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Genome Giants: Stephen Scherer, Director, The Centre for Applied Genomics, SickKids

Stephen Scherer is a Canadian scientist who founded Canada’s first human genome centre, the Centre for Applied Genomics (TCAG) at the Hospital for Sick Children, alongside Professor Lap-chee Tsui. He continues to serve as Director of TCAG as well as the Chief of Research at SickKids. Scherer has made significant contributions to our understanding of genetic variation, particularly copy number variation. He has also led studies exploring disease-susceptibility genes in autism spectrum disorder.

Please note the transcript has been edited for brevity and clarity.

FLG: Hello everyone and welcome to the latest Genome Giants interview. Today, we’re going to be joined by Canadian scientist Stephen Scherer. So, before we get stuck in and look at your career, Stephen, if you could just introduce yourself and tell everyone a little about what you do as well.

Steve: Yes, I’m Steve Scherer, and I’m the Chief of Research at the Hospital for Sick Children (SickKids) and a Professor of Medicine at the University of Toronto. I’ve directed the Human Genome Centre here at SickKids, called The Centre for Applied Genomics, for the better part of 20 years now. I am formally a PhD trained genome scientist, and probably the first of the generation of scientists that would dub themselves as genome scientists.

FLG: If we just take it back to the beginning, you were born in Windsor in Canada. What were some of your fondest memories growing up? And what were you like as a child as well?

Steve: Well, for those of you who don’t know, Windsor is right across the border from Detroit, Michigan, United States. It’s the automotive capital of Canada, just like Detroit is of the world arguably. So, it’s a very blue-collar town, a very humble upbringing. I had three brothers, my parents were working class, we had a completely carefree childhood. I was a second born son, spent much of my time trying to play catch up with my brother and overtake him. I often joke in my presentations to my students about the contributions of nature vs nurture, so genetics and the environment, that the most important event in my life was probably being born second in a family of four boys., My environment was to work hard and try to catch up with my older brother and also beat up my two younger brothers. We lived at the edge of a park, and we spent all of our time outside exploring, playing sports. It was just a great childhood. That was really the major influence in my life.

FLG: When did you first strike up an interest in science?

Steve: Yeah, this is really interesting, because as I said, most people in my high school would not have even thought about going to university, their parents worked in the factories and things. I thought when I was going to high school, I knew you could be a doctor, you could be a lawyer, or you could have some type of a trade or something like that. But I didn’t even know that this thing called science existed. For me, it was in grade 11. We got to select one book in grade level biology and the book that I found in the library, probably because it was the one where there were 10 copies, was James Watson’s, The Double Helix, which is a description from his viewpoint of the discovery of the structure of DNA. That really captured my attention. And it was the major reason. My grade level biology teacher also was outstanding. I think he caught that I had a special talent in looking at things from a different point of view and encouraged me. Then, I took science courses in grade 12 and 13 and right into university. But it was reading that book, that first exposure to some biology. It was the first time I thought about it in a molecular way – life made sense to me.

FLG: You completed your science degree at the University of Waterloo. What was your time like here? And what made you want to select biology and chemistry?

Steve: Yeah, so for those who don’t know, University of Waterloo would be the equivalent of MIT in the United States. It’s very technology heavy, it’s an outstanding teaching school, engineering, math, science. They have a cooperative education programme there. So, you typically go to school for four months, and then work in your discipline for four months. So, your undergraduate is five years, because you’re spending a lot of time in the workforce. And for me, I had to do it because I wanted to go away to university, and I had to pay for myself. I had to work. But at the same time, also having a very practical background, I wanted to have a job when I graduated. I really didn’t know anything about this endeavour called science. I didn’t know when I went to school, you could do a thing called a PhD. I really didn’t know what that was until maybe second year of university. So yeah, it was for practical reasons.

