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Senior Delaney Lehman researched Charcot-Marie-Tooth disease through an internship with the National Center for Advancing Trans­la­tional Sci­ences last summer. Delaney Lehman | Courtesy

Senior Delaney Lehman spent a summer finding a com­pound that could be syn­the­sized to cure Charcot-Marie-Tooth disease, a mutation that causes severe hand­icaps, in her internship with the National Center for Advancing Trans­la­tional Sci­ences.

To clarify: This research had nothing to do with sharks, French mon­archs, or dental problems.

The incurable disease, which affects 2.8 million people worldwide, causes loss of normal function or sen­sation, or both, in legs and arms, but is not fatal, according to the Charcot-Marie-Tooth Asso­ci­ation.

It is named for the three physi­cians who first described the symptoms of the disease and dis­covered the gene mutation it is con­nected to: peripheral myelin protein-22, which is involved in the devel­opment of the myelin cells in the peripheral nervous system.

Since there is no drug treatment available, people with the disease turn to physical therapy, sup­ports, and braces.

It affects any part of the nervous system outside the brain or spinal cord. Since the protein is mutated when this gene is over­ex­pressed, patients expe­rience muscle atrophy, loss of sen­sation, and loss of pro­pri­o­ception.

Lehman was assigned a col­lab­o­rative project when she got to Maryland. Since the research was at its beginning stage, she worked with the biol­o­gists who designed the exper­i­ments, physi­cians who com­mu­ni­cated with patients, and bioin­for­mati­cians who pro­grammed a robot to filter the data.

Lehman’s task was to examine and double-check pos­itive test results. She created syn­thetic organic schemes and trou­bleshooted various com­pli­ca­tions that came up over the course of doing the organic syn­thesis itself. A robot had already done the dirty work — or testing hun­dreds of thou­sands of com­pounds to find any that were pos­itive as inhibitors for the gene peripheral myelin protein-22.

Pro­fessor of Chem­istry Courtney Meyet illus­trated the role of organic chem­istry in medical research with an example: One of the biggest recent devel­op­ments in organic chem­istry has been the total syn­thesis of the mol­ecule taxol, which was first iso­lated from the bark of a yew tree and is used in cancer treatment.

Instead of trying to harvest all the yew trees and extracting the taxol, chemists can syn­thesize the mol­ecule in a lab­o­ratory. This impacts the envi­ronment less and allows them to modify the mol­ecule.

Since this process takes mul­tiple steps, it can be wasteful and unsafe, as it involves toxic chem­icals. Organic chemists research ways to shorten the routes to the com­pound, making it more effi­cient, less wasteful, and safer.

The research was unsuc­cessful, which is a common theme in small-mol­ecule research nowadays, Lehman said. While she was able to syn­thesize the com­pounds cor­rectly, when the com­pounds were tested again in the same exper­i­ments, none of the com­pounds looked like inhibitors — sig­naling it wasn’t a problem with the syn­thesis but with the original com­pound. Her adviser at the NIH Diane Luci said this was probably because the mol­ecule had degen­erated or was con­t­a­m­i­nated. The project was actually can­celed shortly after she left.

“I think it’s a really tough time to be an organic chemist in drug research, just because it’s so hard to come up with

a new small mol­ecule that is spe­cific enough to just act on DNA of interest, not cause damage to the rest of the body and not have a lot of side effects but be strong enough to do what you want it to do,” Lehman said. “We’ll see if there will be more work done on this in the future. I think there will be a lot more emphasis on RNA and DNA and gene editing.”

According to Meyet, some­times projects don’t move forward. Of the drugs on the market, mil­lions of potential can­di­dates came before those on the shelves.

“If you think of it like a funnel, and you get down to the end of the project to one or two can­di­dates, it might not be fruitful,” Meyet said.

Amid the syn­thesis and chem­istry, Lehman inter­viewed people with Charcot-Marie-Tooth Disease and saw how it influ­enced their lives, why they wanted research to happen, and how suc­cessful results would affect them.

She said those inter­views were the most inter­esting and com­pelling part. She had enjoyed organic chem­istry so much that she had ques­tioned that goal, but after her summer of research, it was the inter­views that con­firmed for her that she should become a doctor.

“I really want to be helping people in a one-on-one sit­u­ation,” she said, “as opposed to devel­oping a drug, which, sure, is really good and — if it works out — is going to help a bunch of people, but I like coming to under­stand people for who they are rather than being helpful from afar.”

NCATS is one of few lab­o­ra­tories in America that has a quan­ti­tative high-throughput screening com­puter. The robot allows sci­en­tists to select com­pounds from a chemical library (much like taking books from a normal library) and run mul­tiple exper­i­ments simul­ta­ne­ously.

Testing across two chemical libraries would take years for one person, but Lehman, using the com­puter, could conduct 1,536 sep­arate tests in a 3-by-four inch well, or 440,000 com­pounds overall.

“I know that she was a little dis­ap­pointed in how the research went, but to be able to work this robot to do this high throughput screening, I think that that is cool,” Meyet said.

Prac­ti­cally, Lehman reports feeling more com­fortable. Also, as an organic chem­istry teaching assistant, she said that she is equipped to actually answer ques­tions, rather than par­roting what she had learned but still didn’t quite under­stand.

“I felt like I could solve problems on my own, know what kinds of changes to make to an exper­iment when it wasn’t going well,” she said. “I could look at a com­pound and break it down in my head and say this is what I want to start with, this is how I want to put it together.”