has a gift.

Dr. Strong: Fair enough. It also sounds like you've been really open to "wait a minute, let's go down this pathway".

Dr. Hendricks: Yeah. Although I don't know if this showed up in your background research, but after my undergrad there was a gap.

Dr. Strong: I wasn't going to go there, but let's go.

Dr. Hendricks: There was a gap where I was kind of a late bloomer. I don't think I was ready for graduate school and starting a career. So I just kind of did stuff, you know? Not academic, not science related. Some friends and I all moved to San Francisco at the same time. It was the 90s. So if you had a bachelor's degree and a pulse, you could get a job.

Dr. Strong: Fair enough.

Dr. Hendricks: I always feel kind of guilty about what graduates face today in terms of career prospects. But it was a fun time for me, and I had interesting jobs. None of them felt like they were pulling me toward like a vocation.

Dr. Strong: It's interesting because when I talk to young students nowadays or to teenagers who are thinking about their career, I look at how quickly they will have been through an undergraduate degree. I worry about so many of them right now who come in and say: “Boy - I'm just going to hammer through all of this.” They’re not really going experience the stuff that we got a chance to experience as undergraduates. So there’s a concept of don't be in a hurry - take some time. If we look at median age of survival anyway, you’ll be around until your mid- 90s. So why the rush?

Dr. Hendricks: Exactly. When I did go back to grad school, I was so much better prepared for it. I could offer the commitment and focus to work on something. I had better quantitative and statistics skills from some of the work I did. I had like a clear self-knowledge about what kind of work made me happy. Without that, I wouldn't have been sure that I was going in the right direction.

Dr. Strong: Do you have any kids?

Dr. Hendricks: No.

Dr. Strong: Okay. Obviously there was the influence of your father. So there was clearly a time where you said: “I'm not going to do this.” But now you're there. How did that conversion happen? It was realized in the past.

Dr. Hendricks: Yeah - it became really interesting because it did become something where we started to talk about science a lot more than we would have before. We were not in the same field, but similar enough that I started going to Society for Neuroscience meetings when he kind of stopped going.

Dr. Strong: Was that when they had 30,000 people and it didn’t work?

Dr. Hendricks: A really nice part of the relationship later was talking about science.

Dr. Strong: Would you do it all over again?

Dr. Kendricks: I don't know. Things worked out great. Even during the lost years, that's when I met my wife. I did some really interesting things in terms of travel and life and music and friends. So it was great.

Dr. Strong: I think I know the answer to this question, but I’m going to ask it anyways. Look ahead. Let's make it 5-10 years. Then also let's make it when you're old, gray, and you're done. You're sitting back and saying “man, I did that right.” So the short term and then the long term…

Dr. Hendricks: So what I think I will do or whether I think I'll be glad?

Dr. Strong: I don't know.

Dr. Hendricks: So near to medium term, I guess it depends on how CIHR success rates go.

Dr. Strong: Fair enough - that I do understand.

Dr. Hendricks: I love having a lab, and I don't have aspirations to have like a huge research group or anything. I feel like it's kind of beyond my capacity to effectively be engaged with and manage that. I've got six people in the lab now. It could even be smaller.

Dr. Strong: Fair enough.

Dr. Hendricks: So I'm really happy with this stage of my career, and I think I’ll just keep things going. I'm not someone who wants to work forever either. I think that when retirement age comes, I’ll be done. There's lots of other stuff. We still like travelling when we can, and seeing other parts of the world. It would also be nice to get back to having hobbies. That's something that was familiar. But from the postdoc to tenure time, everything else falls away because of work.

Dr. Strong: Yes, I do understand because it is that time period of pressure. Your wife's a prof as well, right?

Dr. Hendricks: Yeah. She's in the geography department. She teaches human geography, and she studies new master plan cities in the Middle East and in Southeast Asia.

Dr. Strong: So between the two of you do you an opportunity to do a lot of travelling, and have a look at all of that?

Dr. Hendricks: Yes, a lot of the travelling she does for work is kind of to construction sites in the middle of the desert - so it's a hard pitch in terms of a vacation destination. But she's taken me to the Emirates, to Saudi Arabia, and to parts of Southeast Asia.

Dr. Strong: It sounds like things are going really, really well for you.

Dr. Hendricks: Yeah - we're really happy. You know, we have this hugely long training period in academia. To come out the other side and feel like things are going pretty well, it feels like my shoulders are relaxed for the first time in 10 years.

Dr. Strong: Fair enough. So if you had a chance to go back – this is a question that I ask almost everybody - I don't care what the timeframe was, who would you want to talk to?

Dr. Hendricks: I have a hard time with this question. I was thinking about it because I thought you might ask it. I often find that admiring someone's science, and then finding them interesting as a person can be…

Dr. Strong: … two different things?

Dr. Hendricks: Right. So I would be almost worried to guess that it's going to be a huge disappointment. It's always, you know, don't touch your idols - that kind of thing.

Dr. Strong: Fair enough.

Dr. Hendricks: But there are a lot of really fascinating scientists. Someone who I think is such a fascinating scientist and she would have to be interesting to talk to is Barbara McClintock. Her discovery of transposed study in maize is, I think, the single most astonishing feat of inferential reasoning in 20th century science. From the data she had to go to ‘these are moving around the genome’ is astonishing to me.

Dr. Strong: I know what you're talking about. But for those who don't - what was the fundamental thing about the gene moving around? What's actually happening? It's so unique.

Dr. Hendricks: What's actually happening is sections of the genome, sections of chromosomes and DNA, can be excised and copied or moved to other parts of the genome. This is something like almost like a viral infection for the genome. There’s sort of selfish elements - although it's been coopted to have a function, and in many cases an evolution. But she was studying this in corn, and the readout was all the variegation in kernel colours. These are very beautiful heirloom colours of corn.

So corn is a great system because every kernel is a baby. You get this whole population of offspring in one year. You can see how the genetics are playing out in a single cross. From studying the patterns of inheritance and looking at how these things associated with chromosomes, she guessed that this is what's happening.

Dr. Strong: I’ve got to tell you that it's really cool. I knew of the experiment. That's the first time I've heard it explained that clearly to me. But maybe it's because if you hit me over the head enough, eventually I will understand something. That was really helpful. Listen, Michael, this has been a wonderful conversation. I really appreciate it. I wish you all such a great luck going forward.

Dr. Hendricks: Good luck to you.

Dr. Strong: Well, thank you. So that's it for this episode of On the Mic with Mike - and Michael - on this particular episode. I look forward to chatting with you again. Take care.