We went around and looked at several different schools and you can apply in our province in Canada for three at a time. So, I applied to the three that I wanted to go to, and Waterloo was one. I got into this co-op programme. This is the reason I went there. I was very, very fortunate. I had six work terms, all in different areas, that were just outstanding. The first was at Agriculture Canada, it was outside of Windsor, Ontario. I got really lucky and had my first two jobs there where I worked on virus genetics, virology of plants. So, I was working with viral DNA and RNA back when I was 17/18 years old, this was really unbelievable. This will be a theme that comes up in my answers to your questions is to try to expose young students to things as early as possible. Then, I got a job with the Royal Canadian Mounted Police, that’s the equivalent of the FBI in Canada, and I was in Halifax on the East Coast. I was involved in setting up the first statistics for DNA testing in Canada, this was in 1985. So again, exposed to just an incredible environment. To top it all off, my last few work terms were in Ottawa at the National Research Council (NRC), which is really the top place for certainly the physical sciences and in Canada after the war when funding was set up it was first founded out of the National Research Council at the Sussex Drive laboratories, which are still there in Ottawa. For people in Canada, they’ll know what this is, this is a big thing. I got to work with a group there, which was a leading-edge molecular biology group which grew out of the era of DNA synthesis. Michael Smith, Canadian Nobel Prize winner, he wasn’t there, but many of the influences came from there. And earlier, in physical chemistry, there were many advances there, including Gerhard Hertzberg, who eventually won the Nobel Prize and many of the subsequent Nobel Prize winners in physics came out of that laboratory. The director was E.W.R Steacie and I didn’t get to meet him, but I learned a lot about him at the time I was there. Later on in my career, I was so honoured as I won the Steacie prize and delivered my award address at the NRC lab.

A lot goes back to the history of the people I met there. I was a summer student in third year, and I remember there was a group of us who worked very hard, but we played really hard too. Professor Hertzberg, the Nobel Prize winner at the time, came up when we were laying on the lawn outside on the Ottawa River. He came up to two of us and we had a rough night the night before. He said, ‘You guys need to be working harder if you’re going to be successful in science’. In other words, ‘Get back to work!’ He actually kicked me; I loved it). So, it was meeting these giants of science early on in my career that really had a positive influence and understanding the history was very important.

FLG: You had such a broad experience and exposure to different areas. How do you feel this shaped your career?

Steve: Yeah, that’s exactly how it was, always looking for a new challenge and very curious. I was offered to stay in Ottawa to do my PhD. And it wasn’t going to be enough for me, I really wanted to work in medical research. And the work they were doing in Ottawa was more physical. So, I went to the University of Toronto and interviewed and there’s a whole story behind this, we often joke, I didn’t get in until really late in the summer before I started in September. I think I got accepted in June or so because they lost my application three times. Maybe they were intentionally losing because it wasn’t that strong! I don’t know. But since that time, a few years back, I became a distinguished university professor at the University of Toronto, this is the top ranking they only give a few out. In my acceptance speech, I made reference to that. That it was great to win this distinguished honour, but you lost my application!

They again have a great system where you have to rotate through different laboratories before there’s a mutual agreement of the one you’re going to do your dissertation research in. I had heard about this place called the Hospital for Sick Children. Of course, they had these ads on TV, and it was really seen with the Steacie Institute at the NRC. To be the top place in Canada. I thought ‘There’s no way they’re going to take me’. I went to a lecture there in September, and Ron Worton, who is the Head of Genetics at SickKids, he’ll be known to many of you as one of the individuals who discovered the Duchenne muscular dystrophy gene in 1985/1986, it was also found by Lou Kunkel’s laboratory in Boston. And Ron just came back from what was really the first Human Genome Project organisational meeting, you’ll see the pictures of the old group of scientists and Watson was there, and many of the leaders, and Ron was one of the Canadian representatives. He gave an overview and just sitting there and knowing about the double helix and things and I said, ‘This is what I want to do’.

And then, on the way out of that lecture, Lap-Chee Tsui, who turned out to be my PhD supervisor, and of course in 1989, led the discovery of the cystic fibrosis gene. I should say this was 1987. He walked out and he knew who I was – I couldn’t believe it. He cornered me in the hallway. And he said, ‘Why don’t you come and do a rotation in my laboratory?’ and I said, ‘Well, yeah, for sure, this would be great’. Many years after when we became friends, after I got my PhD, I said ‘Remember that day you cornered me, how did you know who I was?’ And he said, ‘Well, in first year I actually looked through all the student applications, I needed someone who had a background in yeast genetics’. And I had done that in Ottawa, in NRC I was doing gene cloning in yeast. Because there was this new technology in 1987 that came out from David Burke and Maynard Olson in Washington, where they were cloning large DNA molecules in yeast. It was really the first primary technology used for mapping chromosomes. And at that time, the cystic fibrosis gene wasn’t identified yet. And Lap-Chee in collaboration with Francis Collins, and Michigan, were developing methods to move faster along chromosomes. So, Lap-Chee said, ‘You have got to come and do this yeast cloning in my lab’. So again, been exposed to this, and one of my heroes and mentors came and talked to me. It was great. So, I ended up at SickKids and I’ve been here ever since. I’ve always looked to try to do my research where I can have the most impact. And this is the place for me that I always have the most impact. And that’s why I’ve stayed for the better part of 30 years now.

