Synthesizing the Natural

For Dionicio Siegel to synthesize compounds in the lab that may someday help treat neurodegenerative diseases like Alzheimer’s, he has to rely on the work of a specialized class of people. Their job, essentially, is to go mucking around in the woods.

“They have some of the best jobs in the world, I think,” says Siegel, an assistant professor of chemistry. “They go out and collect organisms—a fungus, a plant, an animal—and they take them back to the lab and blend them up. They extract compounds and then use those crude extracts and see if they have properties.”

Although scientists can sometimes predict, based on the scientific literature (as well as traditions of folk medicine), what kinds of organisms are likely to have useful compounds, the process, says Siegel, remains one that depends considerably on luck.

“Sometimes we find that compounds have a property when exposed to human cells that is different than the purpose they serve in the original organism,” says Siegel. “Maybe they kill cancer cells. Maybe they make neurons grow. Maybe they help the regeneration of pigment. They do all sorts of amazing things.”

Siegel takes up the baton once a particular natural compound has been identified as having potentially beneficial effects. Working with common substances—often petrochemicals—he looks for ways to artificially replicate the chemical structure of the naturally occurring compound.

If this “total synthesis” can be achieved, it opens up a number of possibilities, including the reproduction of a compound on a scale that’s not achievable when it’s naturally harvested, and the manipulation of compounds to improve their efficacy.

“Some natural products prove so challenging to synthesize that it takes decades and decades of several groups trying to make them in order for it to happen,” says Siegel. “Some never get synthesized.”

As a graduate student at Harvard, Siegel worked with a team that developed the total synthesis of the antibiotic tetracycline. From there, Siegel and his colleagues were able to develop structurally modified analogues of tetracycline that showed activity against bacteria that had evolved resistance to the un-modified form of the drug.

“With the development of the synthetic route,” he says, “we could control basically every single atom, where it’s placed and what’s coming off of it. We could look at the crystal structures, see where resistance elements were binding to them, and put things on them to prevent that binding. Bacteria that couldn’t be affected by tetracycline were now affected by this structurally modified tetracycline.”

Recently, Siegel has been working to synthesize two compounds that are found naturally in the root bark of the Japanese Bigleaf Magnolia tree. The compounds—clovanemagnolol and caryolanemagnolol—have shown the ability to promote the formation of neural networks in rat cells. They also increase the biosynthesis of acetylcholine, which is a neurotransmitter that gets lost in Alzheimer’s disease.

The next step, says Siegel, is to test the synthetic compounds by reproducing the activity found with the naturally occurring compounds. He’s doing that now in collaboration with Kimberly Raab-Graham, an assistant professor of neurobiology. From there, Siegel and Raab-Graham will try to discover the molecular mechanisms with which the compounds are promoting neuron growth and increased acetylcholine biosynthesis.

“We can see that growth and biosynthesis are happening,” he says, “and we know that it’s something we want to be able to encourage, but we have no idea how that’s happening. We’re hoping to fish out the target. That would be ideal.”

Although Siegel’s investigations, even if successful, are a number of links on the chain away from the development of medically viable treatments, it’s the combination of the basic science with the overarching purpose that appeals to him.

“It’s nice to be able to do the thing you love, but in the context of important problems,” he says. “The ability to control molecular architectures, to go in and assemble compounds and make them exactly how you like them, is just fascinating to me. I’m focusing on neuro-regeneration in particular because there’s a dire need for it.

“We’ve become very good at making compounds that stop processes. But we’re not very good at getting things to start going again, at discovering ways to reinvigorate neurological situations.”