From the Seafloor to the Drugstore: Inventor Amy Wright on Marine Natural Products
Chemicals in marine organisms show promise for new medicines. Inventor Amy Wright is discovering why.
Those were the glory days. Amy Wright would plop down into the seat inside a giant acrylic dome to be submerged 3,000 feet underwater, with a front-row seat on the wonders far below the waters off the Florida coast. It was Wright’s first job as a chemist. She didn’t know it then, but she was riding a wave that would rise from expeditions in the Johnson-Sea-Link submersible vehicles to the breakthrough inventions in medicine she is known for today.
Days spent diving from a research ship and using robotic equipment on a manned submersible vehicle allowed Wright and her collaborators to travel to underwater vistas in the depths where, over the course of the next few decades, they would collect thousands of samples of marine invertebrates, the source materials for marine natural products.
“They had these amazing ships and subs and scuba diving. Who wouldn’t want to do that?” Wright said. “It was great. We got to go some amazing places that I don’t think a lot of people get to go, especially in the subs.”
She was working at Harbor Branch Oceanographic Institute with her former mentor and a veteran of the field, Ken Rinehart, who was a pioneer of drug discovery from marine sources and one of the first to bring natural products into clinical trials, she said. The Johnson-Sea-Link manned submersibles owned by Harbor Branch were invaluable for uncovering useful drug sources from the sea.
“They had decided, here are these amazing subs, they can go collect amazing stuff, how do we use them?” Wright said.
Since then, Wright has been the common denominator on a series of successful projects that have figured out how to use source materials from the sea to create new biological technologies that might hold the answers to society’s most vexing diseases like cancer, tuberculosis, Alzheimer’s, malaria and heart disease.
The samples collected over nearly half a century now total 31,500 specimens, including benthic marine invertebrates and macroalgae, or seaweed, molluscs, corals, sponges and soft sponges, tunicates and marine microbes. Understanding the structure and function of these compounds is Wright’s job.
She uses the samples like we use coffee grounds, extracting chemical compounds the way we extract caffeine in our brew, only she uses a liquid much stronger than water, and she extracts hundreds of natural products from each sample. The extract is concentrated into a goo or powder, which is then separated out into the compounds it contains, leaving pure samples that can be isolated, enhanced, and tested to see if they are useful as molecular soldiers. To be successful, samples have to show biological activity, like the ability to battle cancer in tricky ways, by undercutting the survival of mutant cells with the right behaviors at the cellular level.
“We have to get enough compound and enough data to convince a company that they want to invest.”
But before they can test how a compound behaves in the face of cancer or heart disease, the scientists need enough of the compound to work with, and they need a pure version, without any toxins.
It can be challenging, Wright said, “to get enough compound and enough data to convince a company that they want to invest,” in further developing a medicine.
Wright has become an expert at these separation methods, fractionating enriched compounds out from one another like a patient mother untangling a knotted ponytail one hair at a time. But Wright uses chromatography—a method similar to pulling the colors out of a black ink spot by letting water soak upward on a piece of paper, leaving trails of color behind. This capillary absorption method separates the compounds from one another so she can see how many compounds are within a single sample.
Purifying the compounds is important because mixed in with the useful ones, there are some that are toxic. In some cases, “no toxicity is allowed,” Wright said.
“An Alzheimer’s drug [would be taken for a long time], so if there’s any hint of toxicity, you’re not going to be able to use that drug.”
From the Seafloor to the Drugstore
One big bottleneck on the road from the seafloor to clinical trials for new drugs using marine products is having enough of the compound. One sample of sponge might only produce a few micrograms of a compound, while kilograms of it are needed to get to a successful product, Wright said. She is clearly insistent upon conservation.
“When you extrapolate up how much of the organism you would have to be able to either grow or collect, there’s not that much organism [available to us], and it wouldn’t be environmentally sound to [collect too much],” she said.
There are options for creating synthetic versions based on the molecular model of the compound, but finding a compound that performs a useful function is the first step. How cancer cells behave is often not understood until after researchers find a compound that effectively stops them, so synthetic designs can only serve to augment a discovery, not replace it.
Solutions depend on testing new, unique compounds and natural products derived from hundreds of different marine organisms. It is a giant game of trial and error, testing what works and what doesn’t.
The process is further complicated by the fact that there are often hundreds of compounds in a single organism, swirled together in a biological chemical mixture. Some labs Wright works with can run thousands of assays, or biological activity tests, per hour. But mixtures of compounds present a problem for those labs.
“If we want to work with groups like this, we have to change how we work,” Wright said at a 2013 lecture. Much of Wright’s work is in untangling this mixture problem, separating out the compounds from one another so that pure samples are available in the form of enriched compounds.
The pure versions live in the Harbor Branch Peak Library (named for the peaks on chromatographs that show there might be an interesting compound present), and Wright accepts proposals from collaborators who think they might be able to use some of the compounds in their research. For example, she has sent materials to scientists working on drugs to treat complications related to stroke, heart disease, cancer, fibrosis, Alzheimer’s, tuberculosis, malaria, and the waterborne parasite cryptosporidium.
But, each collaborator who taps into the collection depletes the supply a little more. Some need small amounts to test, others need more. How much material a project proposes to use factors into Wright’s decision whether to collaborate. And, each collaboration for use of the materials also requires a new funding source.
Harbor Branch today runs largely on grants, and Wright has become as much of a genius at earning grants as she has patents. She holds 33 U.S. patents to date, each of them for some compound with a particular activity that is useful on the molecular level at battling some disease’s behavior.
