Wednesday, May 16, 2018

Secret Science Club Post Lecture Recap: Finally, a Twin Study!

PREFACE: The mad geniuses at Riddled are often yukking it up about twin studies, so I figured I'd give them a shoutout before writing the bulk of this post...

Last night, I headed down to the beautiful Bell House, in the Gowanus section of Brooklyn, for this month's Secret Science Club lecture. This month's lecture marked the triumphant return of Dr Christopher Mason, associate professor of physiology & biophysics and computational biomedicine at Weill Cornell Medical College, member of the Yale Law School Information Society Project, and director of the WorldQuant Initiative for Quantitative Prediction. Dr Mason's previous lecture concerned his famous 'subway swabbing' project.

The topic of Dr Mason's lecture was 'Subterranean, Pan-Earth, and Inter-Planetary Genomics'... Dr Mason quipped that he is a fan of preposterous talk titles. The broad topic of the lecture involved a study to determine what the human body looks like in space. He displayed NASA's dramatic graphic showing their plans to put boots on Mars by 2035:




Dr Mason then showed the image of the SpaceX Tesla roadster, which is predicted to settle into an orbit just outside the orbit of Mars. He called attention to the library inside the Tesla, and informed us that the creation of a lunar library is scheduled for 2020, with a Mars library to follow in 2030. Dr Mason then mused, "What if it were a human body in that car?" What would the effects of space travel be on that human body. He noted that mutations can change a normal cell to a tumor cell, and that genetic mosaicism increases with age- specifically that cells can shed X chromosomes. He described an 'inexorable molecular march to oblivion'- mutations increase with age, telomeres shrink... the genetic 'bookends' fall away. He posed the question, 'how long can the body survive the slings and arrows of space?' Overall, mortality among astronauts has been significantly higher than for the general public- Dr Mason noted that space travel is not for the sheepish.

An unprecedented opportunity to study the effects of space travel on the human body presented itself when astronaut Scott Kelly was tapped to spend approximately a year on the International Space Station while his twin brother Mark remained on Earth. Dr Mason joked that the first task that NASA undertook was designing a patch for the mission:




He insisted that the patch reference epigenetics.

The Kelly twin study involved a lot of blood testing, and Dr Mason illustrated the complications of astrophlebotomy by showing a video of Japanese astronaut Koichi Wakata drawing blood on the ISS:





After blood is drawn, it is centrifuged and the blood cells are frozen, the frozen cells being sent back on a Soyuz capsule, touching down in Kazakhstan.

After 340 days, Scott Kelly made it back to the Earth, and the stress of space travel was immediately apparent- his post-flight cognition was slightly impaired and his cytokines had shifted. Unused to clothing touching his skin, anything that touched his skin caused a burning sensation. He wanted to wander around naked- Dr Mason joked that that was like a typical Saturday for him.

Genetically, mutations and structural variations had occured. DNA methylation and DNA hydroxymethylation had occurred, as had RNA methylation. Scott Kelly's genome wasn't exactly the same as it had been- for example, the length of his telomeres had increased while he was in orbit, then shrank while he was back on Earth. The press coverage of the study was sensationalized and less-than-accurate- one headline screamed 'Space Made Scott Kelly Taller and Younger'. Dr Mason dryly noted that, due to time dilation, Scott Kelly was, relativistically, .1 second younger than he would have been if he'd stayed on the Earth.

Love level DNA transcription inversions were apparent, and some genetic damage persisted after Scott Kelly had returned to Earth. There was an increase of cell-free DNA in his bloodstream... as cells underwent apoptosis, the cell-free (extrasomatic) DNA was released into the blood. In particular, there was a spike of mitochondrial DNA in his blood. It was also apparent that his white blood cells had launched DNA into his blood to fight invaders. In the absence of gravitational forces, fluids shift around in the body, causing, among other things, facial puffiness.

Dr Mason then shifted the topic of the lecture to epigenetics. The ACGT genome is really just the beginning of gene expression- epigenetic factors control when and where genes are activated.