FLG: During your time as a researcher, you were involved in studies of mapping human chromosome seven. What was this experience like?  

Steve: Yeah, it’s really important for the students to go back and remember the history of the Human Genome Project. And again, I teach this in my courses, although the amount of time I spend on this history gets less and less. But a message for the younger people is learn the history of science. There’s a lot of great lessons there. I’ll try to bring a few of them up. For me, there were stages of the genome project. One was the gene mapping stage, and there used to be these human gene mapping workshops. There was a chair of each chromosome, and these people would get together with their big binders. There was no internet or anything, literally in suitcases full of papers and they would meet at different places around the world. I remember in London it was 1991 and that was the first one I got to go to.

Like the X chromosome or chromosome seven maybe had 100 genes on them and they would pin them up – they did pin the gene on the chromosome. This was the serious state of the art genomics at the time and then that evolved into the technologies for large DNA cloning and pulse field gel electrophoresis analysis and RFLP genetic mapping. So, each chromosome had teams working on them and in Toronto because the cystic fibrosis gene was on chromosome seven, Tak Mak’s work on the T cell receptor was on chromosome seven, there was work on P-glycoprotein on chromosome seven, we claimed chromosome seven as Canada’s chromosome. We started doing the mapping, building out from the cystic fibrosis locus to be honest. So, Lap-Chee, had found the cystic fibrosis gene and I was a student, and he was famous travelling around. So, I just took over the project as a graduate student. But it was great, I got to go to all these meetings, I was at the very first Human Genome Project meeting at Cold Spring Harbour. Again, it’s very important right through the 90s, it was all mapping based. Then, Jean Weissenback and Eric Lander’s group at MIT started really to lead whole genome type approaches around genetic markers and large-scale fingerprinting and things. And these maps provided the basis to hang the scaffolds of sequences that started to come from Celera’s whole-genome shotgun approach, and even the genome projects clone-based approach, they still needed to have these genetic markers. So, through the 90s, with chromosome seven, we had hundreds of collaborations going and you can see on my CV the number of genes – we had identified more than 20 different disease genes using all of these mapping techniques. So, if someone mapped a gene on chromosome seven, they would typically come and talk to us in Toronto, we would try to help out. So again, just to come back to, it was the exposure, I got to meet these incredible scientists. The best scientists, I would say, of that decade were going into genomics because it was big science, and it was something new and people were curious. And there were some naysayers, of course. But it’s just such an exciting place that I think the best talent wanted to be at the cutting edge and that’s where it was.

FLG: You also made significant contributions to the initial description of copy number variants. Would you be able to expand on this? And what was the response like from the scientific community at that time as well?

Steve: I just started my own laboratory in the late 90s. And we were just finishing the chromosome seven project. And our approach for the chromosome seven was to actually use all available information, as a scientist, you have to do that. You should use all data, the positive and negative data, to try to come to the best conclusions. So, we were using data coming from the public project, data coming from our own sequencing, all the mapping, and we also had access to the Celera sequences. We were collaborating with Craig Venter’s group and combining the data. So, we published not a highly cited paper, but I think it’s a very seminal paper in 2003, that was the first integrated chromosome seven sequence of the genome. And in fact, it’s essentially the approach that people are using now for whole genomes. But there were a lot of lessons learned that came from that paper.

