October 29, 2021

Insects as biotech engines

By Conor McKechnie and Dodi Axelson

Insects as biotech engines

We’ve talked about slime, seaweed, mushrooms, and now creepy crawlies. Insects are an important source of proteins in two forms: medicines and meals. Insect pupae can produce recombinant proteins that can be used for vaccines, which also has the potential to replace less sustainable raw materials. Insects are also excellent food sources, not just for bush tucker trials, but also doughnuts, croissants, oils, and hummus, all made from insect lipids.

Join Dodi, Conor and their guests, Dr. José Escribano, founder and CSO of Algenex, and Dr. Daylan Tzompa-Sosa, a researcher at Ghent University specializing in milk fat, in the latest episode of Discovery Matters.

CONOR: So, Dodi you're going to love this one! My inner six-year-old is like bouncing up and down to tell you about this.

DODI: Oh, are we going to talk fungus again?

CONOR: No, we are not!

DODI: Okay. Are you sure that I’m going to be excited to hear this?

CONOR: Yes, you definitely are!

DODI: It's going to be Conor’s favorite.... Poop and microbiomes?

CONOR: No...

DODI: Crabs?

CONOR: No, not algae and slime, not the crabs... Well actually that's pretty close. It's bugs! It's insects!

DODI: So much joy in childish things.

CONOR: I know that's what happens when you let curiosity off the leash! We've talked a lot about how biotech is finding ways of making better therapies and at the same time replacing less sustainable raw materials using poo, and algae, and fungi, and crabs – that actually aren't really crabs – and this time I want to talk about insects as biotech engines. And they could replace less sustainable technologies in the production of medicines and food.

DODI: Yum, okay, I’m all in for bugs and eating them.

CONOR: That's what matters ...

DODI: ...on today's episode...

CONOR: ...of Discovery Matters.

JOSÉ ESCRIBANO : First of all, insects are very, very efficient in producing proteins. Consider that every year around 80 000 tons of silk thread is produced by silkworms. And silk thread is composed by two proteins, it means that the insects are huge in production of proteins in general. Some insect cells are able to produce more than 1 600 times protein that the most productive mammalian cells.

CONOR: So, this is Dr. José Escribano, the founder and chief scientific officer of Algenex. His background is veterinary medicine. And his company was born out of a collaboration with a group in the US, while he was looking for a better way to make vaccines in plants instead of in animal cells. And that's technologically complex and not very cost effective for animal vaccines.

JOSÉ ESCRIBANO : Veterinarians are practical people who solve problems. My group visualized from the beginning that we need to create new vaccines in an easier way. We started to work with plants as living biofactories.

DODI: So, José started off looking into plants. I thought we were talking about insects.

CONOR: Yeah, so the exam question is 'how do we grow large quantities of recombinant protein?' and by one of those happy accidents that we love so much on Discovery Matters, José was contacted for some help.

JOSÉ ESCRIBANO : One laboratory in the United States asked me for one recombinant baculovirus to produce one protein for diagnostic purposes. They mentioned that they are going to produce the recombinant protein in insects. Then, I said to send the recombinant baculovirus and they sent to me some frozen insects to realize the productivity of the system.

CONOR: And these frozen insects are so productive in expressing protein that José immediately switched from plants to working in insects instead.

DODI: So, a chance conversation and collaboration led to the start of a whole new process of using baculovirus to introduce genetic material into insect cells to make them create vaccines.

CONOR: Yes, it's brilliant, isn't it? In fact, it was the cabbage looper moth larvae, and they ate all of my garden kale this year! They become like tiny little bioreactors.

DODI: It must be said I think those things were doing you a favor by eating your kale.

CONOR: I like my kale, you know, green and roughage is good for your microbiome. While we're on the topic of chance discoveries and insects, here's another one.

DAYLAN TZOMPA-SOSA: I had a colleague working on insect protein. She extracted the protein, and she used the fat, or the oil, just to weigh how much it was. And then one day I saw her throwing away the fat into the bin. And I was like ‘No, Oh my God!' because I used that to do all type of chemistry and physical analysis. So, I thought, 'Okay, why don't we work together? You continue your work, and you give me the fat that you don't use.'

DODI: Insect fat! They're too small to have fat. What? What is that?

CONOR: Cool, huh?

DAYLAN TZOMPA-SOSA: My name is Dr. Daylan Tzompa-Sosa. I am currently a researcher at Ghent university at the department of food technology, safety and health. I have been working with insects now for about 10 years, specifically on the part of lipids and fat. So, to make it more layman's terms, oils that you can use at home. My training is in agricultural engineering, and I am an animal scientist. But my PhD, so my specialty, is on milk fat and its chemistry.

CONOR: So, Daylan's PhD supervisor said she could take on this fun project. And she found that there was a lot of interest in the topic and for Daylan, it's just a matter of translating the knowledge she acquired as a milk fat specialist into a new source of fat, and that was the insects. And these insects were a new source of oils and lipids that could be used in food.

DODI: So, you're telling me that chemistry has got to be similar, insect fats similar to other sources of fats, like vegetable fats, animal fats, but why?

