What do cancer, space, and the microenvironment of subways have in common? According to Christopher E. Mason, Physiology and Biophysics at Weill Cornell Medicine, all three impact the human genome in complex ways and therefore fall under his purview. A geneticist and biochemist, and WorldQuant Foundation Research Scholar, Mason creates biochemical and computational methods to understand human genetics and its many influencers—no simple task.
First off, the human genome is impacted by cells that are not human. Up to 10 times the number of microbial cells as human cells inhabit our bodies or are passing through, making up an invisible but influential microbiome. Researchers are also realizing just how complex the process of human gene expression is—how the text of the DNA code is read and revised and interpreted to produce proteins. Mason wants to understand how it all works as a complete system.
“Humans are mobile ecosystems—with an overlapping interplay of human DNA, microbial DNA, viral DNA, RNA, and the environment—and they are constantly in motion and dynamic,” Mason says. “The more integrated and comprehensive our projects are, the more I feel like I’m getting closer to understanding the true biology.”
Mason is motivated by the hope that we’ll someday know enough to repair and strengthen the genome to combat and prevent disease, and even many lifetimes from now, enable human survival in space.
Predictive Medicine, What Is It?
Before we can safely inhabit Mars, we need to understand more fully how the genome operates and how fundamental processes are disrupted to cause disease. The introductory model of gene expression is that every protein has a DNA sequence, or gene, that codes for that protein. Over the last 20 years especially, researchers have been uncovering just how much more there is to the story.
“There’s this beautiful plasticity that’s inherent to all DNA, in each cell, which is called the epigenome,” Mason says. The epigenome represents the many chemical signals that instruct the genome in the process of expression—instructions that, from the same sequence, lead to different products and health outcomes. The result is that there are many more regulatory mechanisms to understand than previously thought and many more places where things can go wrong.
“Some of the fine detail work we do is peering at individual methyl groups and the tiny chemical changes that occur in DNA and how that manifests into disease,” Mason says. Mason has studied numerous cancers including leukemia and brain tumors as well as unidentified diseases with the National Institutes of Health’s Undiagnosed Disease Program.
“Some of the fine detail work we do is peering at individual methyl groups and the tiny chemical changes that occur in DNA and how that manifests into disease.”
The long-term goal of this work is to understand the workings of the genome so well that researchers will be able to predict susceptibility to disease far before it manifests. “There’s a lot of excitement about precision medicine right now. Soon, you’ll hear more about predictive medicine. Given a set of molecular changes, what do they indicate about my risk for disease, what drugs might work for me, or what I’ve been exposed to recently that could have effects down the line?” Mason says.
With the vast complexity of the systems they study, Mason and his team use and develop machine learning algorithms to help cull data. A major aim of the lab is to constantly improve these methods. Mason is even partnering with the finance industry to find new ways of processing data to make predictions.
A $5 million gift to Weill Cornell Medicine from WorldQuant LLC—an international quantitative investment management firm—and its founder, chairman, and CEO Igor Tulchinsky is spurring this effort. The gift establishes The WorldQuant Initiative for Quantitative Prediction, which will use predictive tools to enhance Weill Cornell Medicine’s capability to diagnose and treat a variety of illnesses, with the goal of improving outcomes for patients. “We’re using this as an experiment to bridge two historically very disparate disciplines. That’s exciting,” Mason says.
The Environment, In and Outside the Body
The complexities of the human genome’s processes do not exist in a vacuum. You can see evidence in the sequencing. In a given sample of human DNA, there are often unrecognized fragments. “The more work I did on the human genome and the methods of DNA sequencing, the more I became pleasantly haunted by the fact that we always had fragments of DNA that were in excess—that we could never map to any specific spot,” Mason explains. “One of the main reasons is because they’re from another species.” Some of these DNA fragments are from the many microbes that reside in our bodies as part of the microbiome. Others are from things we come into contact with in the environment—the metagenome.
Knowing this, it was with particular curiosity that Mason watched his daughter, only a year old at the time, lick a pole on a New York City subway. “I wondered, what just happened?” Mason says. When he went to the literature, however, he couldn’t find anything. “In the absence of knowledge, the best thing to do is experimentation and exploration,” he says.
He and a growing team of students and researchers collected samples with the aim of creating a genetic portrait of New York City’s subway ecosystem. Called PathoMap (short for pathogen map), the findings were reassuring in some ways and astounding in others. While the majority of fragments they collected were harmless, about half of the DNA sequences couldn’t be identified, and 12 percent of the bacteria species in the samples had some potential link to disease.
The PathoMap program has now led to an expansion to all seven continents. MetaSub is an international project to map the urban biomes in cities around the world. These maps could help identify new and potentially useful molecules and antibiotics and help monitor for bioterrorism or disease outbreaks. “Whenever we see a peculiar fragment of DNA, we’re thinking about sequencing it, characterizing it, and putting it in the context of the genomes of the world,” Mason says.
How the Human Genome is Impacted in Space
For Mason, the world encompasses more than just the planet Earth. Mason’s group, along with other scientists, are working with NASA to answer questions about how being in space impacts the body’s genome and microbiome.
Mason’s lab has been monitoring genetic data from astronaut Scott Kelly, who spent almost a year in the International Space Station, and his identical twin Mark, also an astronaut, who was earthbound during the same period. The research team has already identified some of the impacts of space travel, including lengthening telomeres, the end region of the chromosomes, as well as a decrease in the addition of methyl groups to DNA, which affects gene expression. Mason is also characterizing what he describes as a space-specific microbiome and potential space genes, genes that are only expressed in space.
The near-term goal of the research is to better protect astronauts from potential negative impacts of space exploration. The research also feeds into Mason’s most far-reaching and long-term of goals. “We want to imagine the idea of a 500-year research plan,” he explains. “We want to think about the ability to genetically protect the human genome for long-term space missions.” In other words, Mason wants to think about the future of the human race.
An Ideal Scientist
Mason was once asked about his image of the ideal scientist. His response was descriptive of a pioneer: a cowboy or cowgirl heading out into the Wild West. Instead of guns in holsters, each scientist would carry a pipette on one side and a keyboard on the other.
“All my lab members have directly participated in or are intimately familiar with how to generate data as well as the algorithms for the characterization and interpretation of that data,” Mason says. “I like to call them hybrid scientists, mixtures of wet and dry lab work. I think a dual computational and biochemical approach is best to understand complicated problems.”
The team also spends time reflecting on the ethical questions that arise as science advances. Mason was deeply involved in a 2013 Supreme Court case that ruled that genes could not be patented, and conversations about issues of genetic privacy and discrimination continue in Mason’s lab.
From large-scale experiments to training well-rounded scientists, Weill Cornell Medicine is a great place for Mason to do his work. “The thing that stood out to me when I came to interview was the people,” Mason says. “I got that immediate sense of the exchange, interplay, and launching and blossoming of ideas, algorithms, and experiments. It’s very fertile ground.”