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Genome Giants: Stephen F. Kingsmore – President and CEO of Rady Children’s Institute for Genomic Medicine

Stephen F. Kingsmore is the President and CEO of Rady Children’s Institute for Genomic Medicine, where they are pioneering the use of rapid Whole-Genome Sequencing™ for early, accurate diagnoses of critically-ill newborns. Raised in Northern Ireland, Kingsmore moved overseas to the USA during his early career to live out his dream of big science. Since then, Kingsmore has become a key figure in implementing advanced tools into clinical care and currently holds the Guinness World Record for the fastest molecular diagnosis using whole genome sequencing.

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

FLG: Hello, everyone, and hello, Stephen, thank you so much for joining me for the latest Genome Giants as we take a look at the lives and motivations of some of the most influential figures within the genomics field. Today, we are joined by Stephen Kingsmore, a leader in clinical whole-genome sequencing. So, Stephen if you could just introduce yourself and tell us a little bit about what you do.

Stephen: Hello, everybody! I’m Stephen Kingsmore, as you’ve heard, and I’m the president and CEO of Rady Children’s Institute for Genomic Medicine. This is a new research institute, which is focused exclusively on applying genomics to the care of children. We live within one of the largest children’s healthcare systems in the US, Rady Children’s Hospital, and we’re located right on the border between the US and Mexico on the Pacific coast in beautiful San Diego.

FLG: If we go back to where it all began, you were born in in Scotland. What are some of your fondest memories growing up?

Stephen: Yes, I was born in Glasgow – I’m still a Rangers fan! And I realise I just alienated half of the Scotsmen and Scotswomen, but that’s okay. But my family moved to Northern Ireland when I was about four, or four and a half. So, I’ve really got no memories that date back to that time in Glasgow. I have a brother who lives there and so I go back and see him once in a while. But most of my memories relate to Belfast and then Coleraine and then finally Portstewart, the three towns where my dad and mum lived and where I grew up. I had a great grammar school education, went to university in Belfast, and then emigrated to the US at age 27, during the end of the Margaret Thatcher era. So, I was one of those Thatcherite useless people, because I was a physician scientist of no possible value to society in her estimation.

FLG: What was it like growing up in Northern Ireland at that time?

Stephen: Well, it was the troubles. It was the height of the troubles, which started in I guess, 68/67. So, I was seven or eight at the time. And it was definitely not a normal upbringing. It was the only one I knew. There was constant tension. There were bomb alerts, which scored us time off school, which was always good! Coleraine itself, where I spent most of my childhood, is right up in the northeast corner of Northern Ireland – it’s well away from the border. And so, there wasn’t so much trouble there. But when I moved to Belfast to go to medical school – boy, I was right in the middle of it! And it was pretty hairy. There were some upsides, you know, one was that the police did not really bother with speed limits – they had other things to deal with. And so, you could drive like a bat out of hell. And this did not serve me well in life. It worked well in Northern Ireland. But when I came to the United States and was stopped by a police officer within about 24 hours of arrival, and of course, I had my stethoscope around my neck and I expected the usual which was, ‘You’re going a bit fast today, sir’. Instead, I got a ticket. And I remember that lasting impact.

FLG: That’s really funny story! What were you like a child growing up? When did you strike up an interest in science?

Stephen: I was an introvert. I was a nerd from the get-go! I had a grandfather who was a general practitioner, up in Lancashire, and he had an inkling about me. And at age, I guess, 9 or 10, he bought me a chemistry laboratory. Can you believe that? We lived in a manse. My dad was a pastor, and we had one of these massive houses with lots of rooms, none of which you could afford to heat. But one of those got converted into a chemistry lab. So even in primary school, I was an amateur chemist. And when I got into grammar school at age 11, I started to graduate to the types of chemicals you don’t normally sell to an 11-year-old kid, like concentrated sulphuric acid. And so, I had to get scripts from my chemistry teacher, which I could then take to our local pharmacy and buy these chemicals and go back to my lab. So that was the start. So that says something about what I was like back then.

FLG: Had your own little lab going on!

Stephen: I sure did! It was about fourth grade in grammar school before the rest of them caught up to me.

FLG: You did your degrees at Queen’s University in Belfast. What was your experience like here? What did you study during your time here as well?