But along the way, we did some very early sequence comparisons, assembly comparisons, of the Celera data, the public data, and there was a lot of overlap in our own data, and we found that there were a lot of inconsistencies. While much of the world was writing off these inconsistencies as mistakes and sequencing or assembly errors, we could start to see, because we were using another technology called chromosome microarrays, that these were likely to be structural changes in chromosomes. They missed the resolution of karyotyping, so smaller variants, and they were larger than what you would see typically using Sanger based dideoxy sequencing. That was in the early 2000s. Really the reason was we were the first lab in Canada to have access to whole-genome microarrays. So, these are the 1 million base pair resolution BAC microarrays. So, there was one clone, roughly every million base pairs spotted on a glass coverslip. There was a company called Spectral Genomics in the United States that made the first microarray slides like this. The scientific aspects were run by a Canadian, Mansoor Mohammed, who I bumped into at a meeting and another scientist who was also a Canadian scientist, Charles Lee, who was in Boston and was using the same arrays. We combined our data, and we could show that we were seeing the same thing because we were using the same technology and there were these unexplainable differences in copy number in a lot of different regions along the chromosome. So, when Charles and I saw our data, we had each done about 25 genomes, and these were expensive experiments to do for a young laboratory. But the reason I could do it was because I had a philanthropic donation from a very wise donor who was supporting our autism research. So, to cut a long story short in the early 2000s, we saw these and the genome project really had missed these dimensional changes because of the result of how the sequences came together. And it was one of these rare events in the history of science again, where the discovery happened at an in between phase. So, most discoveries, if you’re looking at things of size, there’s a continuum, you tend to find something that’s small and then extend out to something that’s big or something that’s big and small. If you think about physics and the universe, for example. Here, because the in between technology, the microarray technology, didn’t exist, karyotyping 60 years ago saw that 0.6% of the population carried chromosome changes, the general population, sequencing largely by the Genome Project, but even earlier, looking at the gene level, found that there was about one nucleotide change in 1,000 or so that was polymorphic. But there was no technology to look in between. There was no technology to find this so of course we were not going to discover this variation. So, because we were the first to do these experiments, certainly in Canada, there were others in the States, and we were very open minded to this. We saw the data first and we discovered it and we combined our data and published it.

Mike Wigler’s group in Cold Spring Harbour were using a different microarray technology that he had co developed and they saw it around the same time using different samples. So, these papers were published in 2004 in Nature Genetics and Science, respectively. It was good they were co published as it helped people believe it. But our paper took well over, from start to finish, 12 months to get through peer review. The peer reviewers just didn’t believe it. I remember spending hours and hours and hours arguing with the editors. I remember one August afternoon at our cottage (pre Zoom) arguing with Nature Genetics and doing multiple experiments. And Charles’ lab in Boston were doing the same and getting more data. And then making presentations, even to the people here in Toronto, I knew how important this was we developed a database for structural variants. And I said we have to start looking in mice, we have to start looking in rats, it’s going to be there. Nobody believed it. The clinical lab didn’t believe it. My PhD supervisor, Lap-Chee Tsui just left at that time to go to Hong Kong to be the president of the University of Hong Kong, he believed it. In fact, he pointed out to me, ‘I told you that already many years ago, you just didn’t listen to me’. And he was actually right. But we had the technology, and it was the open-minded aspect of science. Just to reinforce, now we know when you do whole-genome sequencing, copy number variation in the context of structural variation, it’s the major form. You see roughly 30 million base pairs of heterogeneity compared to the reference per genome compared to the 3.2 million SNPs. So, this is a major player in genetic variation. And it’s like anything early on, it’s hard for people to believe.

FLG: You’ve since gone on to discover loads of disease- associated copy number variants. What is the significance of these findings, particularly your work related to autism spectrum disorder?

Steve: It was really in parallel. I mentioned how expensive it was to do these chromosome microarray experiments in the early 2000s. I remember the first batch of arrays we bought, it was upwards of $2,500 an experiment and it wasn’t unusual for us to be running $50,000 experiments in a week. And most of them failed. So, for young scientists to hedge this, a new lab, we were very well funded in Canadian standards, but like nobody could have afforded this. So, we were actually running mainly samples from individuals with autism, because they had funding also to do that. And if you look in the 2004 Nature Genetics paper we explained that some of the samples were from people with autism. And what we found was that there was a higher rate of CNVs both de novo and rare inherited in people with autism compared to general population controls. We were also doing our own study; we were studying about 400 families from Canada. We published that in 2008. But we were also part of The International Autism Genome Project that was using more of a linkage and genetic marker approach through the late 1990s and early 2000s. But in fact, they were based on Affymetrix microarrays, and we could call CNVs from those too. So, in 2007, as a consortium, with our group leading a lot of the CNV work, we found a lot of de novo variants. We studied 1,600 families across the world, this was unbelievable. We found roughly, I think it was 7% of the families compared to the 1% in controls had these de novo changes, and they often hit the same genes and these genes were involved in synapse development and communication. So, that was the first really entry point, looking at mass rare variants in a particular disorder. We’ve collected now as a consortium here in Canada and across North America, well over 4,000 families, and we’ve replicated this using higher resolution technologies.

