Virtually all 48,000 known spider species are venomous, but only a few are dangorous to humans. Typically, a bite from a spider will cause a minor reaction, which can be compared to a mosquito bite or a wasp sting. However, the venom of a few spiders—such as the black widow or the tunnel spider—is so strong that it can cause serious poisoning if no antivenom is administered, and in these cases particularly elderly and children are at risk.
Sofie Føns holding a bird spider. Photo: Private
Several spider antivenoms based on animal antibodies already exist. The antivenoms are produced by injecting spider venom into a horse or rabbit, whose body then generates antibodies to neutralize the venom. The antibodies can be extracted from the blood and used as an antivenom.
But treatment with animal-based antivenom is not without risk. The human body may perceive the antivenom as a foreign and dangerous substance, thereby triggering an immune response. This means that even the most efficient antivenoms on the market can cause severe allergic reactions, which may, at worst, result in death due to anaphylactic shock.
"I use existing technologies, but it’s an innovative perspective of antivenoms and can help pave the way to how the antivenoms of the future can be developed and produced. The goal is that one day we will be able to produce safe antivenom based on human antibodies in large fermentation tanks instead of in animals."
Sofie Føns MSc in Biotechnology
The purpose of the MSc thesis was therefore to identify human spider venom antibodies that do not trigger a strong response from the immune system. Antibodies are a form of protein produced by the immune system which bind to foreign molecules from, e.g., bacteria or viruses and prevent them from forming and spreading. It is this ability to block foreign bodies that is utilised in antivenom production.
The method used by Sofie Føns moves production from the animals to the laboratory, where genetic engineering can be used to produce human antidotes in cell cultures, thus producing an antivenom that will not trigger an undesirable immune response.
Sofie Føns focused her research on two essential toxins—δ-hexatoxin and α-latrotoxin—from the funnel-web spider and the black widow spider, respectively. Both spiders’ venoms consist of many different toxins, but these two toxins are believed to be the cause of the most serious damage to humans, such as muscle rigidity, prolonged pain, vomiting and, at worst, fluid in the lungs, coma, and death.
The Australian funnel-web spiders cannot be bred in laboratories and must therefore be collected, and their venom extracted through milking. During a stay abroad in Australia with Professor Glenn King, whose lab boasts the world’s largest collection of venoms, including more than 600 spider venoms, Sofie Føns received spider venom to use in her continued work at DTU.
Spider venom consists of toxic proteins that bind to recipients, also called receptors, in the victim’s nerve cells. One can compare the toxic proteins to a spiky massage ball with glue at the end of the spikes. The glue sticks to the nerve cells whose signalling is then disrupted. Antivenom neutralizes the venom via the antibodies, which very selectively glue themselves on to the outside of the spiky ball, preventing the venom from sticking to the nerve cells.
However, if the antibodies are animal-based rather than human-based, the body’s immune system may recognize them as foreign (and hence dangerous), thus triggering a response. Sofie Føns’ goal was therefore to identify human-based antibodies. Her approach was to first isolate the two toxins, before running them through a library of human antibodies to identify the DNA codes for the antibodies that would best bind to the toxins. The DNA codes were then genetically engineered into cells of the bacteria E. coli, which then produced the antibodies. She subsequently ran several different tests to determine how well these antibodies bound to the toxins and ended up with six unique antibody clones.
“I use existing technologies, but it’s an innovative way of thinking about antivenoms, and it can help pave the way for how the antivenoms of the future can be developed and produced. The goal is that one day we will be able to produce safe antivenom based on human antibodies in large fermentation tanks instead of in animals,” says Sofie Føns, who graduated with nothing but top marks and now, after the submission of her thesis, passes on her research to others in the research group Tropical Pharmacology Lab.
Associate Professor and group leader Andreas Laustsen, who was a supervisor on the project, was the first in the world to succeed with this method when, in 2018, in collaboration with researchers from Instituto Clodomiro Picado in Costa Rica and IONTAS from Cambridge in England, he successfully used the method to produce and multiply human antibodies to the venom of the black mamba. He asserts that research into spider antivenoms at DTU does not end with the submission of Sofie Føns’ thesis:
“It’s clear that we need to build on Sofie’s great results. Three of the antibodies she found have been sent to our collaborators in Australia, where they will be tested for their ability to neutralize the spider venom. In Tropical Pharmacology Lab, we expect the antibodies to be used as biological tools for further research, but, more importantly, to potentially be turned into a whole new type of antivenom to widow spider bites.”