Part I 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. Strap in for Part I of II.
Chrysalis: Thanks for speaking with us. Diving right in. The NASA Twins Study clearly made a splash. Can you take us through how it was conceived, what the results were and how they will be used?
Chris: Yeah. I can tell you personally how it was conceived and then from the perspective of NASA. I had just started my laboratory in October 2009 and I go to my first ever AGBT meeting in February 2010. So I get there and at that meeting a certain vendor announces that by the year 2014 we should have a $100 genome available in less than 15 minutes. And it dawned on me that at the time there had been more people who had walked on the moon than had had their genome sequenced (a nod to Nathan Pearson who I think first coined this).
That declaration seems trivial now but was extraordinary then. And it really made me think that studying genomes will become just rote. It won't really be a question of whether you have your genome sequenced but do you have an interesting genome? Do you have metadata? Do you have phenotypic data? And I started to think. I've always been interested in space. I went to space camp twice as a kid. And I have always thought about astronaut genomics and astronaut health. Had anyone looked at an astronaut genome? To my knowledge no one had, and I know for sure now no one had. So, I actually wrote NASA what's called an “unsolicited proposal.” Like the NIH you can apply for grants and get funding but, NASA will also accept unsolicited proposals. You say, “Hey, I’ve got an idea I would like to work with you on.” So, I sent them a grant proposal that proposed sequencing the genomes of astronauts and added that I didn’t even need funding because I had just started my lab, for which I already had funding. I just needed samples.
At the time they had just recently started and hadn't done any of the genomic work. There had been DNA banks for forensic identification if there was an accident, but whole-genome sequencing, RNA sequencing or multi-omic assays had not been done for any astronaut. Some of this was due to privacy concerns, some due to health considerations but some of it was just that it was new to NASA. They didn't even have samples we could use at the time. The program officer did, however, say they were going to start to do more of this type of work. He asked to stay in touch, and that there would be an RFA soon.
Fast forward, at a press conference, Scott Kelly said he was going to do a year in space. A reporter in the audience said, “Hey don't you have a twin? Are you guys going to do something with that?” When it came up, John Charles, Chief of the International Science Office of NASA’s Human Research Program, said, “No way. We're not going to do a study. It’s just going to be viewed as a big stunt. No one would take us seriously.” But the more they thought about it, the more momentum it got. Even though it would clearly be a limited sample set - two people - there was a concern about missing an opportunity. When again would we have identical twins - a perfect genetically matched control - where one would be on Earth and one in space at the same time? They end up deciding to move ahead, and I already had a grant fully written to send to NASA. It proposed integrating genetic, epigenetic and epi-transcriptomic changes in space. Keep in mind the word “epitranscriptome” hadn't been invented in 2012 so there was a lot of new studies on many molecular layers of biology that we could look at from a human being over the course of a year and before and after
Chrysalis: So how do you think the results are going to be used?
Chris: These will be used very much as the first layer, the first sketches of molecular cartography for future human space flight. We know for example when people set out to explore North America, they built the first maps as a key first step; Columbus thought he “found it” first even though the Vikings “found it” earlier (and obviously the Native Americans found it far earlier). Nonetheless, I think the goals and the traits and even some of the methods of cartography very much apply here. We have created sort of the first map of high-, medium- and low-risk changes to the human body for long-term space flights. This sets up the bedrock and the baseline comparison for every other subsequent astronaut to gauge overall health and risk for space flight
Chrysalis: So looking back, anything you wish that you'd have differently as far as setting it up?
Chris: There are many new ways to query cells that we didn’t have available in 2013 when we started planning the study. Like single-cell sequencing. We're doing it on some of the cells, but we didn't' even put that in the grant in 2013 as it was very early and just prohibitively expensive at least for the scale of the study we were talking about. So, I would have pushed for much more granularity of the dynamic measure on a cell to cell level. Regarding the publication and publicizing of the work, as you know some people have misinterpreted some of the preliminary findings, claiming that seven percent of his DNA is different. Obviously, that’s not the case because he'd be a different species! There have actually been these great teachable moments for media and press to learn about the distinction between genetics and epigenetics and transcription and fundamental layers of biology and how to transmit that to the public.
Chrysalis: What does that say about the way science, in general, is presented to the general public and what needs to change?
Chris: The field today changes so fast so anyone who hasn't been in a college or even high school biology class within the last ten years probably lacks the majority of the vocabulary to characterize and describe current genetics and biology questions. If they learned about non-coding RNA's or epigenetics or post-translational modification it would have been very cursory. Understanding the nuance and how those change for an astronaut is something most people haven't thought about before. I see it as a big opportunity to explain what cutting edge technology is, and what it can tell us about interesting biology.
Chrysalis: How do we deal with this in the backdrop of the soundbite world?