Stephen: Yeah, so I had wanted to go into medical school from a very young age. I wanted to be a surgeon, I wanted to be like a missionary surgeon, right, that was my early goal. Fortunately, for me, something wonderful happened in my last year in grammar school. I was 17 and I won a scholarship from Marks and Spencer, if you can believe it, to go to the Weizmann Institute of Science in Israel to a summer school and that completely changed my life. I got to spend six weeks there and I worked with a tumour immunologist, Prof. Shraga Segal, who was studying the impact of natural immunity on cancer progression in mouse models, which at the time was bleeding edge. And, to cut a long story short, I used to go there every summer for three months and do a summer science project, and I got to publish that work.

I would come back completely wiped out, just exhausted, from staying up all night doing the research thing. And then would slog my way through medical school, which was like the most boring thing on planet Earth. Because all you did back then, maybe it’s still the same, was just digest thick textbooks and be able to recite them. It was just mind-numbingly boring. And I’ll never forget, I went into the Medical School Dean’s office, I think the third time I was going back to Israel, to see if I could get some sponsorship. And he looked me in the eyes, Dean Roddie in Belfast, and he said, ‘What are you going to do over there, wash test tubes?’. So that was kind of the mindset in British medical schools back then, you know, that we were little revenue items being clicked along the path and had no brain and were not to be encouraged to step outside the box.

FLG: You went from Belfast and moved abroad to the US. What made you want to leave your hometown?

Stephen: I think for the younger generation, you don’t remember how austere academia was back at that time in the Thatcher years. So, universities were seen as an unnecessary luxury for Britain. And as a result, budgets were slashed. And universities were actually selling buildings to pay salaries. And so, the idea of big science, which clearly now Britain is a global leader in, was a completely unfathomable concept. Departments were just struggling to survive! So, my mentor at Queen’s University in Belfast, Prof. Tom McNeil, said, ‘Go West, young man’. I wanted to do big science; I was used to the temple of the Weizmann Institute. And tragically back then, there were really no avenues, at least provincial avenues, to pursue that in the United Kingdom. So, I moved to the US. The other factor, of course, was that I fell in love and wanted to get married, and I grew up Protestant, and my wife Fiona grew up Catholic. And we had that sort of strange situation where we realised, we were likely to get kneecapped, tarred and feathered and firebombed should we stay in Northern Ireland. And that didn’t seem like the best way to start a marriage. And so, we also moved to the US, I guess, as religious refugees.

FLG: Is there anything that you miss from Northern Ireland?

Stephen: Oh, yeah, there’s a tonne! I was actually back last week. So tragically, my father-in-law died just a week ago. My wife and I had to drop everything and get flights. I have got to tell you, flying internationally during COVID is quite an experience. We could go into that for an hour. But anyway, I was over there a week ago. So, I got my Irish breakfast, or British breakfast or English breakfast, whatever you want to call it! But the one with all kinds of things on it that you can’t really buy anywhere else in the world. They’re probably not even classified as foods, which are quite delicious. So yes, I definitely miss that. I also got a good fix of watching Chelsea, in the Champions Cup. So yes, there’s a lot of stuff that you just don’t get to do or participate in as an expat Brit.

FLG: You did your residency and your fellowship at Duke University. What was your time like here? And how did that compare to your experience in Belfast?

Stephen: I had been waiting for a green card for three years. And so, I had been drifting around in the National Health Service, kind of just waiting to get the green card. I hadn’t got a well thought through career progression. I was a 23-year-old guy. Okay, what guy who is 23 has any thought other than – let’s not go there! So anyway, we arrived in the States, I flew over in December to interview. My interview lasted all of about 17 seconds. I was ushered into the Chair of Medicine’s office, a guy called Joe Greenfield with blazing blue eyes. He had those half glasses that kind of sat on his nose, like this. And he was looking at my resumé and he looks up over the top of his glasses, he fixes me with his glacial stare for a full 15 seconds, doesn’t blink and goes, ‘You’ll do’. That was it. So, I arrived there not really knowing how great my landing spot was. And I spent six years at Duke and that’s where I grew the ability to think.

Duke back then (probably still is) was famous for having taken the Hopkins’ mantra to the next level, which is evidence-based medicine – show me the data, you’re not allowed to go home until I have diagnosed you. And this was a huge difference from the National Health Service approach, which was much more functional – ‘when you’re functionally better, we need to get you out, we are trying to minimise your stay, minimise our costs’. In the US, it was the opposite. It was, ‘You have a problem, until we have data and have solved the underpinning problem, the fact that you’re getting better is awesome, but we’re not satisfied’. And that was mind-changing and life-changing.

