This article was first published on EARTH.ORG.
European researchers are investigating the genetic mysteries of marine microorganisms to develop a range of new “blue bioeconomy” products, including antibiotics that only target harmful bacteria and food products that treat inflammatory bowel disease (IBD).
Up to a million microbes can live in a millilitre of seawater, each potentially containing useful properties that could address everything from climate change to pollution. This aquatic life is known as the “marine microbiome” and its almost limitless genetic reservoir is attracting a wave of new research.
“A microbiome is a group of different bacteria that tend to live together and they are normally associated with specific environments,” said Victor Velasco, a post-doc researcher at the University of Alicante exploring marine microbiomes off the Spanish coast.
Velasco is trying to find interesting bacteria and microorganisms living in or around a type of marine invertebrate called ascidians, to discover bioactive compounds with potential industrial and healthcare applications, such as antibiotics. His work is part of the Bluetools project, which aims to make marine microorganisms easier to research and use.
Velasco is collecting samples from different marine environments, with some possessing more promise than others. He says that underexplored areas offer a higher likelihood of discovering unique bioactive compounds since they are less studied, though shipping ports can also offer unexpected potential. These often contaminated sites are “prime locations” for finding diverse and potentially valuable ascidian microorganisms, which can thrive in such conditions.
“Another reason [we work in ports] is because we want to reduce the pressure we apply to the natural environments out there,” he explained. “It’s better to grab these ascidians from a controlled environment, such as the port of Alicante, and not the [more pristine] natural environment.”
Microbiome Data
Once some samples are collected from promising locations, Velasco stores them at cold temperatures, processes them to extract DNA, and then analyses them to identify the bacteria and their potential bioactive compounds. This includes cleaning samples to remove unwanted organisms, flash-freezing with liquid nitrogen, and grinding them into powder for easier handling. Genomic analysis then helps Velasco identify the specific bacteria and their potential bioactivity.
“I extract the genomic material from the ascidia and also the microbiome related to the ascidia,” he said. “Then, with further analysis, I try to find which bacteria are associated with these ascidia, and which bio-compounds they could hold.”
The next step is to analyse the microorganisms with the most beneficial compounds and rigorously test their potential. This is what Professor Marcel Jaspars, Director of the Marine Biodiscovery Centre at the University of Aberdeen in Scotland, is currently doing with some antibiotic genes his team has uncovered. He explains that some of the most beneficial antimicrobial properties in the marine biome can be found in the unlikeliest of places.
“[Marine microorganisms] often evolved together [with other life], like on the skin of a salmon where a bacterium evolved to protect the fish from infectious organisms,” said Jaspars. He is also part of the BlueRemediomics project, which identifies promising microbes to harness their genetic potential for the blue bioeconomy – solutions derived from renewable, living aquatic resources, such as algae, or microorganisms like bacteria.
Currently, Jaspars is using the project’s marine microbiome data to find the most promising genes to test if they have potential antibiotic properties. His team at Aberdeen is solely focusing on biochemical traits that target harmful bacteria, which would protect the stomach’s good bacteria – something that can support a healthy immune system.
“We look for gene sequences that have these characteristics,” he said, adding that their “genome mining” explores the genetic potential of various organisms to identify the desired new antibiotic compounds.
Mainstreaming Microorganisms’ Potential
According to the World Health Organization (WHO), bacteria resistant to antibiotics were directly responsible for 1.27 million deaths in 2019 and a contributory factor to another 4.95 million deaths. This is largely down to antimicrobial resistance complicating infection treatment and making other treatments riskier, especially for cancer patients or organ transplant recipients whose medicine can compromise their immune systems.
Jaspars has already identified some promising marine microbiome samples from BlueRemediomics’ data for antibiotic properties. These samples were screened to narrow in on the most interesting ones – a process that can reduce over 2,000 samples to less than ten.
After the team better understands how the most promising antibiotics work, the project applies techniques to edit and improve the samples in a cell factory, such as modifying organisms’ metabolic pathways to optimise desired results. “We can test the natural activity [to fight harmful bacteria] and then we can modify the compound using genetics and make new compounds that have higher activity,” explained Jaspars.
The next step is to grow the organism containing the original or modified genes to obtain a batch of the compound to determine if a molecule can maintain its desired antibiotic properties during large scale production. If the antibiotic properties remain effective, trials can begin on animals and, eventually, humans. Only after that would the commercial production of a new antibiotic medicine begin, but scaling up marine microorganisms to such an industrial level comes with its own challenges: volume.
If research has developed an effective blue bioeconomy product, but only a few milligrams can be obtained, its production will not be economically viable. However, some companies have already pioneered a way to scale up the needed supply.
Necton, the oldest microalgae producing company in Europe, currently grows and harnesses microalgae for a range of products – mostly for aquaculture, such as fish feed. Nowadays, they also explore new solutions that could be added to their portfolio, including medicinal products.
Patricia Diogo, Necton’s innovation manager, explains that scaling up production for new blue bioeconomy solutions from laboratory to industrial scale has to be cheap and efficient before it goes mainstream. “Cost is one of the main bottlenecks to their application, despite the fact that high demand exists in Europe,” she said.
Scaling Up Blue Bioeconomy Solutions
The high costs stem from the sophisticated biotechnological processes required to cultivate marine microorganisms in large volumes. For example, once a promising species is selected for its beneficial traits, it needs to be grown in a cost-effective manner to deliver a worthwhile profit. This requires combining optimised growth conditions with those that maximise a microalgae’s traits, which can involve a delicate balance of light intensity, temperature, carbon dioxide (CO2) levels and nutrients.
Patricia is working with Algae4IBD, another blue bioeconomy project looking to use microalgae for new treatments against inflammatory bowel disease (IBD), an illness that affects about 6.8 million people worldwide. Necton’s work is part of the development of new products that can prevent and treat IBD, demonstrating the pharmaceutical and therapeutic potential of microalgae.
“Our aim is to alleviate and mitigate the symptoms of IBD using microalgae-derived extracts,” said Diogo, adding that Algae4IBD aims to develop products like gummy bears and smoothies, which could prevent IBD symptoms from manifesting.
Necton is working to determine the production steps needed to effectively scale up Algae4IBD microorganisms at an industrial level. Diogoexplains that this typically means moving production trials to a pilot system, which often involves large bioreactors or outdoor ponds, where thousands of litres of promising algae can be grown. The production process would then be monitored and adjusted regularly to maintain optimal growing conditions.
“We typically perform semi-continuous model production. This means there is a periodic harvesting of the culture and we analyse nutrients every day to compensate as needed for optimal growth,” said Diogo.
Once a sufficient production cycle is established, the microalgae can be harvested. The biomass is then processed, which may include drying, milling, and extracting specific compounds, depending on the intended final product. Efficient harvesting and processing are crucial to retain the functional properties of the algae, especially for high-value products such as pharmaceuticals. The next and final step involves rigorous testing for quality control to ensure that the microalgae meet safety and efficacy standards before being packaged and sold to customers.
This can be a long journey, one that can take many years and cost millions of euros. Diogo highlights the need for regulatory changes to expedite the approval of new blue bioeconomy products, whether for food or medical use, which can significantly reduce the time and costs it takes to bring an innovative solution to market.
“There are a lot of microalgae-producing companies working together to pressure the EU for this purpose,” she said. “But I think it still needs to be more focused and coordinated by a new dedicated policy.”