Pharmacy From The Sea

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Marine Microbes and the Search for New Medicines 

Early in the morning on a tropical reef, the ocean floor is full of life. Corals form hard, stony structures, and algae grow with thick, tough bodies. But among them are organisms that appear almost defenseless, thin filaments rising from the seafloor and waving in the currents. These delicate strands are marine cyanobacteria. They look fragile compared with the other life forms on the reef. As marine natural products, Distinguished Professor Bill Gerwick of the Scripps Institution of Oceanography explains, they resemble individual filaments that resemble hair, sometimes described as “mermaid’s hair.” As a Distinguished Professor at UC San Diego’s Skaggs School of Pharmacy and Scripps Institution of Oceanography, William Gerwick leads global expeditions to remote marine environments, from Panama and Madagascar to Papua New Guinea or India, to collect unique algae and cyanobacteria. His pioneering research integrates these international field studies with discovery and evaluation in the areas of cancer, inflammation, infectious disease including tropical diseases such as malaria, Chagas’ disease, leishmaniasis, neurochemical pathways, antiviral activity to SARS-COV-2 as well as agricultural uses. 

Unlike corals or many algae, cyanobacteria do not have hard structures or physical defenses. These tufts of cyanobacterial filaments just wave around in the currents, no protection at all. A fish could come and just gobble it up, yet they survive in this competitive environment. 

The survival of cyanobacteria in predator-rich environments is likely due to their "chemical weaponry,” the production of potent natural products that discourage fish and other grazers. Scientists are finding that these same defense mechanisms are what make the organisms such a rich source of medicine, the high-potency molecules they evolved for survival are being repurposed by researchers to target specific disease pathways in humans, such as inhibiting tumor growth or neutralizing infectious bacteria. While more research is needed to fully map their ecological role, this biological defense system serves as a natural library for drug discovery. 

For Professor Gerwick and his colleagues, these defensive chemicals represent more than ecological adaptations; they are potential starting points for new medicines. 

From Ocean Microbes to Chemical Discovery 

The process of studying these compounds begins with collecting organisms from marine environments. Researchers bring cyanobacteria back to the laboratory and attempt to grow them in culture. This is necessary because the compounds they produce are often present only in extremely small amounts in nature. 

“We try to capture the life form and bring it back and grow it in the laboratory to get that large amount that’s needed for chemistry,” Professor Gerwick explains. 

Once researchers have sufficient material, they extract the natural products from the organism. They make an extract of that cyanobacterium and use organic solvents to extract the natural products from the tissue. 

The next step is to determine whether the extract has any biological activity. Scientists test the extract in biological assays, for example, experiments that measure whether the compounds affect cancer cells. 

“Let’s say we found this extract was toxic to cancer cells. We then use that cancer cell assay to guide the isolation of the active compound,” Professor Gerwick explains.

This process is known as bioassay-guided isolation. Researchers separate the crude extract into fractions using chromatography (a separation technique that acts like a "chemical filter," sorting a complex mixture into its individual ingredients by washing it through a material that makes different substances move at different speeds.), test each fraction for activity, and track which fraction retains the biological effect. Over time, this repeated process of separation and testing leads to the isolation of a single pure compound. 

Determining the molecular structure of that compound can be challenging, scientists use techniques such as nuclear magnetic resonance spectroscopy and mass spectrometry to understand the arrangement of atoms in the molecule. 

Understanding Biosynthetic Pathways 

Once researchers know the structure of a compound, they can begin to understand how the microorganism produced it; the structure often provides the first clues about the biosynthetic pathway involved. 

For example, some molecules are built like long chains of fatty acids using simple, vinegar-like building blocks, while others are custom-made in a biological workshop that pieces together protein fragments without following the cell's usual genetic manual, which link together the building blocks of protein. 

“We know that they use a lot of pathways for linking acetate units together to make so-called polyketides,” Professor Gerwick explains. “We know that they use something called a non-ribosomal peptide synthetase pathway to assemble amino acids, and they mix and match those pathways together.” 

These biosynthetic systems function somewhat like assembly lines, adding molecular building blocks step by step to produce complex structures. 

Hidden Potential in Microbial Genomes 

Modern genome sequencing has revealed that marine cyanobacteria may produce far more compounds than scientists have already discovered. Professor Gerwick’s laboratory has sequenced the genomes of more than one hundred marine cyanobacteria. 

“In all cases, we find many more biosynthetic gene clusters than we find compounds,” he says. 