FLG: Did you find that there was a kind of like a culture shock when you went from Belfast to the US?

Stephen: Oh, yes. They couldn’t understand a word I said! And I couldn’t understand a word they said. Two people separated by a common language. I had to learn a whole new vocabulary. And you know, bear in mind that Durham, North Carolina, is predominantly African American. So, Southern US, South-eastern US, African American. And so, they have their own real strong drawl. And a whole vocabulary. It’s kind of like Cockney, the whole vocabulary of words that, as you know as a young Northern Ireland guy, I had no idea what they were talking about. And so yes, there was huge culture shock. You know, I’d never seen a baseball game in my life. Duke happened to be the best college basketball team in the world back then. And I’d never seen basketball. I took my father-in-law to his first American college football game: Duke versus Clemson. And we were sitting in the stands, and at the end of the game, when Duke won, the fans invaded the pitch, tore up the posts, and then marched off down to the local bar. And my father-in-law looks at me and he goes, ‘They’re quite animated, is it always like that?’. So yeah, huge culture shock, but in an awesome way.

FLG: You must get into all the different sports over there!

Stephen: Things are much more homogenised now. All of the fast foods I used to yearn for are now ubiquitous in Great Britain and I lament the fact that we have globalisation and we’ve lost that individuality. And yes, on Sky TV, you can watch every American football game you want to. Stream them all day and all night. In some ways it’s regrettable, but it does mean if I go back, I don’t miss out on sports.

FLG: What was your early career like? And what challenges, if any, did you face during that time?

Stephen: I arrived at a very propitious moment; it was 1989. And the field of molecular genetics had just been born. So, we were able for the very first time to sequence genes. We did so in very short stretches of about 150 nucleotides. We used gels; it was Fred Sanger’s method with P32. We were able to use restriction fragment length polymorphisms and Southern blots to build genetic maps. And that was it. We were starting a brand-new field, using molecular tools in genetics that had never been done before. Genetics had been the stuff of Mendel. It had been a qualitative science, or quantitative only in terms of breeding experiments. So, an amazing time to jump into that and start to think, boy, we could actually clone a disease gene, can you imagine? Wow, how powerful would that be? And it might only take five years! So, it was a wonderful time to jump into this emerging field. And everything you did was new.

FLG: You served as the CEO and President of the National Centre for Genome Resources. How did this role come about? And what did your role entail?

Stephen: So, I had been in academia, loved it, was successful. Unfortunately, I got really bored, and wanted a new challenge. And at the time, the first commercial genomics revolution was happening, when there were genomic companies. Who would have thought? These companies were springing up to billion-dollar valuations with no product, no revenue, but just a promise of genomics doing stuff. And I found that I couldn’t not do that. So, I jumped up to New Haven, Connecticut, and became the VP of Research at CuraGen Corporation. After I’d been in that life for about 10 years, I got tired of that commercial biotech life, you know, living quarter to quarter on earnings statements. And I no longer fit academia because biotech puts its imprint on you, and you’re used to highly engineered solutions. I was very fortunate to land at NCGR, a little research institute in Santa Fe, New Mexico. Now, they are the organisation, nobody knows this, that spun off a company called Molecular Informatics, which became Celera.

So, you remember back to then, Celera went from an idea by Craig Venter to a fully-fledged organisation. Well, that’s because they bought what was NCGR. So, I arrived after the no compete expired, NCGR could get back into human genomics. And I arrived there right at the time that Jonathan Rothberg produced the first next-generation sequencing platform, the 454 technology. And I had been working with Jonathan at CuraGen and I knew those guys really well. And we took NCGR, which was a bioinformatics research institute. Again, what was that (back then)? And we completely flipped it so that it built the foundational software systems for handling next-generation sequences. And we had a sea of fun. And in particular in agricultural biotechnology applications, sequencing things like cDNA libraries, so expression analysis of all kinds of important crops, to fundamental decoding genomes, all of that stuff. It was, again, a marvellously rich time.

FLG: How did you then go from that role to your role at Mercy Hospital and working in paediatric genomic medicine?

