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.

Image courtesy of Amy Wright (Photo credit: Brian Cousin)

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.

Image courtesy of Amy Wright (Photo credit: Brian Cousin)

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.

Image courtesy of Amy Wright (Photo credit: Brian Cousin)

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.

Image courtesy of Jason White (Photo credit: Brian Cousin)

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.

Image from the paper, “Dragmacidin G, a Bioactive Bis-Indole Alkaloid from a Deep-Water Sponge of the Genus Spongosorites” by Wright, Killday, Chakrabarti et al. in Marine Drugs. Image used under the MDPI open access policy.

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 Ghas shown promising results including “inhibition of methicillin-resistant Staphylococcus aureusMycobacterium tuberculosisPlasmodium 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.”

Image courtesy of Jason White (Photo credit: Brian Cousin)

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.

Image courtesy of Jason White (Photo credit: Brian Cousin)

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

Image courtesy of Amy Wright (Photo credit: Brian Cousin)

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.

VideoRay to Release the Defender at Oceanology International

VideoRay Pro 4 (Photo credit: Christian Skauge)

VideoRay, the leading manufacturer of portable observation-class ROVs in the world, will be attending Oceanology International Mar. 13 to 18 in London, where the company is launching its new mission specialist series (MSS) technology and the primary configuration: the Defender. MSS vehicles use modular components, providing customers unrivalled flexibility and reliability for their underwater missions. Larger and more advanced than the VideoRay Pro 4, the Defender configuration is designed for greater control of the vehicle position, heavier payloads and demanding intervention.

VideoRay has been developing mission specialist technology for several years now—as the next evolution of ROV technology.

“By using identical modules in different ways for different missions, we can provide both optimized solutions and benefit from the many advantages of modular design,” VideoRay CEO Scott Bentley said.

Each MSS module—including thrusters, communications, power, cameras, sensors and tools—is being manufactured in large quantities by both VideoRay and the leading vendors in the industry.  This economy of scale, and distribution of research and development cost across many configurations, yields the best performance, reliability and flexibility for MSS configurations across a wide range of mission requirements. Spare parts availability is expanded and repair speed is improved, making MSS vehicle’s reliability and uptime inherently higher than competitors’ offerings.  MSS vehicles have been delivered in many markets on a global scale, including oil and gas, aquaculture, research, defense and port security.

VideoRay’s booth will feature product demonstrations and presentations throughout the week, including the Defender and Pro 4. Stop by during the show for giveaways and a sneak peek at new MSS configurations VideoRay has planned for future release.

Source: VideoRay LLC, USA

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Cable Survey Completed for Offshore Renewables Wave Hub Test Site

UK-based Rovco performed a subsea cable survey and inspection for the world’s largest and most technologically advanced offshore renewables test site, Wave Hub. Located 16 km off the north coast of Cornwall at the eastern edge of the Atlantic Ocean, the Wave Hub site offers four cable connection points for testing offshore renewable energy technology as well as purpose-built and commissioned grid-connected infrastructure.

The inspection program included the first commercial trial of Rovco’s 3D visualization technology to create scaled, high resolution models of subsea infrastructure with millimeter accuracy. Rovco also delivered a detailed bathymetric survey utilizing a state-of-the-art multibeam echosounder (MBES) alongside an ROV video inspection with ultra-short baseline tracking for Wave Hub’s entire offshore cable network, located off the coast of Saint Ives Bay, Cornwall.

The 3D system collects raw data which is then processed to obtain 3D volumetric information. With short mobilizations and no need for large specialist vessels or technical support teams, the system generates cost savings of up to 80 percent compared with traditional survey methods.

The first phase of the project utilized the MTS Xplorer vessel to carry out the MBES survey. The second stage included deployment of Rovco’s Sub-Atlantic Mojave ROV equipped with the latest Sonardyne Nano beacons, Rovco’s prototype hi-res camera system, and a fiber optic gyro to gather accurate heading and point references. The final stage involved the Severn Sea vessel, which was used to complete the ROV visual and 3D survey.

Learn more about the Wave Hub test site.

 

Drilling and Survey Ships Assist Engineering of 1,100-Kilometer Coastal Highway

Engineering projects along a coastal highway route that crosses fjord locations in Norway will require a variety of solutions that may include above and below sea level tunnels, an end-anchored floating bridge, a submerged floating tube bridge and a multi-span suspension bridge. To inform the foundation designs of the bridges and tunnels, the Norwegian Public Roads Administration contracted with geotechnical survey company Fugro to perform seabed investigations and gather geophysical and geotechnical data.

The project includes use of two vessels to perform geophysical mapping of the fjord-crossing areas including multi-channel sparker data in nearshore areas and geophysical data in deeper fjord areas using an ROV, plus seabed sampling and cone penetration testing.

Using this data, Fugro will also perform geotechnical drilling at selected locations using its high-tech drillship Fugro Synergy. The fjords involved include Vartdalsfjorden, Sulafjorden, Romsdalsfjorden and Halsafjorden located in the county of Møre og Romsdal.

The E39 coastal highway project is the largest road project in Norway’s history, involving a 1,100-kilometer-stretch from Kristiansand in the south to Trondheim in central Norway and is estimated to require investment of approximately NOK 340 billion. Fugro is also involved in a 12-year environmental measurement relating to the building of the route with the Norwegian Public Roads Administration.

