Gene Expression
Chroma Medicine, a biotech startup, is changing the face of medicine through epigenetic editing, a process to regulate genes without permanently altering DNA.
As the first two employees of Cambridge-based biotech startup Chroma Medicine, Morgan Maeder ’06 and Sam Linder ’11 had many important orders of business. But at the center of it all was a simple question:
“Which diseases should we cure?”
Both admit it’s a bit surreal. A decade ago, when the two first worked together in the Massachusetts General Hospital laboratory of gene-editing pioneer J. Keith Joung, Maeder, then a Harvard graduate student, and Linder, a technician fresh from graduation at Conn, ran very early experiments aimed at changing the way genes were expressed without cutting or permanently changing the DNA sequence.
But actually using that technology to make medicines to cure or treat genetically based diseases—in humans—still seemed like the stuff of science fiction.
Now, it’s their job.
Maeder is the director of payload sciences at Chroma, and Linder is a scientist. The company was launched in 2020 by four academic researchers—including Joung—to revolutionize the treatment of genetically driven diseases using a brand-new epigenetic editing tool, called CRISPRoff.
Traditional gene-editing tools, including the popular CRISPR-Cas9, use DNA-cutting proteins to cut out a piece of the DNA strand, and then allow the cell’s natural DNA repair process to patch it. The process can be used to delete or correct precise regions of DNA, but the modifications are irreversible and the repair process can sometimes be unpredictable, especially if multiple cuts are made.
CRISPRoff, on the other hand, mimics one of the ways cells naturally regulate gene expression, called epigenetics.
“All of your skin cells have all the same genetic information as, say, your liver cells,” Linder explains. “It’s epigenetics that basically puts little signs on top of the DNA strand to tell a cell, ‘You only use this one genetic transcription code and only turn these genes on, so you can be a skin cell. And you, over here—you only keep these genes on to be a liver cell.’”
By attaching a chemical tag to targeted parts of the DNA strand, CRISPRoff can tell a cell to turn a gene on, off, up or down. It can be used on multiple genes at the same time, and it is completely reversible.
“We are sitting on top of the power to tweak gene expression in a way that doesn’t cut the genome and in no way permanently changes the sequence of the DNA,” Maeder said. “There are a lot of things that gene editing does really well, but there are some areas where I think epigenetic editing is going to prove to be more powerful.
“A good analogy is: Why would you break a lightbulb if you could just switch it off?”
Since most human diseases have a genetic component, epigenetic editing could be used to create therapies to treat everything from inherited conditions like sickle cell disease and cystic fibrosis to cancers, neurological disorders, metabolic diseases, and even viral and bacterial infections.
“There are many diseases for which the fix actually isn’t all that complex, and we know if we can just do this one thing and get it where it needs to go, we can help so many people,” Linder said.
While they now work together daily on the edge of scientific possibility, Maeder and Linder may never have met if not for Associate Professor of Biology Deborah Eastman.
Eastman was Maeder’s senior thesis adviser at Conn, and it was in her lab that Maeder discovered a passion for hands-on science. But Maeder had already graduated and was working in Joung’s lab when Linder arrived on campus. During her time at Conn, Linder took many classes with Eastman, whom she considers a mentor, while working in Chemistry Professor Bruce Branchini’s lab.
“In my senior year, I was doing some more intense science and I realized I really liked bench work, but I still didn’t know what I wanted to do post grad,” Linder remembers. “Professor Eastman said to me, ‘You have a scientific mind. Would you consider working in a lab for a few years?’ She told me she knew someone who might be interested.”
Maeder remembers catching up with Eastman over tea. “She said, ‘I don’t know if you’re looking for technicians, but I’ve got a student who reminds me of you and who is really awesome.’”
With Linder officially on board, the two experimented with early epigenetic editors and published their findings. In 2013, after earning a Ph.D. in genetics from Harvard University, Maeder was hired as the first scientist at Editas Medicine, a CRISPR-based gene-editing company, where she eventually worked her way up to senior scientist before moving on to another biotech startup. Linder went in a slightly different direction, earning a Ph.D. in biological and biomedical sciences at Harvard and working in a chromatin biology/cancer biology lab to learn more about human therapeutics.
The two stayed in contact over the years. Then, in early 2020, they were both recruited by Joung, their former boss, to join Chroma. Linder signed on as the company’s very first employee, and Maeder soon joined as the second.
“Everything was coming full circle,” Linder said. “I get to start this company with Morgan, and we get to apply these tools we developed so many years ago to actually help people.”
They may have had the tools, the ideas and each other, but the two scientists still needed to build a company from the ground up—in the midst of the COVID-19 pandemic.
“Sam and I show up in the summer of 2020, and we’re in a completely empty lab incubator space, and we look at each other like, ‘Okay, what are we going to do first?’” Maeder said.
“This is my third startup, but the first one we’ve launched during a pandemic. Sam and I benefited greatly because we already knew each other and had a great working relationship, which helped us through those times we had to minimize exposure and work on Zoom.”