Stephen: We were all sitting around in a conference room in NCGR, you know, having one of those brainstorming sessions. And collectively a group of us realised that genome sequencing was going to completely transform medicine. What we could do in maize or some pathogen, we were going to be able to do for the human genome. If we were going to do that we couldn’t be in a beautiful spot in New Mexico; we had to be inside a hospital. You had to have patient access, you had to have medical record access. Hey, let’s go do that! So, three of us left NCGR and moved to Children’s Mercy Hospital, who were foolish enough to bankroll our crazy idea. And we had a foundational project, we had some entrepreneurs, the Beyond Batten Disease Foundation, who were keen for us to build the world’s first carrier screening test. One of them was a dad who tragically had a child who has Batten disease, a recessive genetic disorder with a bad prognosis. And the idea was a very simple one, if we could test couples prior to conception, we could avoid genetic disease. Well, the idea was flawed. Number one, there are major ethical obstacles. Number two, the bulk of genetic disease is actually dominant, not recessive and de novo (not inherited). Nobody knew that back then. But that project was our entree then to getting into mainstream medical problems. And so, we wound up in a children’s hospital and realised we were surrounded by kids with single locus genetic diseases who had no good options.

FLG: What was your greatest achievement during that time? And what did you learn during experience?

Stephen: Well, the nice thing was, we were applying these biotechnology lessons for the first time in a hospital. So, we were able to set up a little company inside the hospital with some kind of hierarchical structure and team spirit, the idea of multidisciplinary teams. So probably pulling that off was the greatest accomplishment, because it allowed us to do things that were only being done at other such organisations, like the Broad Institute. And so yes, we were in a children’s hospital, but we had this unique structure. So that was the trick. In terms of practical accomplishment, that’s a really easy one. In 2011, we decided, with the help of Illumina, to think about how fast we could decode a human genome. We were able to do it in 48 hours. I remember it vividly. It was in October, it was leading into the general election in the US, and it was the night before a presidential debate. And we were on the front page of the New York Times. And we had no idea what the impact of that would be. But it was a revolutionary idea, which was if you can decode a genome in a day, you have a tool that’s ready for inpatient management, a practical management tool, as opposed to what had been happening before, which was it took months to decode a single genome. And so honestly, its prior clinical relevance was only marginal. It was used for chronic conditions where you needed a diagnostic label. But instead, now we were able to open up genomes into Intensive Care Unit settings with critically ill children.

FLG: You’re now the President and CEO of Rady Children’s Institute for Genomic Medicine. What has it been like for you watching technology advance and how that impacted your work?

Stephen: I was incredibly blessed to wind up at Rady Children’s Hospital. So, Ernest Rady is this incredible Canadian billionaire who has decided he wants to give the vast majority of his money away before he dies. And so, the hospital approached him and said, ‘We think we need a genomics centre, would you please consider giving us $20 million’. And this discussion went on for a period and a business plan was evolved. And at the end of it, Earnest said to them, ‘You’re thinking far too small, I’ll give you $120 million, as long as you match it with $40 million’. So, that was the start of Rady Children’s Institute. And you got to remember that San Diego is kind of unique. In the US, we kind of have three major hubs for biotechnology. We’ve got Boston, the Bay Area, and San Diego. We have 800 biotech companies in San Diego. ThermoFisher is headquartered there, Illumina is headquartered there. So, we have this amazing hospital, Rady Children’s Hospital, embedded within what’s been called the genomics capital of the world. And so, we have this amazing opportunity to do something that has never been done before – create an institute from scratch, post the year 2000, with all of the lessons learned based on the genomics industry, in the world hub for such activity. It’s been a whirlwind over the last six years!

FLG: What has it been like for you working in that kind of setting, where you can see the impact of genomics first-hand?

Stephen: It’s hugely motivating. Every week, we in all likelihood have saved a child’s life. We now have, believe it or not, 70 children’s hospitals, all across North America (so US and Canada), who send us a small blood sample, and a copy of the medical record (or at least part of it) and these are all kids who are critically ill in intensive care units. And in one in three, we diagnose a genetic disease. In two in three, while we cannot rule out the genetic diseases that we’re worried about, at least, we change the posterior probability that they have those. And so, 90% of the time this information has impact on management. And sometimes, like the case we published yesterday in the New England Journal of Medicine, it saves a life. It’s just like – boom – that was a little baby with an encephalopathy, we diagnosed him within 13 and a half hours. He was on the right treatment, which was biotin and vitamin supplements, within three hours of us communicating the diagnosis.

FLG: What research are you focussed on at Rady Children’s Institute for Genomic Medicine trying to improve this area of diagnosis?