While Wright separates compounds and maps out their structures, collaborators work to modify these compounds so they will function more like drugs—to be stable, to stay in the bloodstream longer or to enter the cell better.
Modeling New Medicines
Today medicine is more complicated that just trying to find something to kill the cancer cells, Wright said. It is more nuanced, and researchers are working on finding a compound, for example, that reduces the cancer cell’s production of a protein it needs to survive, or a compound that gives your immune cells a new signal to recognize cancer cells instead of ignoring their camouflage.
When a natural marine product works, Wright’s job is to then figure out exactly how it works and what it is doing—the details of its biological activity—as well as its structure. Chemical structure maps look like a cross section of a honey bee’s hexagonal hive structure, with six-sided shapes strung together and stretched out across the page. Understanding a marine chemical’s structure is important because it helps isolate one compound from another, like choosing the part of a street map that shows only your neighborhood without the rest of the streets in town.
The chemical structure map helps scientists separate the compound out to its pure form apart from the rest of the material extracted from an organism. But structure is also important because it provides synthetic chemists, who want to try to recreate the compound, a picture of the compound’s molecular infrastructure, which can then be mimicked to create a synthetic version or altered to give the compound characteristics that are more useful for medicines.
In place of having endless amounts of material, Wright’s fellow scientists have other options, including organic synthesis to make copies of the compounds in the laboratory, creating invertebrate cell cultures to grow the cells of sponges, fermenting compounds that might be made by microbes living in the marine organism, or using biosynthesis techniques to pull out genes that make the compounds.
“We think some of the compounds are not actually made by the sponge itself, but may be made by microorganisms, bacteria that live inside the sponge,” Wright said. “So if we could ferment those bacteria, then it would be similar to the way that they make penicillin or erythromycin.”
Though fermentation is proving difficult, for those compounds produced that way, it would provide a solution for growing large amounts in huge fermentors similar to those at a microbrewery. Other options exist on the frontier of medical and biological science, Wright said.
“We need to look for other options, either synthesis or to try to find the microbes from that organism that can make it, or even just get the genes that are responsible for making it and then try to get that into [a host organism]… a genetically engineered microbe that can pump out the compound,” Wright said.
Some of Wright’s collaborators are also working on solutions to battle the “superbug”, an antibiotic-resistant bacteria called Staphylococcus aureus, also known as MRSA. The solution they extracted from a sponge of the genus Spongosorites—a compound they named dragmacidin G—has shown promising results including “inhibition of methicillin-resistant Staphylococcus aureus, Mycobacterium tuberculosis, Plasmodium falciparum, and a panel of pancreatic cancer cell lines,” according to their paper published in the journal Marine Drugs this year. (You can read the full text here.)
Freezer Full of Gold
At Harbor Branch, in a freezer a quarter of the size of a large conference hall, sit 31,500 samples of marine organisms, including more than 15,000 that are large enough to test. The collection also includes 19,000 marine microbes.
“Old [specimens] that we never thought were interesting, now it turns out, some of them are interesting. These are totally new ways of approaching cancer cells. I figure we need to save it for the future,” Wright said. “We find new information about diseases every day, and new ways that maybe we could intervene that maybe we never knew about before, so you want to make sure that you’ve saved [material] for that new assay.”
Wright’s conservation sensibilities have served the collection well. For each organism collected, only a small piece is cut off for testing. The rest is frozen for future use.
Today, in place of the Johnson-Sea-Link submersibles with their giant acrylic domes to carry people underwater, Harbor Branch uses unmanned remotely operated vehicles (ROVs) that are tethered to the ship and operated by drivers using cameras to direct its action and collect samples into a basket.
Harbor Branch built the instrument package to be installed on an ROV called Mohawk that is operated by the University of North Carolina in Wilmington with tools similar to the Johnson-Sea-Link instruments. While the tools on the ROV were designed to mimic the function of the Johnson-Sea-Link, Wright says it’s not the same as going down to explore with your own eyes.
“It was always more effective to have a person in the manned submersible because you can see things that you may or may not see with the ROV,” Wright said. But, while looking with your own eyes was optimal, she said she can’t complain about the approximately 200 samples the last ROV expedition brought back to the lab.
There is a documentary component to the process of marine specimen collection. Each sample was archived together with pictures of the organism, its habitat, video of where and how it was collected, characteristics of its environment and plenty of other metadata to go with each sample. This week, Wright and her collaborators earned a $500,000 National Science Foundation grant to process the video from the collection and put much of the data, including video documentation, online so it is more accessible.
“Every time, we find new compounds that we haven’t seen before.”
There are a total of approximately 230,000 marine vertebrates and invertebrates that have been documented as species. And while the Harbor Branch Oceanographic Institute collection is unique, along with several other large collections around the world, actual numbers of undiscovered species range from two million to 10 million. There is plenty of work left to do to explore and find undiscovered chemicals from marine organisms.
“Every time, we find new compounds that we haven’t seen before. So I imagine for a while people will keep doing that,” Wright said, reflecting on her experience across more than 30 years of diving into deep water habitats. “It can be very rich in organisms, and [many of] those [deep water places around the world] have not been looked at. So I’m sure that people will keep finding stuff.”
—Story by Amelia Jaycen
Amy Wright was inducted this week into the National Academy of Inventors at a ceremony held in Washington, D.C. The Johsnon-Sea-Link manned submersible vehicles were retired in 2011 and are now on display at Harbor Branch Oceanographic Institute.