In fact, it’s interesting that CNV is playing a major role in many neurodevelopmental gene disorders modelled after this early work in autism, many other studies of schizophrenia, and others have found similar things. The reason is, is that 70% of our genes are expressed in brain development. And brain genes tend to be much longer with lots of different isoforms. And I think the reason CNVs have such a role is you need to knock out a lot of the different isoforms. Otherwise, if you have a point mutation, you can skip over that exon and still get some form of functional protein. But the CNV is bigger and may knock out the entire gene, the entire locus or multiple exons. I think that’s probably the reason.

FLG: How is this work being translated into the clinic? And how is it informing management of this condition as well?

Steve: We’ve been very well funded and supported by Autism Speaks, which is an international organisation. But we’ve also been supported by the United States and Canada and philanthropic donors and granting agencies to successfully use the different higher resolution technologies from high resolution microarrays, we pretty much skipped over exome sequencing, we moved into whole genome sequencing. We knew we had to have all classes of variants, and in particular, structural variants for autism. So, we started that in 2012. It was pre all these other projects you’ve heard about. We were paying like $7,500 a genome. I spent most of my time fundraising. But anyway, so now we’ve collected over 4,000 families across Canada, there’s more across North America. But you know, I say Canadian because we’ve enrolled these families, all the clinicians know the families, we communicate with them in regular workshops and we ask them the question you just asked me, ‘Why should we do this research?’ And the answer from the families was, ‘We want to know why – why did autism come about in my child or my brother or sister? We want to know what we can do to help in the research? What do we do now with this information?’

So, to cut a long story short, for roughly 20% of the families, we can start to answer those questions. If we do a whole genome sequence, there’s roughly 100 different genes or CNVs, that are identified through worldwide efforts that are clinically signed out as being involved in autism or the related medical complications. And in many cases, the information used is a confirmatory diagnosis to explain that it’s genetics and nothing to do with the environment or the vaccines that you took or what you did or didn’t do during your pregnancy. Often that can also inform on genetic counselling for family planning or older siblings, for example, on likelihoods. We’re starting to see now for some of these very highly penetrant genes, like synaptic scaffolding protein three or SCN2A (sodium channel gene), there’s a genotype-phenotype correlation, which may inform on things like anti-epileptics. Epilepsy is a big player in autism – 50% of autistic individuals have seizures and anxieties and things. We’re starting to see that it’s influencing medications that exist. But for autism there’s actually no medication. There are behavioural therapies, but there’s no medicines to treat the core features of autism. So most importantly, I think is we’ve identified pathways now. We have answers for maybe 20% but the other 80% is much more complex, very heterogenous. We’ve got good pathways now, lots of great animal models, cell-based models, and many biotech and pharma companies are interested in this again. There are actually some new drugs going through clinical trials on the patients that we’ve done the genetics, and this is relatively new. So, I was very fortunate to be in the lab, as I said earlier, in 1989, where the cystic fibrosis gene was identified. And I don’t think any of us could have really predicted it. Everyone wrote it in the grants – in the first period, you get the gene, you’ll get diagnostics, of course, that’s immediate. But then there’ll be medicines, and now for cystic fibrosis there are effective medicines for specific mutations. So, predicting that same outcome for autism, absolutely, it will come, it’ll come faster. I don’t know when. But it’ll come probably in the next decade.

FLG: That’s exciting.

Steve: Very exciting. It’s incredible. It’s really incredible.

FLG: It would be good to discuss some of the contributions that you have made to genomics within Canada. One of these is founding the Centre for Applied Genomics at the Hospital for Sick Children. What was this journey like and what are some of the significant contributions that this Centre has made in the field of genomics?