Stephen: A couple of things. First of all, we’re trying to do rapid genome sequencing at scale. Our vision is not for this to be for the rich few, or the few who are lucky enough to be in leading academic centres. It’s how do we change paediatric practice, how do we make this true for every child, at least in the first world, and, in some form factor, in the second or third world. And so, we’re thinking always about scalability, scalability, scalability. How do we drop the cost, how do we improve the turnaround time, how do we make this scalable? We’re getting there. It’s realistic now to think about genome sequencing every child with an unknown aetiology of disease who is admitted to a hospital. That’s occurring right now in Wales, it’s going to happen soon in England, it’s happening increasingly in Australia.

And we’re doing our best to have that happen in the US. We’re also able to think about other indications, for example, decoding the genome of every newborn as newborn screening. This is something that will happen over the next five years. Right now, for us, it’s all about scale, scale and more scale. It’s not so much that we still need bleeding edge technologies. No, the technologies we have are awesome. What we now need to do is to educate and engage the entire healthcare workforce so that they are able to catch back up and implement this for their local community. That’s the big gap now. Number one, building the evidence so that commercial payers will reimburse this to make it universally available. And second of all, that we educate practically the frontline physicians, nurses, social workers, genetic counsellors, and so on. So, that they can practice genome-informed medicine routinely, as opposed to being scared to death of it.

FLG: What do you think will need to be done to increase the accessibility of these technologies?

Stephen: In the US, UK and Australia, accessibility is increasing rapidly. For other countries, it’s a matter of education and engagement. Right now, we are focused pretty strongly on South America, because San Diego is right on the border with Mexico. Brazil is a great case in point. There are a number of groups there who want to adopt what we are doing in the Brazilian healthcare system. The form factor will look different, but the intent and the deliverable will be as similar as possible. And so, it’s all about education and engagement and influencing, and then getting alongside them and saying, ‘Here’s all of our protocols, here’s all our methods, here’s the phone number of the guy at Illumina’. And it’s happening! We have a conference once a year called Frontiers in Pediatric Genomic Medicine. We now do it in three languages – English (obviously), Spanish and Portuguese. Why? Because there’s that huge South American population with healthcare systems poised and ready for this. Well, as ready as the US healthcare system is. They just need some help to get it off the ground. Other parts of the world are not so much on target for us but are also catching up, such as the Middle East who are right there. Thanks to time at the Weizmann Institute, I have strong feelings toward Israel who are now doing Project Baby Bambi. Baby Bambi is their exploratory project to prove for the Israeli system that genome sequencing of infants in intensive care units works in their system. So, it’s happening all over the world, and it’s really exciting to participate in it.

FLG: What do you think are some of challenges in trying to get whole genome sequencing into mainstream clinical practice and trying to reduce the time to diagnosis?

Stephen: As I said, technologically, we’re there. We have a 13-and-a-half-hour method, which is pretty much off the shelf. So, the methods are there. There’s still a cost challenge. Basically, you have a choice – you can do a genome for about $500, or you can do a genome in less than a day. The price point is completely different, and one is regulated and clinical, and the other is research. So, cost in clinical settings is still a big number. But having said that, it’s certainly less than the cost of a day in an intensive care unit for a patient. And typically, by diagnosing a patient, you save multiple days in hospital, because a large part of being in an intensive care unit is spent getting to the aetiology. You really need to fix the aetiology in order to truly deliver a critically ill child from illness to health. So, the cost effectiveness needs a bit more evidence.

But we now have study after study showing this. Just this morning we published in the American Journal of Human Genetics the results of project Baby Bear, where we show that in the US system, you will save $20,000 per day if you do a three-day genome within 96 hours of intensive care unit admission. And that’s in Medicaid babies, that’s babies whose insurance bill is paid for by the US government. That’s about 55% of US admissions to intensive care units. So that piece is happening. The other big bit is education and engagement. And this is all the way from policymakers, through the insurance companies, through C suites of hospitals and chief medical officers, through leaders of divisions like neonatology and intensive care medicine, all the way through frontline physicians.

FLG: What are the challenges relating to variant interpretation?

Stephen: There are challenges, but people get themselves all twisted up on this. Whenever you have a marvellous new technology, you don’t expect it to be perfect out of the box. You take what it can do, and you do it, and you scale it to populations, and you don’t lament the fact of what it can’t do. I know a lot of my colleagues get all twisted in their head about variants of uncertain significance, genes of uncertain significance, negative findings, incidental findings – it’s like ‘Grow up guys, okay! These account for 5%, probably less than 5%. Why don’t we focus on scaling the 95% where it does work today?’ And you know what? It gets better every year. We tackle little pieces of the 5%, where the technology is not scalable today, a little bit at a time. So, let’s focus on what works and scaling that rather than focusing on what doesn’t work.

