Part II of our interview with Dr. Chris Mason.
Throughout our careers, the principals at Chrysalis have built strong, lasting relationships with those pushing the boundaries of genomic technologies into uncharted territory. Few people embody that spirit more than Dr. Chris Mason. Chris is probably most well-known for being the architect and driver behind the recently publicized NASA Twins Study and MetaSUB programs, but did you know he coined the phrase, "epitranscriptome"? We sat down with, or rather tried to keep up with, Dr. Mason – a mild-mannered professor by day, prone to fits of extreme innovation – to discuss a broad variety of topics. We hope you enjoy the discussion as much as we did.
Chrysalis: Several years ago when I was working for Illumina, you, Gary Schroth and I came up with this idea called “Stuck on You”, where you take a swab from a conference participant’s mobile phone or shoe and see what organisms are present at the beginning and end of the conference. Can you tell us a little a bit about that and how it’s been implemented and who's been involved?
Chris: To be fair, some work had been done on phones and shoes previously by some others in the field like Jack Gilbert, Jonathan Eisen, and Rob Knight. People had looked at this question, but no one had ever done it with shotgun sequencing, or across all species (prokaryotes and eukaryotes), and also no one has ever done it within 48 hours. It has always been sort of post-hoc of a meeting as an idea. Part of it was this excitement of showing people what can you learn with metagenomics not just doing 16S sequencing. Not just doing an examination of a very limited functional classification and taxonomic resolution area of a genome but actually looking at everything that's there. What food are you eating? What pets do you have? What can you tell about your own microbiome? What viruses do you have? What antibiotic resistant markers do they have? So there had been some backdrop but we wanted to do it faster and do it more broadly and on multiple layers that had not been looked at before. Hence was born “Stuck on You”. Wouldn't it be fun to see what happened to your phone between the start and end of the meeting, and get the report back within 48 hours? This was done last year at the J.P. Morgan Healthcare Conference, The World Government Summit, and ABRF, and more recently at the Milken Institute Global Conference. There we got 1,000 phones in 48 hours and then presented what we found on the first 100 at the meeting.
Chrysalis: What's been found and how has it been received?
Chris: It's been really extraordinary how much your phone can reveal about you. There's a couple of interesting things. Some people said wait, wait, don't you need an IRB (Institutional Review Board) for that? It turns out you don't need an IRB to sequence a surface”. You do need an IRB to sequence a person. The irony is the phone is pretty much an echo of a person's life. So, we have been able to use a variety of classification algorithms and some machine learning algorithms, to predict the likelihood of someone owning a dog. It’s about 94% accurate. We can determine the food that the person has last eaten. We’ve detected fruits - orange, banana, apple- and meat (a guy had a pulled pork sandwich and his phone had porcine DNA). You can see a little bit of the history of what people have been doing and eating and what they’ve been interacting with. More recently we added the hops genome to the database, so you can detect that people that have recently been drinking beer, which is kind of fun.
We can also look at human DNA on the phone and determine ancestry. We are getting about 80-90% accuracy of what was expected based on individuals’ self-reporting. We’ve had some interesting results. For example, a person may have Asian DNA come up, but they aren’t Asian, and it may be because they have been shaking hands with someone who is. Ideally, you’d want to follow someone around for days and look at every surface with which that person interacts and track the DNA on the surface, on the phone, on the person and characterize the immune response that also might be mitigating or changing some of the molecular features. That would obviously be a much more involved procedure. The whole thing does also raise questions of privacy and identification and what you can do. This has also been in the news lately about people making fake profiles for genealogy databases to solve crimes, so it raises some timely ethical questions, too.
Chrysalis: Have you had situations where you have blinded the submission and matched the phone with the person?
Chris: Yes. Actually, we had an even more interesting situation. We placed positive and negative controls on the microtiter plate and were able to confirm a classic x-y coordinate switch on the plate. We immediately saw many things were not correlated that should have been like ancestry and pet ownership. We then went back to the technician to check with the person who had done the wet lab work. They checked the lab notebook and found the mistake. Everything matched up with having rotated the plate 180 degrees by accident. We have had these basic QC moments but have also been able to really tell people a lot of their ancestry just from sequencing the surface of their phone.
Chrysalis: All right you're known for taking samples from the New York City subway and characterizing them. How did doing that influence what you work on today? And what's been done with the information from the follow-on subway studies like MetaSub?
Chris: The main genesis of that project was actually purely curiosity. I just wanted to know what's there. I had this stark realization that there was literally no information about mass transit systems, at least in New York used by 5.5 million people every day during the week. There's this entire shared invisible microbial and genetic ecosystem that everyone interacts with, but we know almost nothing about it.