Steve: Well, yes, for me, it was in necessity. We were always developing the technologies, I talked about large cloning and then eventually moved into sequencing. Early on, it was co-developing and taking other ideas and making them better. Then, when it came to sequencing, these were things developed in industry that we implemented, but then made them better for our own circumstances and more efficient. The most important advice I can give to young trainees is, you need to be close to the technology so you can see the data for the first time. Now, in a genome centre you need to be in the genome centre so you can see the data coming off the machines for the first time. It’s relatively easy to make a discovery, if you’re the first to see the data and you have some good ideas. So that was really the reason we did it.

And in the Canadian scheme, for us, many of these technologies were very high throughput and we didn’t have the funding to run them at full capacity in our own labs. So, we opened it up. And the model was we ran a service laboratory, where my lab was the biggest user. And this has been consistent. We support well over 800 different laboratories. In some cases, there could be 10 different people in the lab using it. That’s how the Canadian funding system has also developed around putting infrastructure in place, there’s the Canada Foundation for Innovation then Genome Canada. So, it was out of necessity to get the data, and also to keep the machines running and be able to pay for the whole thing, and it worked.

And then what we did, just more recently, around five years ago, is we linked the three major sequencing centres in Canada. So, McGill Genome Centre led by Mark Lathrop, the Vancouver Centre led by Stephen Jones and Marco Marra at the BC Cancer Agency and then our Centre here at SickKids. We are linked together through this Canada Foundation for Innovation major science innovation grant called CGEn. And now we have this big infrastructure grant. And we work together, and we share samples and data and things. It’s really quite spectacular. So again, you have to figure out how to make it work in your own environment. I think that’s going to be a theme of genomics globally going worldwide. The power of genomics is global, it’s the study of the human population, or any other population (animal species). I actually think the key discoveries are going to come from studying these unique populations now. So, other countries, other groups that are starting out, you have a chance, you have to do it your way that’s going work for you. And again, look back at the history of other projects, I think there’s a lot of lessons to be learned.

FLG: Alongside your colleagues, you also launched the Personal Genome Project Canada, in 2012. What was it like launching this project and what’s the significance of this project as well?

Steve: Yeah, so a little bit of history again, my kids get to hear this at home, and they just walk out of the room. But the story was, we were working with Craig Venter’s group after he left Celera and started his own institute, they were doing his genome. A lot of the data was the Celera data, but they enhanced it and published his own genome in 2007. It’s probably still the best reference sequence to be honest, but it was based on Sanger sequencing. And because of our work on CNVs, and the previous chromosome seven collaboration, he had asked our group to do the CNV annotation and medical interpretation with their group. So, we got to see first-hand what the impact of having a “full” diploid genome sequence was. So, this was through 2000 up to 2007.

And then, George Church had started his project in the United States called the Personal Genome Project, where the idea was that the genome is a composite of our humanity, it is your genome, but it should be shared, why don’t we just put them all out there as long as you consent to do that. And George and his wife, Ting Wu, and his daughter came to Toronto and gave a talk. I remember saying, ‘We should do the same in Canada’. And so, they provided their consents, we “Canadianised” them and developed a project that went in parallel. It was really, really important and the motivation for the project, I was funding this off philanthropic donations we had, was to really learn all of the lessons that we needed for things like the Autism Genome Project and cancer projects later on. Because consenting here is different than in the United States. Healthcare is administered provincially, not nationally, there are all kinds of nuances, and every country is going to be different. We wanted to learn all these things and we also didn’t have a genetic non-discrimination act at the time. So, we had to learn how to develop a consent for patients, we had to figure out the technologies – at the time it was still $10,000 a genome using Solexa and the data wasn’t that good, etc. We wanted to check all the boxes and learn each step along the way. That was the project. And we did that. So, in the end, we had very ambitious goals and a national paper in Canada ran ads, we had thousands of people register, we enrolled through a private healthcare clinic here, called Medcan, which were incredible collaborators. We did the sequencing, fully consented, it is the most open release I think anywhere. You can go to the website now, click on the data and download it, you don’t have to go through any data access committee or anything. It’s all been consented this way. But it was tough to do a lot. We didn’t do as many samples that I would have liked. But the most important thing is we primed the system here and I think shared our data and our experiences. And when Canada matured to the point where it needed a genetic non-discrimination act, we were able to provide the data that ‘We’ve got this out there and it’s not that harmful. In fact, no one has had any problems so far’. And because we had these experiences, when the legislators and politicians and government agencies were putting this bill together, we could provide the scientific support for it and brought the Canadian community on side. It was really that event that pushed this bill across the threshold. So, we now have a very comprehensive bill and in large part I would say was built on the experiences of the Personal Genome Project. So, it’s one of those things that I’m really proud we did it at the time, but I could see there would be an endpoint. And now looking back, it was really the fact that it helped get this bill passed and led to legislation in Canada. So, we continue the project, but we go deep, we go small and deep. We are really doing a few samples and a lot of genetic counselling. I should say that we published our first paper in 2018 in the Canadian Medical Association Journal. And we published it in the Canadian Journal because we wanted to have impact in the Canadian system, and it was amazing because they used to still print the journal back then, they don’t do anymore. But that articles on the cover. It landed in I think it was 40,000 doctors’ offices the next day. And in the old days, you would get all your information sitting, both the patient and the doctor, sitting in the doctor’s office. And they learned about genomics through this paper. And it was on the cover of all the newspapers, and I don’t think anything had more of an impact, maybe COVID now, educating Canadians on the impact of genomics. Even though it’s only been cited a few dozen times. And so, we continue that. But all of our consents later coming from the Autism Project, and many other Canadian projects, in part were built on that initial project, which built on George Church’s project. So, it was a great example of collaboration.