FLG: You hold the Guinness World Record for achieving the fastest molecular diagnosis using whole genome sequencing – what was it like achieving this?

Stephen: It was super fun. We’ve done it twice now. And we tried to do it a third time. And the Guinness guys said, ‘No, we’re kind of sick of doing your world records, go do something else’. I swear last time they said, ‘We don’t want to give you a third one’, because we just broke the record last October. It’s now 13 and a half hours. So now that it’s published, maybe we’ll go back to Guinness and say, ‘Come on, guys!’. Anyways it was a lot of fun. So first of all, I grew up in Northern Ireland, so I like Guinness. So that whole aspect, that works. And then the whole thing, the pageantry of it, is kind of mystical. So, this Guinness guy flies in, he’s got this smile four yards wide and has a special suit and a little presentation thing. If you grew up in the UK, back when I did, it was the McWhirter twins, if you remember those guys, well, they still have guys like that. And they fly in, they present it to you and all this.

It’s actually really exacting; it’s a pain to actually meet the criteria. We had to set up video cameras all night long to video the sequencer, for example. We needed proctors on site to witness that nobody was like wandering into the lab and swapping out the sample. So anyway, it’s a lot of fun. And it’s very cool. Scientists, again, sometimes forget who pays their bills – it’s the public. And there’s this huge need to excite the public about what we do. And so, something like Guinness World Record, people get that, right, they have no idea what we actually did but it’s a Guinness World Record, that’s very cool, talk to me about that. So, it’s opened up a lot of doors with mainstream media, and hopefully influenced a lot of people, because ultimately, it’s parents who make decisions for their children. And the day to talk to them about a genome sequence for their baby is not the day you meet them in the intensive care unit, it’s to have them pre-aware that the genome is good.

FLG: Do you think there will be a time where a child is born and they have their genome sequenced regardless of whether they are critically ill or not? And do you think that should be done? And what are the ethical issues surrounding that?

Stephen: Yeah, that ship has sailed, actually. So, for 60 years, in many countries, maybe nearly all countries, we screen babies at birth for genetic conditions, and it’s mandated by law. So, that ship sailed many, many years ago. It’s just that we don’t do it by genome sequencing; we do it typically by a battery of tests, the best well known of which is mass spectrometry for metabolic conditions. But now we also do it for deafness disorders, and for other things like congenital heart disease and immunodeficiencies by counting T-cell excision circles. So, we do it, it’s just a matter of scale. Up until now, we’ve been able to do it for somewhere between 20 conditions and 70 conditions, depending on where you’re born. With genomes, we can take that number up to 600 or so with identical criteria. You’re only going to screen for it if it’s a really bad disease that has a really effective treatment, right? And in which a delay in treatment results in poor outcome. Where if you navigate the normal route, where your baby becomes sick, and then you see a doctor, and then you advance along the diagnostic odyssey. You don’t have time for that, for these diseases you’d develop organ damage that that would be wrong. So, it’s a very special set of conditions. But with genomes, we can take that number up to about 600.

So, will it happen? Yes, it’s definitely going to happen. Pilots are being planned of this in several healthcare systems. Is it fraught with ethical and legal issues? It is, yes, because newborn screening traditionally had a waiver. You don’t go ask a mum’s permission to do a heel prick on their baby. And so, we have to ask ourselves as a society, if we’re going to broaden this from 20 or so conditions, to 600 or so conditions, what’s the framework for that? And as a society, we will need to make those decisions about what we’re comfortable with and we probably will be quite disparate across the entire planet in how we think that through. But the actual thing itself, newborn screening for genetic disorders, it’s somewhat mundane and it is really well-shown that this saves lives without much noise in the background, other than people who screen positive and then turn out not to have the condition. And so, you do have those weeks of uncertainty where you’ve screened positive, and you have not yet had a negative test. So, we do have that issue to overcome. But other than that, the issues are much more about technological maturity and when will this be well enough baked to actually have that be realistic for all live births. It’s going to take several years.

FLG: I saw you speak at the Frontiers in Pediatric Genomic Medicine conference recently, and you said how in the future, we’ll stop talking about the diagnostic odyssey and it will be more about the therapeutic odyssey. What do you think needs to be considered in this area?