Chrysalis: So, I'm going to pause you there. How do you come up with that? Are you in the shower, or sitting around playing with your kids and then - wham - we've got to go somewhere, and we’ve got to take the subway? What's the genesis for it?
Chris: It’s very much kid-driven. So, there are two things that really drove this. First, I was trained first in Drosophila genetics, then human genetics, then a lot of genome technology methods. So, my background was never really originally microbiology or metagenomics. Every time we sequenced a whole new genome or exome since 2007 we always had read that didn't match the human genome. Some of this was because the genome is different between all of us there is structural variation, there are unique features, etc. But it always nagged at me that we had all these reads left over that we knew were high quality (all above Q30) but where did they come from? The simple answer in a lot of cases was that they were of microbial origin, especially if it was like a buccal sample. But it just it bothered me to have really high-quality data that didn't map to anything. We knew these reads came from something but they weren't part of the standard pipeline. So, that was kind of nagging at me for a few years. But then around the same time, I became a father and watched my daughter ride the subway. She grabbed the subway poles, dropped food on the subway floor and put it back in her mouth, licked the subway pole. These things created a moment where I thought, “Well, something has clearly happened right there. There has been a microbial exchange and I really want to know what the exchange was.” So, I couldn't even get a sense of what was there to begin with, let alone what the transference was or what it might be, since there was no data to look at. It was just pure curiosity of what's there. And that's led to all sorts of other implications of public health or just managing subway systems, mining the data for all sorts of other things which we can talk about later. But, yes there was really a pure curiosity and also an annoyance with having sequence reads that were of high quality that could not be mapped.
Chrysalis: How did doing it influence what you work on today and what's been done with the information from the follow-on studies?
Chris: Today our work in the lab has become much more kingdom-agnostic. I think about any biological problem and all you could argue is an ecological perspective. Some people think of this as “systems biology,” but most people are still thinking about their system of single species, not of the totality of what's called “holobiome.” It’s really led me to view, without prejudice, the providence of any molecule and how it might influence health or disease. Is it microbial, viral, human, a parasitic organism or protist? If your goal is to have a better model of health and disease you can’t have that species-level bias or have any preordained guesses as to what might be driving your phenotype. You should take in as much and all of the information as you can. It’s made me do metagenomics - which looks at all DNA - and look at multi-omic data sets as we can. It’s made me train medical students with this perspective, teach graduate students in postdocs with the same view and philosophy. It’s driven by how much more granular what we can measure. It’s as old as ecology, frankly, but now we can actually measure a lot of it.
Chrysalis: To your critics who may challenge the science you do as not necessarily “hard science” but more PR, how would you respond?
Chris: No one has said that to me directly so that’s an interesting question. If someone just came up to me and said, “I don't think anything you’re doing is serious.” I would say, ”Look at the over 150 papers that are published that document the work, some of which are the near pinnacle of boredom in terms of technical questions.” You really have the most rigorous assessment in clinical grade sequencing methods...algorithms, best practices...all in the name in building a better mousetrap for genomics. But you know I do all those studies because if you can't get it right in a controlled environment you will have no hope to figure out what your sequencing machines and algorithms will look like in space or the mountains or other places. Stepping back, I would say critics are great. Criticism is the bedrock of science. Ad hominem attacks are pretty useless, and I don't really listen to them. I take a lot of encouragement from people that have come up to me and said, “I saw you speak and I went into a Ph.D. program because I got so excited about science”, or “I became so inspired.” I was at NASA in January and ran into a guy who said he had been reading my papers since he was in high school, and he asked me to sign her pipette! I just feel like I'm climbing around in the dark discovering things as we can, improving science and doing genetics as best we can. To occasionally have someone say it really helped those people launch their career or get excited about science or helped lead them to think about a problem and discover something new - that’s all the justification I need. So critics should be as loud and critical as possible but just don't be ad hominem because it’s not a good use of time.
Chrysalis: Moving back to metagenomics in particular when do you see that being routinely applied in the clinic versus all the DTC applications and what's the spearhead application?
Chris: We’re are doing it already. We have an IRB protocol that I set up at Weill Cornell called Precision Metagenomics to that very thing. We are doing shotgun sequencing on and all the clinical cases that do and do not culture. Like those mysterious organisms that are in the middle of an abscess that you can’t culture. It’s actually one of the best use cases of applying sequencing. Some people have done a great work in the space already like Joe DeRisi and Charles Chiu - they’ve improved a lot of methods essential for this work. So, again, this idea has been pioneered so we know it’s possible but now we can actually do it at scale and for every single clinical sample. So, I think it is already started and will become more and more common as the prices keep coming down.
