This post was authored by Kelvin Ng and James Smith. Completing his PhD this year in the Karp lab at MIT/Harvard, Kelvin focuses on strategies and technologies that guide or accelerate the translation of therapeutic extracellular vesicles. His multidisciplinary research stems from a background in drug delivery, medical devices and cell therapy. Kelvin holds an 8-year National Science Scholarship by the Agency for Science, Technology and Research in Singapore.
The now famous Minions from the film “Despicable Me”
The super villain Felonius Gru, from the film franchise Despicable Me, was obsessed with stealing the spotlight from other villains so he came up with the ultimate plan to steal the moon. What he couldn’t foresee was that the cute little creatures who did all the dirty work for him would end up with their own movie deal, and a new Minions franchise was born that stole all the attention from him. Sorry, Gru, let go of your pride. This is how the world works. Talk to our bosses.
And the world is perhaps no different to a cell, particularly when administered therapeutically. For many cell therapies, it is increasingly recognized that the mechanism of action is largely conferred by the cell’s secretome. Leave the cells on the dish, administer what they secrete instead, and it may be possible to achieve the same clinical benefit.
Over the last decade, a particular component of the secretome has spurred a tsunami of research interest. Extracellular vesicles, or EVs, are membrane-bound organelles released by a cell into its surroundings. One class of EVs is already well-known—apoptotic bodies, vesicles released when a cell systematically disintegrates during a form of death called apoptosis. The recent finding that a healthy, living, far-from-apoptotic cell also releases EVs has been a source of excitement in the field. These EVs bear many names: exosomes, ectosomes, microvesicles, microparticles, etc. It has been known for a while that neurons release synaptic vesicles capable of carrying a wealth of biomolecular information, recognizing another cell, and fusing with that cell to elicit a potent series of reactions. While synaptic vesicles are not novel, EVs bearing similar functions from most if not all other cell types are certainly worthy of intense attention.
Known for his work in intracellular vesicle trafficking, Nobel Laureate James Rothman delivered a plenary speech at the International Society of Extracellular Vesicles meeting last year. He saw vesicles as curious ‘bubbles’ that are way more complex than they appear. Whether the ‘bubbles’ are inside or outside the cell, as Rothman called them, they must serve some purpose to have survived evolution. When EVs were discovered in the 1970s, they were thought to be a way for cells to dispose of unwanted biomolecules. Now, EVs are considered an important and unique mode of intercellular signaling, particularly in immunology and cancer, with the ability to elicit functions unseen in conventional modes of signaling.
A significant portion of the EV market is dedicated to cracking the information carried by EVs, which can be as complex as the Minions’ language. EVs are highly variable in size, ranging from 20 nm to 2 μm in diameter. Because each class of EV is different, a given isolation method may bias towards contents or functions of a specific EV subset, even when prep is free of contaminating agents (i.e. free of non-EV material). Furthermore, EVs contain lipids, proteins, RNA, and even DNA, making it unclear which component is responsible for a given function. Just imagine the task of understanding how a group of Minions works, when each one is differently shaped and sized, dressed up differently, and speaks from a slightly different vocabulary.
Nevertheless, the EV market is not thwarted. The first EV-based diagnostic kit was commercially released by Exosome Diagnostics in January this year, adding to the repertoire of ‘liquid biopsies’ for cancer detection first made possible by circulating tumor cell analysis. Meanwhile, at least four companies have publicly disclosed ongoing efforts in developing EVs as therapeutics, and some already have cell therapies in their pipelines. Isolation technologies, as the market has correctly identified, are key to establishing cGMP bioprocesses and advancing EV-based products into the market.
EV-based products are beginning to challenge their cellular counterparts in both the diagnostics and therapeutics arenas. Whether hype or ripe, the demand for new tools and perspectives offers an alternative ‘franchise’ for companies that have traditionally focused on cell-based products. So, boss, do you believe in your minions?
Keep an eye out for more blogs covering EVs as we attend and cover the SELECTBIO EV conference in Cambridge, UK, July 12th – 13th.
James Smith
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