This suggests that many pathways are either inactive or produce compounds at concentrations too low to detect with current techniques, sometimes referred to as silent gene clusters. 

Researchers have attempted to activate these pathways using various strategies, including adding chemical elicitors that might trigger gene expression. However, the results have not been consistent. 

Understanding how these pathways are regulated in bacteria remains a major challenge. 

Engineering Microbes to Produce Marine Compounds 

Another approach to studying marine natural products involves transferring biosynthetic genes into other organisms, this is known as heterologous expression. 

The idea is to clip out that set of genes and move them into the heterologous host. Researchers have used

several different host organisms for this purpose, including other cyanobacteria, species of Streptomyces, and Escherichia coli. 

However, going from gene insertion to actual compound production in a new host is difficult as some host organisms lack the necessary accessory enzymes required to activate biosynthetic pathways. For example, certain pathways require a protein called SFP that modifies enzymes so they can function. 

Another challenge is the size of the DNA involved, as some biosynthetic pathways span more than 100 kilobases. In this specific context, 100 kilobases is exceptionally long, it is the difference between copying a single recipe and trying to photocopy an entire encyclopedia without losing a page, which makes it difficult to transfer between organisms and differences in codon usage between species can also interfere with gene expression. 

Even when the genes are successfully expressed, the compound produced may be toxic to the host organism. There are many ways to fail and only a few ways to succeed. 

Sustainability and the Ocean 

Despite these challenges, heterologous expression offers an important advantage: sustainability. Rather than harvesting organisms from marine ecosystems, scientists can produce the compounds in laboratory cultures or fermentation systems. 

Professor Gerwick emphasizes that researchers should look to the ocean for inspiration rather than treating it as a commercial source of materials. “I do not think we should be looking to the sea as being a commercial source of those compounds,” he says. “History would show that we can devastate a resource very quickly.” 

Instead, scientists aim to learn from marine organisms and replicate their chemistry in controlled environments. 

From Marine Compounds to Cancer Drugs 

Marine cyanobacteria have already contributed to modern medicine, for example, one compound, dolastatin 10, has inspired several drugs currently used to treat cancer. 

According to Professor Gerwick, seven drugs on the market today are based on modifications of this molecule, and these therapies belong to a class known as antibody-drug conjugates. 

In these treatments, the toxic compound derived from the cyanobacterium is attached to an antibody that specifically recognizes cancer cells. Think of an antibody as a custom-made key, it only fits into one specific lock (like a virus or bacteria), and once it clicks into place, it locks the invader down so it can't cause harm. The antibody then binds to the cancer cell and delivers the compound directly to it. 

The drug complex is taken into the cell through endocytosis. Endocytosis is the process cells use to "eat" or "drink" by wrapping their outer membrane around a particle and pulling it inside in a small, bubble-like pouch.Think of it like a beanbag chair, if you push a heavy ball into the side of the chair, the fabric folds inward around the ball until it’s completely swallowed up and tucked away inside. Inside cellular compartments such as lysosomes, enzymes break the linker connecting the drug to the antibody, releasing the toxic molecule inside the cell where it kills the cancer cell selectively.

Possibilities in Neuroscience 

Professor Gerwick describes compounds discovered in a cyanobacterium collected in the Caribbean that affect neurons in laboratory experiments. When applied to neurons, these compounds cause them to proliferate and to grow dendrites with a lot of branch points, such effects could be useful for studying nerve regeneration, including recovery from injuries such as spinal cord damage. 

Other work in Professor Gerwick’s laboratory involves modifying natural compounds to improve their ability to cross the blood-brain barrier so they could potentially be used to treat brain cancers such as glioblastoma. 

The Future of Marine Drug Discovery 

Looking ahead, Professor Gerwick believes several emerging technologies could accelerate discoveries from marine microbes. One major opportunity lies in activating the many biosynthetic pathways hidden within microbial genomes. 

Another promising development is artificial intelligence, which may assist in identifying promising organisms, helping determine molecular structures, predicting biological targets, and planning chemical syntheses. 

For researchers in this field, the excitement often comes from discovery itself. When scientists analyze extracts from marine microbes using tools such as liquid chromatography and mass spectrometry, they may be seeing molecules that have never been observed before. 

“We’re the first humans to ever see what it makes,” Professor Gerwick says. 

Each new organism collected from the ocean may contain unknown chemistry and possibly the starting point for the next generation of medicines.†

Written by Editor and Staff Writer Meher Kevani (mkevani@ucsd.edu)