In one case of epigenetics, DNA methylation can predict an individual's age, which has great forensic utility. Dr Mason joked that YOLOIDs is now obsoletel because now bouncers can sequence a patron's DNA to check their age. Besides age, there are other reasons for epigenetic shifts- in the case of Scott Kelly, the epigenetic age was dynamic, early in the mission it appeared lower, mid-mission it appeared higher, then it appeared lower after he landed. In the three to six month range, there were 6,976 changes in gene expression. In the 6-12 month range, the amount of changes was seven times higher. 93% of the gene expression returned to normal when he landed, but 7% did not- a phenomenon promptly dubbed 'space genes'. The 'space genes' were disrupted by space flight, but Dr Mason noted that permanent genetic change only occurs when a subject is dead.

In response to the dramatic reports that 7% of his DNA had changed, Scott Kelly joked that he didn't have to call Mark his twin brother anymore. Even The Daily Show had a segment on Space Genes. NASA stepped in to set the record straight, noting that Scott and Mark Kelly are still identical twins, and that if 7% of Scott Kelly's DNA had changed, he'd have to be considered a different species. Dr Mason described this overly sensational media coverage and the subsequent scientific correction as 'a good teachable moment'.

Dr Mason then cataloged the factors which may have caused the changes in Scott Kelly's genetic expression- hypoxia, hyperemia, immune system responses, DNA repair, and disruptions to bone formation. In the ISS, carbon dioxide levels fluctuate. High levels of mitochondrial DNA in Scott Kelly's blood were thought to come from platelets and white blood cells, indicating a response to stress.

Dr Mason went on to discuss changes to Scott Kelly's microbiome- there are more than just human cells in the human body. In space, microbial diversity was largely maintained, but there was a slight shift in the Firmicutes to Bacteroidetes ratio. Dr Mason noted that it was hard to collect fecal samples in space, but refrained from describing the process. He noted that fecal and oral samples allowed researchers to determine what Scott Kelly had been eating, noting that the DNA of vegetable matter tends to survive in poop. At one point, it was suggested that Mark Kelly maintain a similar diet to synch up with his brother Scott, but he refused to do so... there aren't any 5-star restaurants in space.

The genetic study of Scott Kelly marked the first 'cartography' of a body in space, but more samples are needed, a problem compounded by the fact that there are only 556 total subjects- there just aren't many astronauts out there. Questions remain- are the patterns of changes linear, quadratic, or exponential? One potential advance is the sequencing of DNA in space- at $10K/kilogram for sending stuff into orbit, nanosequencers would make this feasible. Dr Mason joked that the first order of business was producing a Biomolecule Sequencer patch:




Sadly, the DNA sequencer was a casualty of the Falcon 9 rocket explosion. As Scott Kelly put it: "Space is hard."

To lighten the mood after that bummer, Dr Mason showed us a funny video of researcher Andy Feinberg attempting to microgravity pipetting on the 'Vomit Comet':





Eventually, a commercial DNA sequencer, MinION, was used by astronaut/microbiologist Kate Rubins to sequence DNA in space for the first time, a feath that Dr Mason described as a game-changer. A billion genes have been sequenced in space susequently, notably a sequence of E. coli's genome. Now, new infections in the ISS can be sequenced in real-time.

Dr Mason then posed the question- where else can sequencing take place? The Gowanus Canal? The subway? This was a perfect segue into the topic of his grand subway swab. He began with a great aphorism: In the absence of knowledge, the best thing is to discover. His goal was to conduct a Metropolitan Genome Project, an exploration of the metropolibiome, if you will. In the course of the subway swab, fifty percent of the DNA recovered had never been seen before- half of the world under our fingertips is unknown. He joked that, from a biological standpoint, a subway railing should be as inspiring as a rainforest. The species diversity varies by area of the city, with one particularly interesting locale being the South Ferry subway station, which had been flooded by Superstorm Sandy. Post-Sandy, the South Ferry station has exhibited a persistent molecular echo of cold ocean water. One particular organism, Shewanella frigidmarina, which was located there can produce eicosapentaenoic acid, the consumption of which may reduce suicide rates. Dr Mason seems to be particularly plagued by sensational media responses to his research- the Gothamist headline about his subway genome project read: Licking Subway Poles "Probably Fine," Says Expert. The hygiene hypothesis posits that bacterial exposure early in childhood is important in immune system function. Dr Mason then introduced us to the work of Heather Dewey-Hagborg, an artist who uses DNA from discarded cigarette butts and chewing gum to create 3d images of faces WHICH IS NOT CREEPY AT ALL!!!

