Algae have proven to be experts in molecular warfare with bacteria – and now is the time to apply that expertise to drug discovery and development.
Andrew Dahl |
Certain algal species have been cultivated in Asia as both a source of nutrition and as a traditional medicine for centuries. What most people don’t realize is that algae range in size from microscopic cells floating in freshwater, to the huge kelp beds off the California coast, and everything in between. The very smallest, as you can imagine, are referred to as microalgae, and most of the green stuff people consider seaweed is technically macroalgae. About 72,000 species of algae are known – and in my view there are probably double that number yet to be discovered and classified. Of that enormous number, only about a dozen are being cultivated commercially anywhere in the world. Algae can be cultivated in natural and artificial ponds, on wooden frames set in estuaries, in photobioreactors and fermentation tanks. There’s plenty of opportunity to cultivate something that has never been grown or consumed by humans or animals, and some of these could be very useful for new pharmaceuticals.
Algae are incapable of movement on their own and are completely exposed to their environment. To regulate their immediate environment and to protect themselves, algae excrete many different types of exogenous secondary metabolites. One of the biggest threats to most forms of algae is dissolved oxygen in the water, which can degrade the cell wall (even though algae produce oxygen as part of photosynthesis and excrete it into the water). One protective measure is to allow certain types of bacteria to form a plaque over the surface of the algae, but not so thick that it prevents light from reaching the algae’s chloroplasts; the bacteria will absorb the oxygen and also produce a clear protective slime that protects both algae and bacteria. However, some bacteria are more aggressive and begin to attack the host algae, which responds with an arsenal of bioactive molecules that can paralyze the bacteria – sometimes killing it altogether – or fool it into thinking there are already too many bacteria on the host algae and, thus, the bacteria stop reproducing.
This warfare at the molecular level is why algae should be taken more seriously as a source for new and novel therapeutic agents. Algae can produce both small and large molecules – some are toxic, but most are not. The challenge is that a single strain of algae will produce dozens, if not hundreds, of different compounds over the course of a single day, and separating the active from inactive is a gigantic task. However, well-documented bioassays, as well as knowledge regarding gene signaling, histopathology and mechanisms of action can help guide researchers to particular metabolites. For the past 10 years, I’ve been involved in testing select algal strains both in vitro and in vivo, and the results are promising, especially with respect to immune/inflammatory modulation and hypercholesterolemia modification, both in mammals.
Algae much like many other natural sources, have been overlooked in current drug development initiatives, which instead focus on computer-generated 3D structures, predictive modeling and high-throughput screening to comb vast libraries of seemingly random molecular combinations, looking for a beneficial effect. Certainly, these are crucial developmental tools, but it is unfortunate that the field of pharmacognosy, or the study of medicines derived from natural sources, has become somewhat esoteric and uncommon in drug development circles.
In Asia, especially Japan and China, research into algae-based drug candidates has been ramping up over the past two decades, and I think we will see a pipeline developing in time. Fascinating work is also taking place in the US – particularly the work of William Gerwick at the Scripps Institute in La Jolla, and Stephen Mayfield’s work at the California Center for Algae Biotechnology, also located in La Jolla, where marine algae metabolites are being investigated for new cancer drugs. As of today, there are a handful of algae-based pharmaceuticals in pre-clinical trials. As well as aiding drug discovery, algae can be modified to produce biopharmaceuticals, and in some cases, more efficiently and safely than other recombinant platforms. For example, research presented in The Proceedings of the National Academy of Sciences has highlighted how a genetically engineered strain of algae can be used to produce a complex human therapeutic drug. According to researchers at the University of California-San Diego, this particular strain, Chlamydomonas reinhardtii, can produce a wide range of human therapeutic proteins more efficiently than bacteria or mammalian cells (1). In fact, many of the algae being investigated are modified strains designed to produce a therapeutic that’s been previously produced by other recombinant platforms, such as yeast or E. coli. In the near future, popular drugs like insulin, cytokines, monoclonal antibodies and subunit vaccines may be produced by algae at a lower cost and higher purity. The variety of research being conducted with algae for the potential development of pharmaceuticals has been widely reported. For example, work on the ability of genetically engineered algae to selectively kill cancer cells has been reported in Nature Communications (2) and a more comprehensive review of the role of algae in pharmaceutical development has been published in the Journal of Pharmaceutics and Nanotechnology (3). The field is developing slowly, but I’d like to see it pick up pace and head towards more mainstream adoption.
- M Tran et al., “Production of unique immunotoxin cancer therapeutics in algal chloroplasts”, PNAS. 2, 100, 14 (2013).
- B Delatat et al., “Targeted drug delivery using genetically engineered diatom silica”, Nat Commun (2015).
- T Aditya, G Bitu, EG Mercy, “The role of algae in pharmaceutical development”, Pharm Nanotechnol, 4, 82-85 (2016).