CONOR: Okay, yeah, sorry, I got a bit ahead of myself there! It turns out that ignoring insects because of the kind of 'ick' factor...

DODI: And it is a big 'ick' factor!

CONOR: Yeah, I mean, as a source of materials, they can be pretty amazing. Insects make up more than 50% of the animal biomass on the planet. And they're a sustainable and really efficient source of fat and protein, when you compare them to, for example, you know, conventional livestock. And they're really highly nutritious.

DODI: So, they're everywhere, and they're sticking around so get used to them.

CONOR: Exactly, and they've been around forever. And, you know, the interesting thing about this is that nature has evolved over millions of years to solve a problem, which we're trying to solve using technology. So, we're kind of backwards engineering nature, and nature has solved this problem already.

DODI: That's amazing.

CONOR: But Daylan is looking into insect fats as food ingredients. And that means she needs a deep understanding of their chemical and physical characteristics and how they function.

DAYLAN TZOMPA-SOSA: There are thousands and thousands of different species of insects. So, some of them can have a very high content of omega-3 fatty acids. Until now, to my knowledge, there are no insect species that we have studied that can get so high, because omega-3 fatty acids in the fish oil is 40%. And sometimes they're like super, super high percentage. One of the insect species that we have studied now, and is commercially available, is Tenebrio molitor. In larvae stage, they have about 1.5% of omega-3. So, you see, we will never get to 20%, 30%, 40%. But that said, that’s only with the insect species that we have studied until now.

DODI: So, we simply need to look to insect farms for the future of food and medicine.

CONOR: Yes, they could play a really important role. But of course, we kind of need to look after them properly so that we can coax them into doing exactly what we want them to do. Different insects like different environments. So back to José and his little, tiny moth larvae bioreactors.

JOSÉ ESCRIBANO: Part of the know-how of the company was to optimize the biology of this process, because the differences are critical in the productivity of the insects. The number of insects that you put in a specific sort of phase is also important because we need to synchronize the growing of the insects in order to get to the pupa stage, which is the production unit. At the same time, all the insects react in the same rearing box. Of course, part of the technologies has been patented, for example, the rearing boxes, the robots, also the trays in which we put the pupae which are compatible with the inoculation robot.

CONOR: So, José and his team have mastered the cultivation of the moth larvae at scale. And then of course, using the baculovirus to transfect the cells to make the medicines that they want.

DODI: So, the production of recombinant proteins is happening in the insect pupa form?

CONOR: That's right, because José and the team can keep millions of cells in the perfect physiological balance in that form. And they deliver the instructions to the cells in the pupae using the viral vector. And what’s even more exciting, earlier this year, in the summer, the European Medicines Agency and the UK regulator validated an animal vaccine made based on Algenex’s technology. It’s paving the way for the potential use in human health applications as well.

JOSÉ ESCRIBANO: The insect that we are using is the natural target of this baculovirus in nature, okay? And then it means that all the cells from the insect are really infected by the vector that we have genetically modified in the laboratory. And then we insert different genes in these vectors. We infect the pupae by an automatic process by robots, and then after four to five days, we have all the cells already infected by the vector and producing the molecule that we want.

DODI: This is so insanely sci-fi. Now I understand why you were jumping up and down to talk about this. Robots inoculating insect pupae for the production of recombinant proteins in these teeny-tiny bioreactors.

CONOR: It's just so super cool! It's beautiful, isn't it? It's like a mash up of the Matrix, and Blade Runner 2047, and Alien all in one, but without like the horrible dystopia bit.

DODI: So, what about Daylan? Is she using pupae as well for the fats?

CONOR: Not quite, but it does rely on the juvenile phase of the insect, or worm, or larval phase that grow from pupa into adults. And it's in the larval phase where they have the highest content of fat because, well, they're just like little eating machines. Nom, nom, nom, accumulating energy for metamorphosis.

DODI: And now we're into The Very Hungry Caterpillar. And why are they so good at making fats?

DAYLAN TZOMPA-SOSA: To make a fair comparison, in milk fat, we have 4% of fat in weight basis. And in weight basis we will have 12% of fat in insects. So, it's more, at least three folds more the amount of fat in the insects. This is similar to what we have in seeds.

DODI: Okay, so let me try to restate and just level set here. We've got our insects, we get them at the right phase in their lifecycle, and we use them as factories for fats or medicines. Long term, what are we talking about? What is the opportunity?

CONOR: Well, look, no one technology is going to solve all the problems in biotech production, whether it's food or medicine, or what have you. Insect cells just can't compete with the productivity of mammalian cells, for example, when it comes to making monoclonal antibodies. For vaccines, yes, because there it might not be about productivity, as we've learned over the last couple of years, it can also be about speed.

JOSÉ ESCRIBANO: I think we can provide many advantages. Also stockpiling, we can generate an insect biomass containing the recombinant molecule, freeze this biomass and keep frozen for more than two years. And the moment that you need a new vaccine or these diagnostic reagents, whatever, you can just do the downstream from this insect biomass and produce a molecule in less than a week. And the stockpiling of this insect biomass is very cheap, because the most expensive part of generating biotechnology products is the downstream. As it is a conventional technology, we can apply conventional technology to the downstream of the molecules using our platform.