FLG: Were there any major missteps in your career that you learned from and helped you?

Steve: We wrote a paper, just recently came out in Human Molecular Genetics, it was the 30th anniversary of that journal. I was thinking I am going to write something a little bit unique. And it was essentially the lecture I give to the first-year genetics students is, when you’re doing any experiment, you don’t want to rely on one data source, especially if you’re going genome wide. I learned early in my experience, if you just use one technology to look at anything, you’re probably going to get the wrong answer, or not a complete answer. So, I always lecture that you need to have at least two technologies. And this plays larger into life as you need to always have a plan, you need to have a backup plan or a way in and a way out. And so that’s my major advice. I was able to learn that early on. It was really through success, but more so failure. If you do 1,000 experiments, and you’re really at the cutting edge, probably about 995 of them should actually fail. And that’s what I tell my students. Genomics has kind of normalised everything, a lot of the experiments work because it’s high throughput technology now, it wasn’t always that way. So, it’s good to fail, as long as you can extract something interesting out of the data. And that’s really been the foundation for most of our discoveries, looking at outlier data.

There wouldn’t be anything I would do different. I’ve been very fortunate. I think challenge yourselves and don’t just take the normal route. This is the most exciting time in biology even more so than the early stages of my career. You can read, write and edit genomes, and essentially, you’re only limited by your own creativity, and the ethics boards that you need to work through to make sure the experiments are socially acceptable. But it’s been a great career so far and I hope to have another leg in it.

FLG: Outside of your career, what do you like to do in your spare time?

Steve: That’s evolved over my different decades of my life. I was very athletic as my earlier years playing highly competitive to the national level in hockey and baseball. And then I went to graduate school, I threw my competitiveness into that and biking and things. Now, I have two high school aged children, so I guess that would be my hobby. We have a cottage in Northern Ontario, so kayaking and fishing and like every good geneticist, usually after they retire, but I am an avid gardener. Many of my peers, they say ‘What?!’ It’s the one thing I can go out and do and relax. That’s where I get all my new ideas. And I say, ‘If you do a good job, your plants actually listen to you and most people at work don’t listen to you’.

FLG: That’s funny. If you could turn your career into a book or a film, what would you name the title?

Steve: I think probably something like Bruce Springsteen’s Never Surrender. And you really can’t, you can’t give up if you have an idea. You’ll hear this over and over and over again from scientists. You have an idea – it’s usually right, you just have to figure out how to make it right or how to get to that point. And that’s the characteristic of being a scientist, in particular genome scientists, I would say in this era you just have to stick to your ideas and go, go, go! And eventually it’ll work and sometimes it may take decades, but it’ll work, so that’s why I would pick never surrender.

FLG: I like that! Thank you so much for talking to me today, Stephen. The work that you do to propel genomics in Canada is so amazing and I’m excited to see how it evolves as well. So, thank you very much.

Steve: Thank you very much.