The new E39 coastal highway will function without the seven ferries currently used along the route, will be 50 kilometers shorter, and it is expected to cut the current 21 hours of travel time on the route in half.

Image Caption: E39 orthomap courtesy of Norwegian Public Roads Administration

U.S. Navy ROV Deployed to Recover Argentine Sub

RV Atlantis, operated by Woods Hole Oceanographic Institution, departs today on a mission to locate and recover the Argentine submarine, ARA San Juan, which went missing Nov. 15 with 44 crew members aboard. Atlantis was equipped this week with the U.S. Navy’s cable-operated underwater recovery vehicle (CURV), a 6,400-pound ROV that is equipped with high-resolution camera systems and sonar to detect targets in deep waters.

CURV can dive to 20,000 ft. and transmit real-time data back to the ship. If the sub is located, the CURV will conduct a close-up inspection, document its condition and look for clues to determine the cause of the accident.

Read more: Woods Hole Oceanographic Institution

Image Caption: The Cable Underwater Recovery Vehicle (CURV) was deployed aboard the Military Sealift Command fleet ocean tug USNS Apache (T-ATF 172) in Norfolk, VA. on Oct. 19, 2015 to search for wreckage from the missing U.S. flagged merchant vessel El Faro. CURV was recently loaded aboard the research vessel Atlantis to begin searching today (Dec. 7) for the Argentinian submarine ARA San Juan. (U.S. Navy photo)

Aquabotix Goes Public: Web-Based Tech and Underwater Vehicles

Aquabotix is a company that specializes in portable underwater vehicles. Its products include ROVs, hybrid AUV/ROVs and underwater camera systems. Aquabotix recently made the transition to become a public company and is now listed on the Australian Securities Exchange. ST caught up with CEO Durval Tavares and engineer Joshua Normandin to talk about the IPO and the company’s latest tech developments.

What prompted you to go public?    

DT: One of the things we were looking for was to raise some capital dedicated strictly for growth. We strongly believe the Asia-Pacific market is a huge opportunity going forward. We wanted to have physical presence in that part of the world.

Also, the Australian market has an entrepreneurial spirit. We felt strongly we could do better things in Australia than in the U.S.

We’re living up to our expectations in sales and marketing [since the IPO]. We’ve announced a couple of new tech features in our products, and we have some more features to announce in the next six months.

Has your company grown since the IPO?

DT: We have 26 people on our payroll. That’s double the size of the company before the IPO. We also do a lot of outsourcing for engineering services.

Now that you’re public, you’re beholden to shareholders. How does that change things?

DT: We were always beholden to shareholders. We used to have five [before the IPO]. Now it’s 500 shareholders. Our fiduciary responsibility has always been at the top of the list. What has changed is we’re now a public company, so there’s additional things you have to do as a public company. We have a physical presence in Australia [for example].

There’s a little more burden as a public company, but it’s something we knew ahead of time, and we’re handling it.

Tell me about new tech developments.

DT: We’ve increased our engineering team and budget. We released a couple of announcements having to do with our remote control and remote viewing capabilities. It’s more on the software side of things, the ability to interact with technology anywhere in the world. As long as you have that, you have control and see the result of the vehicle you’re working with.

You’ve now got tech that allows for vehicle control via smartphone and tablet.

DT: We’re a company that’s providing easier access for remote control. We first introduced an iPad-controlled vehicle. It was new to the world. We’ve had an iPad and a Windows app for a while. The technology for the Internet, and specifically for browsers—developing these applications is what we’re doing now. As long as you have browsers, you can access and have control over your system. We’re leading the tech trend. I expect that everybody else will be doing it in a couple years.

Who are your competitors?

DT: For ROVs, Teledyne, SeaBotix, VideoRay, Deep Trekker. For the hybrid—ROV and AUV—we break the mold by being able to go across those two markets. In terms of the hybrid market, there’s only two other vehicles commercially available, from SRS and Saab.

Our product is lower cost in the ROV market. Our value proposition is to provide the latest in tech and functionality at a price point that’s affordable.

Who are your target customers?

DT: We have multiple products. We go across a few markets. For the Endura ROV—aquaculture, infrastructure inspection, imaging generation markets, hydrogeneration, oil and gas. For the hybrid—hydrographic survey, the military and government, environmental monitoring and research.

The remote control capability will open up opportunities we haven’t seen in the past. Quite often, you have to have all experts present on a mission. This virtual presence allows you to have expertise available during remote vehicle operations.

What is the focus on the engineering side?

JN: We’re pushing on that hybrid front. We’ve been pushing tremendously. You’ll see very exciting things coming up. We’re working on Internet of Things and cloud computing.

We’ve seen some holes in the market we can address with our product line. You don’t see people taking off-the-shelf tech that exists and providing a framework that works with these components.

Cybersecurity is a big issue in the industry. How are you dealing with it?

DT: Internet of Things, remote control, remote viewing, these are based on cloud computing. The whole system is very secure. The data is only available to you. Security is in place to avoid rogue control. We use the Amazon cloud as our backbone for our services throughout the world.

What can we expect from Aquabotix in the next 6 months to a year?

DT and JN: There is a place for Web-based and cloud-based tech and a place for the hybrid. We’re going to do more exciting things with the hybrid. Autonomy is big—connectivity and intelligent behavior and autonomy, the availability of sensors, from low cost to high precision. You’ll see more intelligent behavior, connectivity through cloud computing and better sensors to gather data.

─Interview by Aileen Torres-Bennett