Stephen: If you’re a pathologist, and I started life as a pathologist, you’re hung up on diagnosis. If you’re a regular physician, a treating physician, you’re hung up on treatment, you’re hung up on outcome, you’re hung up on fixing symptomatology. And in this journey, the diagnosis it is important, but it is not the end. People talk about ending the diagnostic odyssey, and I get that, and it’s really important. But it’s not the endpoint. Ending the diagnostic odyssey doesn’t end the odyssey. It ends a step in the odyssey, which was, we were stuck without a diagnosis. Next is, for 90% tragically, we’re stuck without an effective treatment. We have a diagnosis, that journey is over. But tragically, there’s not an effective therapy being deployed in my newly diagnosed baby. We’ve got to fix that. And ending the therapeutic odyssey is going to be a sea change. Because right now, we regard diagnosis as this holy grail thing, right? It’s mystical and beautiful. And we have got to say, it’s not, actually, it’s an intermediate step in the practice of medicine. And we have to demystify that. Like I said, let’s get over ourselves on genes and variants of uncertain significance because the diagnosis is not the end. We’ve got to push through and say every child deserves a trial of therapy. And how do we engineer, now, that diagnostic interim step as a qualifier for a clinical study of treatment?

FLG: What is the future like for Rady Children’s Institute for Genomic Medicine?

Stephen: We want to make Intensive Care Unit rapid genomes normative in the US. So that’s number one. And our Board of Directors and our hospital leaders have committed to funding us to decode 10,000 babies’ genomes (Tipping Point 10,000) in order to make that a reality. And so, as I said, scale, scale, scale. So that’s a huge component. But the other component is what I just addressed, which is 90% of these babies who we diagnose, we don’t immediately move them into lifesaving treatments. Oh, my goodness, I can’t sleep knowing that! We’ve got to fix that. We are entering a new world where we can make a genetic therapy for one patient in less than a year. We are now entering this new era of customised, individualised genetic therapies. That’s the future for us. Let’s jump into that. Let’s think that through and let’s figure out how to do that at industrial scale, so every child we diagnose moves into that next phase – that’s the next big thing!

FLG: How do you see the field of genomic medicine as a whole evolving in the next few decades?

Stephen: During my career, we’ve identified over 6,000 new genetic diseases, we know their molecular basis. The next 30 years, we’ll have 6,000 treatments for those 6,000 genetic diseases. That’s what’s going to be true. We will look back on the current era where we were hung up on diagnosis and then didn’t have treatments and say, ‘That’s kind of like how we used to treat infections before Sir Ian Fleming discovered penicillin. You know, we could diagnose it, and then the patient died of sepsis.’ We’re going to do the same, it’ll be before and after the management of sepsis with and without broad spectrum effective antibiotics.

FLG: If we can just go back to your career – are there any missteps in your career that you feel have shaped your career today?

Stephen: Oh, yes! I remember interviewing for the Rady Children’s Institute job and the then CEO of the hospital, Donald Kearns, said to me, ‘You know, Kingsmore, you are pretty impressive, but why should we hire you?’. I looked him in the eye, and I said, ‘Well, I’ve screwed it up before enough times, in enough places, and have the scars, that I know what not to do’. And they hired me. And so yes, you know, in life, we regard missteps sometimes as bad. And I actually think missteps are fine. That’s the only way you learn. Well, it’s one of the only ways you learn; you can learn from other people’s missteps. But the thing is to say, well, I was blessed with something that didn’t work out, what have I learned from that? How will that never happen again to me, to my team and to my organisation? How do we use this to beat the enemy? The enemy is not success and failure; the enemy is the disease affecting these poor kids who need effective treatments.

FLG: What would you say to someone who is starting early in their career?

Stephen: Data science is this extremely exciting new field. I still am not sure how to define it. But it’s kind of like an elephant, when you see one, you know that it’s an elephant. That’s really exciting, the idea that we will be able to use massive amounts of data to have novel predictive insights in medicine. We’ve never been able to do that before, medicine has always been seat of the pants. But for the very first time, we’re going to be able to have massive datasets that start to allow us to predict trajectories. And the public health implications are profound. This is a field that’s now the way molecular genetics was back in the late 80s; it’s brand new. We don’t have too many clear-cut examples of how that’s going to transform healthcare, but it will. And so, jump on in, but make sure you know how to programme!