DODI: So, José is still working on veterinary medicines, but what about human therapies?

CONOR: Well, like any other medical intervention for humans we want the regulatory hurdles to keep people really, really safe, right? So, in proteins for chronic diseases where people are being injected all the time, you really need to ensure that if you make a biologic drug in insects, it really has exactly the same structure and characteristics and capabilities as the original technology that was used for the production and is of the same quality. But interestingly, when it comes to vaccines, this original mirroring is not quite so important.

JOSÉ ESCRIBANO: For vaccines it's not so relevant, because it's a single shot, or are a couple of shots, and then the function depends mainly on the conformation of the protein. The other thing that we need to demonstrate is that we are getting a protein free of any other tissue, or any protein or component that may produce allergic reactions in the patients receiving the vaccine.

DODI: So, Algenex purifies the molecule, makes sure that there's nothing foreign in there. But it also sounds like in the process, Algenex is solving a lot of the upstream issues in terms of scale. So, this solution for upstream issues allows scientists to focus on downstream.

CONOR: Yeah, absolutely. So, you know, Algenex doesn’t have issues associated with upstream bioreactor bags and cell culture media and so on, they can focus on the purification of the protein soup, essentially, that comes out of the moths.

DODI: So, if anybody's been paying any attention at all this year, we understand how making a like-for-like vaccine or biologic should be regulated, should be safe, needs to be tested. And if you switch manufacturing from conventional bioreactors, those big stainless-steel vats to moth larvae, if you're replacing actual insect fat into foods, are the fats the same? I mean, what does that even taste like?

CONOR: That is a super sharp question, because that is exactly what Daylan is focused on. How do you replace conventional animal fats like lard, for example, with insect fats? So, remember she said that each insect species has its own makeup and percentages of fatty acids, and sugars, and proteins, and what have you, that gives each lipid from each insect a different taste. Now, her favorite oil is made from the mealworm.

DAYLAN TZOMPA-SOSA: Every insect lipid has a specific smell. All the ones have different smells like for instance, the mealworm oil for me has a smell like pork fat. It's lard, the correct name. But it's like when you fry pork meat in its own lard and then for a long time. I'm from Mexico, in Mexico we have a traditional dish that has exactly that smell, and I love it.

DODI: Okay, I don't have a favorite oil personally, that's kind of cool to hear.

CONOR: And it's not like essential oils. It's not like multilevel marketing. Or olive oil, no.

DODI: Okay, but she's describing a pleasant animal smell.

CONOR: That's correct. But cockroach apparently tastes like vomit.

DODI: Predictable! I think I’ll take the mealworms aroma. Thank you very much.

CONOR: Yeah, I mean, why not a mealworm. I mean, it even says it in the name, right?

DODI: Yes, it does! Truth in advertising.

CONOR: Indeed. So, look, these lipids, they can be used to produce a huge range of foods. So, after deodorization, which reduces some of the smells, the oils can be used to make hummus, and crackers, and doughnuts, and you can fry dough using this oil or potato chips. And you can make muffins!

DODI: All things that we enjoy. But each one of those foods must require different lipids, if every application requires a different type of physical property, if I’m following this all the way down?

CONOR: Exactly. So, you want a hard fat at some point and flowing fat at other point, and so on. So, for croissants you need a hard fat. And you can basically use that in any food application if you have the correct physical properties. And the fats and the proteins are already being produced in huge quantities. There's very little waste from this process.

DAYLAN TZOMPA-SOSA: There's nothing left, everything is used from the insect. If you separate the protein rich fraction and lipids, then both of them have applications. And there's the chitin part. So, the exoskeleton of the insects is also used to produce chitosan which is also a molecule that is used, which has different applications. And even the poop of the insects, that is called 'frass', is also used for fertilizers.

CONOR: So, the fact that these lipids can have almost any application in food, who knew? This could be really useful in so many different ways.

DODI: Fascinating! Now we've gone from silkworm production in the time of the silk road to now. Insects are just the bee's knees, so to speak.

CONOR: They are the bee's knees. But it's just extraordinary, isn't it? Because what's happened is in the age of biology, instead of trying to work out how to make things using chemical synthesis, we've gone back to nature and we're using nature's evolutionary development to essentially reverse engineer biology and use the biological processes to make what we need. It's just extraordinary.

DODI: Why have we resisted so long?

CONOR: I know nature has had billions of years to sort this out.

DODI: Listen to your mother people!

CONOR: Listen to mom. And on that note...

DODI: Executive producer of Discovery Matters is Andrea Kilin and was produced with the help of Bethany Grace Armitt-Brewster. Editing, mixing, and music, and sound by Thomas Henley - soon to be a papa - and Banda Produktions. My name is Dodi Axelson people!

CONOR: My name is Conor McKechnie, and my mum who I always listen to is doing the ironing. Make sure you give us a rating on the platform you used to listen to us. And thank you so much for listening.

DODI: Do insects go now on your list of new obsessions?

CONOR: They do – bugs are on the list!

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