In another project, 2010 Census data was campared to humans' molecular echoes, to determine if neighborhoods could be distinguished using DNA samples. Regarding privacy, an individual can choose, to some extent, what DNA they leave behind... at any rate, one should not avoid riding the subway out of privacy concerns. Dr Mason then showed images of the early morning subway cleanings, comparing these daily events to forest fires, with the subsequent press of commuters representing a 'reseeding'.

The Metasub project is a multi-city transit system metagenome project- once a year, multiple subway systems throughout the world will be swabbed for genetic material to sequence. The next big swabbing project will take place on June 21 of this year.

Other topics are ripe for research... Where does antibiotic resistance arise? Can an engineering approach be brought to medicine? Can we tweak something and predict what will happen if engineering occurs? Pigs could be genetically engineered to grow human organs. Hypertrophic cardiomyopathy repair can be performed in fetuses. Fragile X syndrome can be repaired. Using genetic engineering, how can astronauts be 'armored'? Could TP53 be enhanced to guard their DNA? What about the prospects of adding chloroplasts to human cells to allow photosynthesis? In that case, a surface area of two tennis courts would be needed to replace one hour's worth metabolic needs fueled by eating. Dr Mason characterized the prospects of such research both terrifying and exciting- there is a real chance that NASA could meet its precision medicine goals, but what if we do something wrong?

The lecture was followed by a Q&A session, led off by some bastard in the audience asking if there had been genetic surveys of people who have spent large amounts of time in underwater environs. Dr Mason indicated that there haven't been any genetic testing of SCUBA enthusiasts, but that there is currently a twin study of mountaineers who are tackling Everest. Another question regarded the percentage of subway microbes which are pathogenic- about 98% of subway microbes are not pathogens, but Dr Mason wryly noted that some of the microbes in the subway could kill you if you were a lobster. If the subway were swarming with pathogens, we all would have died already. That being said, there is a danger from aerosolized particles- it's best to avoid red-eyed, sneezing people. The odds of getting sick from subway exposure are low.

Regarding twin studies, Dr Mason joked, "I wish you all had a twin." He noted that the fact that the Kelly brothers the only twin astronauts, and that even then they had both been in space, so Mark wasn't a perfect 'control', even though Scott's time in space was orders of magnitude longer.

Another question regarded telomere elongation- one proposed mechanism is that enzymes regulating telomere length become more active. In cancer cells, telomeres tend to be too long.

The last question of the night was hilarious, a real doozy: "Given a CRISPR and no ethical qualms, how would you engineer the perfect spacer?" Dr Mason suggested that smaller size would be beneficial, as would cancer repair, photosynthetic enhancement, and a tweak to the LRP5 gene to maintain bone density. He then noted that, like Dr Moreau, geneticists in popular fiction are usually depicted as evil, he then flatly stated, "We're not evil." Yeah, you're not evil, in fact you're awesome!

Kudos to Dr Mason for another fantastic lecture, a heady blend of molecular biology, outer space adventure, dry wit, and a cautionary note about sensationalistic science reporting in the popular media. Once again, Dr Mason hit one out of the park. Special thanks to Margaret and Dorian, and the staff of the beautiful Bell House as well. High fives all around.

Now, here's a video of Dr Mason delivering a TED talk about genetics, epigenetics and the Kelly twin study:





Pour yourself a beverage and soak in that science!

3 comments:

Smut Clyde said...

At last, a scientific explanation for the absence of lobsters in the NY subway.

Big Bad Bald Bastard said...

Are you sure the pizza rats didn't do them in?

Big Bad Bald Bastard said...

Forgot to add my joke concerning using a CRISPR to genetically engineer spacers... this is how 'Dune' style Guild Navigators are created!