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糖心TV
Office of Communications
270 Mohegan Avenue
New London, CT 06320

Amy Martin
Editor, CC Magazine
asulliva@conncoll.edu
860-439-2526

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Gene Expression

Picture of droplet being put on DNA chart

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.

By Amy Martin

A

s the first two employees of Cambridge-based biotech startup Chroma Medicine, Morgan Maeder 鈥�06 and Sam Linder 鈥�11 had many important orders of business. But at the center of it all was a simple question:

鈥淲hich diseases should we cure?鈥�

Both admit it鈥檚 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 糖心TV, 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鈥攊n humans鈥攕till seemed like the stuff of science fiction.

Now, it鈥檚 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鈥攊ncluding Joung鈥攖o 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鈥檚 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.

鈥淎ll of your skin cells have all the same genetic information as, say, your liver cells,鈥� Linder explains. 鈥淚t鈥檚 epigenetics that basically puts little signs on top of the DNA strand to tell a cell, 鈥榊ou only use this one genetic transcription code and only turn these genes on, so you can be a skin cell. And you, over here鈥攜ou only keep these genes on to be a liver cell.鈥欌��

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.

鈥淲e are sitting on top of the power to tweak gene expression in a way that doesn鈥檛 cut the genome and in no way permanently changes the sequence of the DNA,鈥� Maeder said. 鈥淭here 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.

鈥淎 good analogy is: Why would you break a lightbulb if you could just switch it off?鈥� 

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.

鈥淭here are many diseases for which the fix actually isn鈥檛 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,鈥� 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鈥檚 senior thesis adviser at 糖心TV, 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鈥檚 lab when Linder arrived on campus. During her time at 糖心TV, Linder took many classes with Eastman, whom she considers a mentor, while working in Chemistry Professor Bruce Branchini鈥檚 lab.

鈥淚n my senior year, I was doing some more intense science and I realized I really liked bench work, but I still didn鈥檛 know what I wanted to do post grad,鈥� Linder remembers. 鈥淧rofessor Eastman said to me, 鈥榊ou have a scientific mind. Would you consider working in a lab for a few years?鈥� She told me she knew someone who might be interested.鈥�

Maeder remembers catching up with Eastman over tea. 鈥淪he said, 鈥業 don鈥檛 know if you鈥檙e looking for technicians, but I鈥檝e got a student who reminds me of you and who is really awesome.鈥欌��

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鈥檚 very first employee, and Maeder soon joined as the second.

鈥淓verything was coming full circle,鈥� Linder said. 鈥淚 get to start this company with Morgan, and we get to apply these tools we developed so many years ago to actually help people.鈥�

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鈥攊n the midst of the COVID-19 pandemic.

鈥淪am and I show up in the summer of 2020, and we鈥檙e in a completely empty lab incubator space, and we look at each other like, 鈥極kay, what are we going to do first?鈥欌�� Maeder said.

鈥淭his is my third startup, but the first one we鈥檝e 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.鈥�

A good analogy is: Why would you break a lightbulb if you could just switch it off?

Morgan Maeder 鈥�06

One of the first priorities was hiring more of the team. They brought on another scientist, a CSO, and then a CEO: biopharmaceutical executive and physician-scientist Catherine Stehman-Breen, a woman with more than 15 years of experience in the still-male-dominated biotech industry.

That was a particularly exciting hire for Maeder and Linder, both mothers with young children who say they have benefited greatly from women mentors in the field.

鈥淚t鈥檚 really important to me to show people that you can do it,鈥� Maeder said. 鈥淵ou can have a really successful career in science. You can have children. I鈥檓 not going to say it鈥檚 easy. I鈥檓 exhausted all the time. But there are ways that we can continue to make it easier. I want it to be easier for the women on my team to, say, take maternity leave, than it was for me. I think we can get there, and I think the way you get there is by having women who advocate for other women and who are conscious of those efforts.鈥�

Added Linder, 鈥淭he great thing about being at a startup like this is that we get to make a lot of important decisions for the company. We are talking about designing the employee handbook and about our company culture and the things we value. As women who are part of the founding team, we can make decisions we know will benefit other women.鈥�

Now, with a team of nearly two dozen, Maeder says the company is off to a great start.

鈥淲e鈥檝e accomplished a lot of experimental work in the lab, and we are really starting to build out the vision for the company in terms of, what we are going to do in the next year? The next five? What鈥檚 our path to get our first drug into the clinic?鈥�

Maeder and Linder can鈥檛 say exactly which diseases they are currently working to cure, as Chroma Medicine is still in stealth mode, meaning the startup is operating largely under the radar with seed funding until they are ready to raise the Series A venture capital funding necessary to launch the company to the public.

As they develop their plan to eventually tackle a wide range of diseases, Chroma scientists will have to contend with one of the biggest roadblocks in the field of gene therapy: limitations in the delivery mechanisms.

鈥淲e need to be able to get these molecules into the target cells,鈥� Maeder explains.

鈥淲e are very good at doing that in some situations, like when we can take the cells out of the body, which is called ex vivo therapy. Then there are some organs that are easier to target in vivo, which means in the body, like the liver, which sucks up everything you put in the body, and others that are much harder to deliver to, like the lungs and the brain.鈥�

Several trials are already underway that use gene-editing strategies to treat the blood disorder sickle cell disease, for example, since the blood can be removed and gene-editing machinery can be used to target the single mutation that causes it.

In vivo CRISPR drug trials are rarer, but Maeder has experience: She led the development of the very first CRISPR genome-editing medicine to be dosed in a human.

At Editas, Maeder and her team developed a CRISPR-Cas9-based gene-editing approach to target the mutation responsible for a specific type of Leber congenital amaurosis, which causes childhood blindness. The therapy was used in a trial setting for the first time in March of 2020.

鈥淔ive years ago, a patient would have been told, 鈥楽orry, there is no treatment for your disease.鈥� Now, the patient is told there is a trial they can join where they will receive a subretinal injection that will cut the mutation and functionally correct the gene,鈥� Maeder said.

鈥淭hinking back on all the experiments that I did, all the gut decisions that I made over the past five years to get to something that they just injected into a person鈥檚 eye鈥攊t鈥檚 amazing.鈥�



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