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RNA Researchers Making an Impact on Modern Medicine and Graduate Education

Matthew D. Disney, Ph.D.Ian J. MacRae, Ph.D.

Located on TSRI’s La Jolla, California campus, Ian MacRae’s laboratory studies how certain types of small RNAs control gene expression in cells. In the process, he’s shedding light on the complex inner workings of RNAs.

MacRae’s research is focused on better understanding a process within cells called RNA interference (RNAi), which is involved in many critical biological functions. The process of RNA interference involves small RNA molecules essentially shutting off gene expression, also known as “gene silencing.” While this may sound like an undesirable outcome, it is actually a critical biological process that, among other things, protects cells from viruses.

A key driver of this process is a type of protein called Argonaute, which essentially “sticks” to several types of small RNA molecules, together forming a structure that facilitates the gene silencing process.

“We have figured out how Argonaute holds the RNA and then uses it to find matching RNAs,” said MacRae, an associate professor in the Department of Integrative Structural and Computational Biology. “Now we are trying to understand, once Argonaute finds a gene—a messenger RNA to regulate—what happens next. We are doing well on that goal.”

There’s a lot at stake. By studying the structure and function of some of the underlying mechanisms of RNAi, MacRae hopes to uncover clues that will lead to the development of RNAi-based medicines for the treatment of human disease. Several labs and companies are working to design synthetic RNA molecules that could be given to patients as highly targeted treatments for a wide array of diseases.

“There’s a huge effort in the pharmaceutical industry, and there has been for a decade, to tap into this system and use it,” said MacRae. “The general idea is that if you could get the RNAs to where you want them to go—if you can deliver them into cells—you could control gene expression and a lot of what is happening in the cells. In principle, it’s a very powerful approach to treating many diseases. It’s clear that if you can get the RNA into the cell that you want, it will do what you want it to do. The challenge has been to get it into the cell.”

A breakthrough in this area would open many therapeutic doors. One of the key challenges has been to prevent the human body from recognizing these synthetic RNAs as foreign and eliminating them before they can reach their disease targets.

“We have a collaboration with one company that has done some of this work,” said MacRae. “We can look at directly at how the modified RNAs work with the Argonaut protein then start to understand why the things they’re doing work, and maybe help direct making better versions of the RNA. In principle, you could treat a ton of different diseases if you can deliver these RNAs. Most of the diseases they’re looking at now are liver diseases because everything (medicines) first goes to the liver.”

Education-Driven Research

MacRae’s laboratory seeks answers to these difficult problems using a diverse set of research disciplines ranging from structural biology to chemistry, in an academic setting focused on the training of doctoral students and postdoctoral fellows. With three doctoral students currently working in his lab, he has been a consistent supporter of TSRI’s graduate program.

“The graduate students are treated really well here,” said MacRae. “They are respected as important members of the institute, which I haven’t seen in other places I have worked. Students’ committee meetings are also different. At other institutions it felt like students needed to prove they were worthy. We have already decided that students are good because they are here. The goal of [TSRI] committee meetings is to answer this question: ‘How can we help this person get as far along in their research as possible?’ There’s not a lot of space for accolade and messing about. It’s a ‘roll up your sleeves and get this done’ mentality. Messing about with whether you are worthy is not in line with where you want to go. This goes back to why I really like TSRI. We just want to move forward. Our focus is to get to the goal, not who gets there first.”

MacRae’s own path toward a career in biomedical research was shaped by early exposure to skills that would ultimately prove invaluable in the lab. With several family members in construction and carpentry, a career involving excellent spatial understanding and a curiosity about how things are put together may have been inevitable.

“A lot of what I do in my work is structural biology, which is seeing things in shapes and using a lot of the same parts of the brain,” said MacRae. “I was always a little scientist. I was always tinkering with things trying to figure out how things work.”

As a college undergraduate at the University of California, Davis, he decided to study medicine, partly because of his love of science, but also for a reason considered by many undergraduates: the potential for a successful and lucrative career.

“I figured I’d be a physician because everyone likes them, they make a lot of money, and that sounds good,” recalled MacRae. “Then during college I started doing research, because I could get a letter of recommendation to go to medical school. I liked it and so I kept doing it. I published a first author paper as an undergrad and my advisor said, ‘You almost have a Ph.D., you should just stay on! You can go to medical school afterward.’ So I stayed in the same lab that I did my undergraduate work in.”

Powerful Moments of Discovery

The process of discovery was the spark that ignited his love for research in college and it’s the fuel that still drives his work today.

“Discovery is the thing you are always looking for, and it’s probably like a drug,” laughed MacRae. “You have a mystery, and your mind is working on it and working on it. You pick at it and then, finally, some observation or insight or breakthrough happens and, suddenly, all of these things that didn’t make sense, make sense. That feeling is a very, very good feeling. It’s addictive, and it’s fantastic.”

MacRae added that the only thing better than this process of discovery is the opportunity to experience it with colleagues and students.

“It’s so fun to be able to share those moments, as it’s usually with someone else or a couple people. And you all realize it. Often times one person will have one part of an idea and another person will think, ‘Oh that reminds me of something else’ and the third person will say, ‘I see the connection,’ and that is so much fun.”

Scripps Education Reporter

Edition 5, Summer 2016

IN THIS ISSUE

Edition 5 Home
TSRI Celebrates 24th Commencement

Graduate Faculty Profiles 
New Philanthropic Fellowships
Alumni Website Update
2016 DiVERGE Dates Announced
Catching Up with TSRI Alumni

 

RELATED LINKS

Scientists Capture Picture of MicroRNA In Action

Team Finds Key to Gene-Silencing Activity

Scripps Research Institute Scientists Find the Structure of a Key ‘Gene Silencer’ Protein

 

 

Image

In a recent study, MacRae and members of his lab were able to determine the structure of human Argonaute-plus-microRNA in the act of binding to an RNA target—adding greatly to the understanding of a fundamental system of regulation in biology.
(Image courtesy of the MacRae lab.)

 

 

 

 

 

 

 

 

The MacRae Group

The MacRae Group
(click to enlarge)

 

 

 

 

 

 

 

 

 

 

Link to Jessica Youtube Video

In this video, meet Graduate student Jessica Sheu-Gruttadauria, who is a structural biologist and biochemist studying in the MacRae lab.
(click above to watch on YouTube)