With a million species described, insects are the most diverse and numerous class of animals that populates the Earth. For thousands of years we have consumed them as food and we use them to obtain everyday products, such as honey or silk. They have also been key in the advancement of some disciplines: for example, intensive agriculture uses bumblebees as pollinators, and for decades genetic researchers have used the vinegar fly to study DNA. Their short life cycle, rapid generational intervals and the possibility of being grown in large quantities make insects extremely attractive to the world of research. Their latest use is to turn them into biofactories in which to produce different types of proteins, transforming them into producers of vaccines, diagnostic reagents or molecules with therapeutic effects. Although this may sound like science fiction, this technology is here to stay.
Nowadays, most proteins with pharmaceutical uses are manufactured in complicated and expensive bioreactors—machines where cells are grown to make vaccines and other treatments. However, insects are a cheaper and faster alternative to obtain those same molecules: the larvae of some Lepidoptera—butterflies such as the silkworm (Bombyx mori) or the cabbage looper moth (Trichoplusia ni)—are the key. The greatest disadvantage of these two species, being potential pests, has become their most valued virtue, as they are able to produce proteins of interest on a large scale. The process is simpler than one might imagine, according to what José Ángel Martínez Escribano, founder and scientific director of Algenex, a Spanish company that pioneered the production of proteins using cabbage loopers, explained to OpenMind: “We genetically modify a virus into which we insert the necessary gene so that it produces the protein that interests us. Then, we infect the larva of the insect with that virus, which multiplies in its cells, like the flu virus does when we get it. Thus, after 3 or 4 days we have accumulated a large amount of the protein of interest inside the larva and we can extract it.”
The lepidoptera are the best
To carry out these techniques the same type of virus is always modified, never the insect that it infects. “The process is based on the genetic engineering of a baculovirus that carries in its genome the gene that codes for the protein you want to obtain,” says Alexandra Marisa Targovnik, a researcher at the National Council of Scientific and Technical Research of Argentina (CONICET) to OpenMind. In this way, each time you want to get new products, a different baculovirus is generated, which always infects a lepidopteran. “Lepidoptera are the best insects because they are the natural hosts of baculoviruses. What is manipulated is the virus. Making a new one takes less than a month, so it’s very easy to produce new molecules in a very short time,” adds Escribano. This resulted in the first product manufactured inside insect larvae marketed in Europe: “It is called Virbagen Omega, a drug used to fight certain viral infections in cats and dogs,” says Silvia Gómez Sebastián, researcher at the Spanish National Research Council (CSIC), to OpenMind.
In the whole world there are only three products on the market produced by these new biofactories. They are for non-human animal use, but “precisely because of their potential, there are more and more awaiting preclinical and clinical trials, for example viral proteins for vaccinal purposes,” says Gómez Sebastián.
Escribano points out the advantages of using insects: “The fact that insects are used is because they permit a very efficient system, where most of the insect’s cells are infected with the virus, and thus the productivity is very high. For example, we have vaccines in which more than 160 doses are produced from every small chrysalis that we infect. In addition, from one pair of butterflies, in nine weeks it is possible to obtain 250 million pupae. With that amount you could supply an animal vaccine to everyone for five years. This makes it a technology that, for example, can produce flu vaccines to quickly address a pandemic situation.”
Obstacles to overcome
The new system still has some obstacles to overcome. “The main problems in the production process are related to obtaining proteins of adequate quality for their use, especially in humans,” explains Targovnik. On the other hand, Escribano adds: “Whenever a new system for the production of injectable molecules is developed, it must be validated in what are called regulatory agencies, which not only analyse the quality and safety of the final product, but also the system that generates it, to see that it is a consistent technology. This is something that takes several years before being able to take the product to market.”
Regarding the safety of the process, Targovnik is clear: “The system is safe for mammals, especially for humans. Baculoviruses do not have the capacity to multiply in human cells, which makes it a bio-secure process. The insects are raised in a controlled way in laboratories, where it is almost impossible for them to escape.” And even if some did manage to get free, Escribano points out: “In those viruses to which we introduced an extra gene, we have also extracted other genes, in such a way that it can only reproduce if it is injected into an insect. In other words, an insect infected with that virus cannot infect another insect.”
While it’s clear that new technologies are not established overnight, the use of larvae as biofactories does seem to be the future for the production of therapeutic proteins.