FLG: Are there any notable people throughout your career that you felt inspired you or encouraged you?

Stephen: Oh, yeah, always. Without mentors, without colleagues, without co-workers, you can’t be successful. You’re interviewing me as a ‘giant’, well I’m not a giant in any manner. The only thing I can do is, hopefully, get a group of people around me and excite them about an idea. It’s they who do all the stuff, it’s they who have all the insights, it’s they who slog through all of the intermediate steps. And then you interview me as a ‘giant’! We believe in multidisciplinary team-based work. My role is not to have a big head, it is to realise that, yes, they call me boss, but honestly, they call me boss kind of as a label. I am there to help them and to incentivise them. But yes, throughout my life, I’ve been very fortunate to have had these people, who somehow see me as a leader, and go, let’s do this together. And it’s all about them. For me, as a Christian, it’s all about God. It’s all about him. He’s the guy who’s got the smarts. And this is something that in our Western world, we deemphasise, which is the spiritual element behind creativity. And for me, it’s the essence of all creativity, is that spiritual element!

FLG: How do you feel your spiritual beliefs combine with the science and how do you deal with that day to day?

Stephen: Well, as a CEO, I have got to be very careful. I can’t proselytise, that’s no longer kosher. So, I have to be very, very careful. I can only speak to this when somebody like you asks me a direct question. And then I’m allowed to answer it honestly. But I’m not allowed to really bring it up. And especially with people who report to me, I have to be incredibly careful to make sure that I’m not trying to do anything that might be considered pressurising. And that gets to be frustrating, but it’s just life. But, to respond, it’s huge. Every good idea I get, like in the middle of the night, or in the shower, you know, it’s like, ‘Wow, that is really smart! Where did you [God] come up with that?’ It’s this serendipitous thing. And, you know, I’m 60 going on 61, so I’ve learned to cultivate that. And this is going to freak some people out, but I talk to God all the time. I mean, 24/7. And he talks back, and we have the best chats. Understand, he created everything, right? So, it’s like, [God speaking about] CRISPR: ‘Dude, I created CRISPR. What you guys don’t know about CRISPR would floor you. Why don’t you ask me? I could share a few tips with you.’ This happens to me all the time. And so, I’m fortunate that then I have some people around me who get comfortable with that. And they go, ‘It’s Kingsmore’, and some of them have the same belief system as me. And some of them just go, ‘No, he doesn’t know’, but they put up with it. And so, I’m very fortunate that I have people, even board members, who go, ‘I’m not sure how the sausage gets made, but I like the flavour of the sausage, so just do it, don’t tell us how you do it, just do it’.

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

Stephen: Ok, I got to tell you, all those of you who are young and want to be a ‘giant’ – you don’t have spare time! You’ve got time to do your busy work and then sometimes, in the middle of a night, like this morning between 1am and 3am, I get to do work that’s for me, my research. So, what do I do outside of work – I sleep, I sleep. I like to drink beer. I’m an avid runner. And that’s really necessary. That gives you that whole spiritual temple thing and I like long distance running. So, when I was over in Northern Ireland, I managed to run 100 miles. You know what, Britain had the coldest May, I think, ever. It was like unbelievably cold. Ridiculous! Made me realise why I like to live in San Diego. Anyway, I have a very tolerant wife, and she’s awesome. And she insists that we do stuff other than work. If not for her, I probably would only just work.

FLG: If could turn your life and career into an autobiography, or a film, what would you name it?

Stephen: Something about grace or faith. Clearly, I believe, I’ve been blessed. I believe I’m the beneficiary of an unlikely series of events where people have done good stuff for me, like my grandpa giving me a laboratory aged 10, all the way through to Marks and Spencer. I’m a very avid Marks and Spencer’s shopper, and always will be, because of that. A lot of people have invested in me. And God has been essential. So, it’s all about grace and faith. And you know, we’re still in a very nutty pandemic world and for research institutes, it’s a crazy season and we’re figuring out how to work virtually. And grace and faith have come to the forefront again. With everybody we encounter and every deadline, we got to have grace and patience with one another. So those are two great words.

FLG: Thank you so much for joining me today Stephen, it’s been really, really great talking to you. And I still think you’re a giant whether you think you are or not! And keep up the amazing work you are doing at the Rady Children’s Institute for Genomic Medicine! Thank you so much.

Stephen: Pleasure. Thanks a lot.

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