Chris: The political climate notwithstanding I think there is just a fundamental healthy skepticism that is missing from most people. But eventually, this does catch up. We have a 24-hour news cycle that gets some of the science completely wrong but the majority of cases I've seen gets corrected generally. It's both sad and hopeful at the same time.
Chrysalis: So, is it the role of science or the scientist to distill or spoon feed or is it the role of the journalist to understand and get under the hood and ask the right questions and interpret? Or is it a combination of the two?
Chris: I’ll take both answers for 200, Alex [Trebek]. I'll say yes. You do need to meet people in the middle. People have not taken the nuances of codon optimization usage in your system into consideration into their daily life or in their science report, even if they're well-heeled science reporter or keep up with the vast enterprise spanning material science, computer science, engineering, biology, or genetics. So you do have to meet them there. But then also at the same time, there are the challenges of investigative style reporting, of digging deep into a story. Reporters should also meet the scientists in the middle and say, “Tell me more about this”, and ask, “Why it is significant?”, and ask other scientists to weigh in. But that takes time. You’ve got to call a lot of people. You can't just write up a report an hour as it is throw it up there and be done with it. It might take eight hours, it might take a couple of days.
Chrysalis: I recently saw on Facebook that an acquaintance of yours is collecting samples at a most unusual place - Mount Everest. What samples are being collected? How are they being preserved for the descent? Perhaps most importantly what are you expecting to find?
Chris: This came out of a really opportunistic email. Someone wrote me saying, “Dr. Mason, I hear you study twins in extreme environments. I have a twin who is staying at sea level while I go climb Mt. Everest. I'm being accompanied by another guy who also has a twin. So, we have two twins going to the top of Everest. Could you help us?” I replied, “Sounds great, when are you leaving?” They said, “We are leaving in four days.” I said, “All right that's a bit short notice but let’s see if we can do it.” We replicated as many aspects of the twins protocols for NASA as we could. This includes microbiome banking before, during, and after their expedition. We collected blood samples, plasma for cell-free DNA. We are looking to see how many of the aspects of the NASA study get replicated for the Mount Everest expedition. We are trying to separate and disentangle and characterize what is just bodily stress and maybe hypoxia and what is the impact of space flight in microgravity and zero gravity. Mike Moniz and Matt Moniz are working on it. It’s as close as you can get to the space station on Earth. And it was my first IRB for the Nepalese government - so that was new. We basically replicated the tubes, protocols, and preservative agents from the NASA study. A lot of the samples follow what is called our ambient protocol. Within 48 hours you can get samples and fresh cells from the space station to Soyuz to Kazakhstan to Houston in 37 hours, and also then get viably frozen cells. We did the same thing for cells from Everest. They drew blood, which gets difficult at high elevation because the Vacutainer doesn't work as well. It was put it into a helicopter in Kathmandu, spun down and froze the cells and then we should be getting them all shipped back here in a few weeks.
Chrysalis: So when are the results going to be published?
Chris: The NASA Twins paper just finished the internal NASA review and will be submitted for formal publication next week actually. So that paper will be out later this summer or in the fall. We will get the Everest samples back and process them as fast as we can, in order to submit a parallel paper. In short, the paper should be later this year, or at the latest early next year. We will probably put things up in bioRxiv to get the data out so people can use it.
Chrysalis: Can you name a pioneer in the genomic assays space whose “killing it: that our readers might not know about? Can you give a shout out to a great technology and the visionaries behind it?
Chris: Well there's a lot. I've got a lot of favorites. Some of them are really straightforward. There's everything from the deeply technical people making great advances to people uncovering really novel biology. On the technical side, there’s Justin Zook and Marc Salit who run a lot of the work on the Genome in a Bottle Consortium. This is giving us the meter stick of the genome which has led to so many other revelations as to what we are missing. Without a sense of reality, it’s hard to find out what's mystery. It’s often an underappreciated but very important aspect of science, genomics, and technology. Those two guys have been working on it for years. I'm part of that consortium and I enjoy that work a lot. On the technological side, I think of the CITE-Seq protocol and Rahul Satija at New York Genome Center. They’re doing these great things. I think of Dan Landau’s lab also at New York Genome Center and Weill Cornell doing single-cell epigenomic profiling. I’m impressed with Eran Segal a lot for his work in metagenomics, the microbiome and how both influence glycemic index, and Joel Dudley and Olivier Elemento for leading work on precision medicine and precision wellness. And then there are people who have been in the field forever who I’ve liked for a long time like Leming Shi who was involved in the original MAQC projects long ago. I still work with him a lot. Then there are people obviously like Francis Collins and Craig Venter who gave us some of the first genomes we could look, or George Church, Ting Wu, and David Sinclair and other as the Consortium for Space Genetics. I was just a snot-nosed college kid when that work got started, and I’m elated to contribute to the science now.
This concludes Part I of our interview. Stayed tuned for Part II, “The Right to Look at Everything: Personal, Cultural, Clinical Metagenomics”