Chrysalis: Do you think that's going to be the first application that gets broad coverage from public and or private payers?
Chris: That's a good question. Yeah, I think so. There are some companies like Karius and Arcbio that are really pushing hard to apply it to UTI, sepsis or strange infections. I think those will get reimbursed first. There are already people paying out of pocket to get that done.
Chrysalis: Pivoting, do you think ultra-portable technology is going to deliver on their lofty promises of decentralization and democratization? Does the world need a SmidgeION?
Chris: I think it's analogous to asking if the world needs kids to have microscopes at home. Yes, it does. It’s a good thing. I view it as a “genetic right” and personal liberty to look at any and everything. If you touch something with your hand you have a genetic and microbial exchange with whatever that surface was. I think it’s your full right to look at whatever that is that you just engaged with genetically. The same way you would want to look at something with a microscope you should be able to do so with sequencing. So yes, I think it will help in that regard, but I don't know if it will be on the SmidgeION. It could be something different. It could be a miniature version of a MiSeq or a MinION. We have used the MinION literally to sequence in space with Astronaut Kate Rubins, NASA scientists Aaron Burton and Sarah Castro-Wallace and it worked well there. We are doing follow up missions doing metagenomics for astronaut health in space so clearly going already in this direction. I think if it’s not that it will be something very much like that. I don't know if you remember this but when the Personal Genome Machine came out from Ion Torrent it was $50K. Jonathan Rothberg was out there saying this was “for the masses.” But most people do not have that kind of money. It’s a bit of a tone-deaf statement. So even if something is a $1,000, which is extraordinary cheap in historical terms, it's still a big expensive toy for most people. Genomic enthusiasts would probably go for it and love it, but for the everyday person that’s a bit much right. Or for example for schools - to teach people - you would spend $2K-3K for a machine and flow cells for one thing you do one day? Schools can't afford that.
Chrysalis: When does it make it on Amazon?
Chris: Have you heard of the spouse price? It’s a price at which you don’t have to check with your spouse before you buy it. If something gets into the $100-200 range... that's something you can spend at a bar in New York in 20 minutes.
Chrysalis: So, what's on your bucket list?
Chris: Although I’ve crossed out a large majority of my bucket list, any good bucket list should always get longer over time. I think doing really remote diagnostic and sequencing in space and doing astronaut genomics that I fantasized about 8 years ago. Now we are doing it in space and doing it again. So some of those things have been taken off the bucket list. I think we are in the hyper-exponential pace of discovery now. The fundamental units of genetic code and regulation of the human genome are still being discovered. The total number of species that are present on Earth, the number of biochemical products they can make are still going up at an exponential rate. I think a lot of things on the bucket list are to continue that discovery but to do it in more places and to start to do more engineering of organisms. I want to be able to protect astronauts on their way to Mars to help get the planet ready for people to go there. It is the first big step on a ladder towards preserving humans for the really long haul. I think it's a duty and a responsibility for our species, so if there is any way I can contribute to that through human biology, microbial biology, engineering technology, diagnostic technology any and all of it is on the bucket list.
Chrysalis: How about the personal bucket list?
Chris: I still want to publish a book of genomic poetry which I’ve almost finished. I think no one will buy it other than my mom and my wife. It's a collection of poems that are pretty science heavy and have interesting thought experiments. Part of a stanza in a poem was like a transposon where it was hopping in and out of other parts of the poem itself...or funny rhymes that would anthropomorphize chloroplasts and talk about them in a personal way. I'll send you some if you like. I published a couple of them. I'm working on a book about the 500-year plan. I'm still working on one book with a hedge fund manager combining quantitative finance and quantitative genomics. We have one daughter, who I’d like to see grow up well - so that's on the bucket list. I’d like to give her the opportunity to do anything she dreams. I want to be a good father, to at least stay in decent shape and live a long life. And then maybe someday travel. Well, I travel anyway so that's not really on the bucket list I do that all the time. And SCUBA dive more. Every time I'm SCUBA diving I look at weird species and think, “Oh, we should sequence that thing!”
Chrysalis: All right we know your brother Cory who is smarter and better looking, of course, was recently elected mayor of Racine, WI. Is a Chris Mason 2020 run for presidency out of the question?
Chris: It's not out of the question. I need the requisite $100M to start the campaign.
Chrysalis: Start signing pipettes, baby.
Chris: It's not out of the question. It's an honor and privilege to be here as a human and to help other humans, so anything I can do to help that. That actually makes me sound like an alien when I say it that way but that's how I feel.