In Feng Zhang’s laboratory at MIT’s McGovern Institute for Brain Research and the Broad Institute, members “share a sense of excitement and urgency,” says Omar Abudayyeh ’12, a sixth-year MD/PhD student in the Harvard-MIT Program in Health Sciences and Technology. That’s because they are propelled by a common purpose: expanding the toolkit for manipulating genes in eukaryotic cells, and engineering genes in order to understand, treat, and cure some of our most intractable diseases and disorders.

“What Feng instills in us is the desire to do science at the edge, to push the needle,” says Abudayyeh.

The group’s most recent research accomplishes just that. They have devised a gene editing tool called REPAIR that can make precision fixes in human RNA. “It’s exciting because there are thousands of diseases caused by genetic mutations,” says Abudayyeh, who is co-first author, along with fellow graduate students Jonathan Gootenberg ’13 and David Cox, of an October 25, 2017, article in Science describing this work. “REPAIR revolutionizes how we can do genome editing, and makes it possible to correct problems, even down to a single letter of genetic information.”

The acronym stands for “RNA Editing for Programmable A to I Replacement”—referring to the tool’s ability to change a single RNA letter, or nucleic acid base, to another. A is adenosine, and I is inosine (which cells read as G, or guanosine). Single-letter mutations from G to A—the kind REPAIR targets— have been identified in such devastating human diseases as Duchenne muscular dystrophy and Parkinson’s.

This work springboards from prior discoveries by Zhang, the Patricia and James Poitras (1963) Professor in Neuroscience at the McGovern Institute, a core institute member of the Broad Institute, and an associate professor in the departments of brain and cognitive sciences and biological engineering. Since opening his lab at MIT and Broad in January 2011, the 36-year-old Zhang has been pioneering the development of CRISPR genome editing tools, technologies based on naturally occurring enzymes derived from bacterial immune systems, which can precisely snip the DNA of mammalian cells.

New domains of medical treatment


In the long slog to make personalized medicine a reality, CRISPR technology represents a potential superhighway. CRISPR systems have made it possible both to diagnose infections and diseases in people with incredible speed, and to inactivate genes associated with many diseases. With REPAIR, CRISPR-based genetic engineering takes another leap forward. Says Zhang, “The REPAIR system brings all the machinery necessary to generate changes at the RNA level into a cell, fixing genetic sequences and producing the correct proteins.”

It’s a tool that lifts a burden for biomedical researchers. “REPAIR eliminates problems that have inhibited therapeutic possibilities until now,” explains Abudayyeh. “When you edit DNA to make a correction, you worry that if the edit goes off target, it might create a mutation that accidentally turns a gene on, a mistake that gets replicated in the genome, potentially making cells cancerous.”

But because RNA itself doesn’t naturally replicate, cells subject to REPAIR’s RNA fixes don’t pass on changes to the next generation of cells, and engineered genes can revert to their original form. “We have a technology that’s like a small molecule drug: when it’s taken, it has an effect, and when you stop taking it, the effects stop,” says Abudayyeh.

This technology breaks open new domains of medical treatment. Certain kinds of liver diseases and anemias, unyielding to current therapies, are likely susceptible to REPAIR. “And it will be great for illnesses that are temporal,” says Abudayyeh. “Imagine taking something to alleviate a migraine flare, or defend against an RNA-based virus infection, like influenza.”

The technology also offers new possibilities for disorders of the brain, which Zhang has long sought to address. “During college, I had a close friend who suffered from a psychiatric disease, and from that point on, I became determined to help such patients,” he says. REPAIR provides hope, because unlike with previous CRISPR technology, says Zhang, “We now have an opportunity to make precise therapeutic corrections in neurons.”

For certain types of mental illness and other disorders and diseases that have been associated with specific, inherited mutations—think autism and Alzheimer’s and Huntington’s—novel therapies can’t come fast enough. “I get emails from patients who are affected by certain diseases,” says Zhang. “It makes me very motivated to work on these problems.”

Pushing discovery forward


“REPAIR is a broad platform with applications for many diseases, and in order to realize its full potential, we’d like to see as many different researchers as possible explore and apply the technology,” says Zhang. “We make progress when technology is open and many groups adopt these tools.” So Zhang is sharing the REPAIR system, as well as earlier CRISPR tools, through the genetic material repository, Addgene. More than 2,300 labs in 62 countries have taken advantage of the lab’s free resources.

While seeding medical research laboratories around the world with the products of their work, Zhang and his industrious team continue to refine current gene editing tools and seek fresh RNA-based applications. Their next hurdle: determining the best ways to deliver the REPAIR system into the human body.

“For both genome editing and gene therapy in general, we are trying to figure out how to get our tools into the right organs and tissues,” says Zhang. “It’s especially difficult to get payloads into the brain,” adds Abudayyeh. “We need new kinds of molecular biology to enable delivery vectors for difficult tissues.”

Team members rarely lose sight of the need for their work, or the challenges ahead. “Our lab feels like a startup,” says Abudayyeh. “I have never been in a place with such energy, or such a density of talented people.”

Today, Abudayyeh is teasing out new enzymes from bacteria and finding ways to engineer genetic systems that he hopes will soon make an impact on human health. And while participating in this biotechnology revolution can be exhausting, says Abudayyeh, “doing science at the edge is exhilarating.”


Spotlight on Professorships

Doing More for Mental Health

In 2017, Feng Zhang became the inaugural chairholder of MIT’s Patricia and James Poitras (1963) Professorship in Neuroscience. This new endowed professorship was made possible through a generous gift by James ’63 and Patricia Poitras that extended their longtime support for mental health research.

According to Zhang, the endowed chair “helps me advance developments in bioengineering, and gives me the ability to also target some technologies for treating brain-related diseases. The professorship and interactions I have with other members of the Poitras Center for Affective Disorders Research”—established by the Poitrases at MIT’s McGovern Institute in 2007—“together support more innovative and risk-taking research. It helps us do more.”


Spotlight on Fellowships

The Gift of Intellectual Freedom

Among the honors and fellowships that have fueled Omar Abudayyeh’s graduate education and research is the 2015 Friends of the McGovern Institute Fellowship. The fellowship represents the collective power of numerous MIT supporters to champion the potential of a promising scientist.

Explains Abudayyeh, “When I received my Friends of the McGovern Institute Fellowship, I was working on methods for applying CRISPR technology to target sequences of RNA. Because the fellowship covered my tuition and stipend, I had the freedom in the lab to explore different types of experiments, and maybe tackle bigger questions than I normally would. It gave me intellectual freedom, because I didn’t have to think about my budget all the time.”

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3 comments

  1. Fernando Martínez de San Vicente

    Would these techniques help a 10 month old baby with trysomy 13 (Patau’ s syndrome)?
    Would Prof. Abudayyeh or anybody in his team be aware of any existing corrective treatment and where is that treatment being used?

  2. José María Larrauri Ucelay

    I think that, in people with Down´s syndrome, in the case known as trisomy, one of the 23 pairs of chromosomes, number 21, presents not two but three chromosomes. Instead of there being one chromosome from each parent, there are three chromosomes, due to the fact that in one of the parents there has not been a previous splitting. Therefore they present 47 chromosomes in all, instead of the usual 46 chromosomes.

    I also believe that, nowadays, the splitting and the splicing of genes can be carried out in the laboratory.

    I wonder whether it would be possible to carry out these operations with the three chromosomes, to obtain the two normal ones, in blood stem cells, for example.

    And since the bloodstream reaches all the organs of the body, whether it could have any beneficial effect in patients with Down´s syndrome.

  3. Lisa

    Very impressive work!

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