GEM
iGEM stands for International Genetically Engineered Machine, and is an international competition in which participants try to solve societal problems using synthetic biology. In synthetic biology (parts of) cells are used and modified in order to develop various products and applications. This year you can follow the adventures of three Dutch teams on biotechnologie.nl, where the teams from Leiden, Groningen and Maastricht blog about their projects. A background piece about each project is published on NEMO Kennislink, in which relevant experts have their say.
There is a good chance that you have heard it in the news: the bird flu virus is spreading again in Dutch poultry houses. To prevent further spread of the virus, the entire stable is cleared when an infection is detected. This has already cost the lives of millions of birds in the past year.
Obstacles to a vaccine
Can these birds not be vaccinated, just like people against corona? Unfortunately this is not so easy. The most effective vaccines have to be injected into birds, but this is very labor intensive and expensive. It costs less money to clear the bird flu stables – no matter how much animal suffering this causes.
However, money is not the only problem. Birds that have been vaccinated make antibodies that protect them against the virus. When birds contract bird flu, they make the same antibodies. Vaccinated and infected birds are therefore difficult to distinguish from each other. In addition, it is possible that vaccinated birds will not get sick themselves, but will still spread the virus. For these reasons, international trade in vaccinated birds within Europe is prohibited.
Nanobodies as a solution
To remove the obstacles to a vaccine, the team from Groningen is not working on a vaccine, but on a preventive treatment against the bird flu virus. This treatment focuses specifically on chickens and consists of a spray that contains bacteria. The chickens do not get sick from these bacteria. In fact, they occur naturally in the lungs of the chicken. The team therefore expects that the bacteria can nest and multiply well in the lung tissue, where they form a protective layer against the bird flu virus.
But it is not the bacteria themselves that protect the chicken against bird flu. The team genetically modified the bacteria, causing them to secrete so-called nanobodies. These are small pieces of antibodies that bind to the bird flu virus, allowing them to disable it. By using nanobodies, birds protected with this therapy can be distinguished from sick birds that produce antibodies. In addition, the spray treatment, unlike injections, is relatively cheap.
The iGEM team from Groningen.
Copyright iGEM team Groningen
The efficacy of the treatment
Nanobodies can also be used in other ways. Cell biologist Paul van Bergen and Hainaut of Utrecht University has been researching these small pieces of antibodies for over fifteen years. Van Bergen en Henegouwen is investigating whether they can be used as cancer therapy, but also uses them for medical imaging.
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With his years of research into nanobodies, Van Bergen en Henegouwen is able to assess whether the project has a chance of success: “I think it’s a great idea. The technique the team uses to produce nanobodies can be scaled up well and could therefore be widely applied. They do use a genetically modified organism, which is subject to strict rules. You must prevent the modified bacteria from ending up in the environment. So the team still has to come up with something smart about this.”
“I also have my doubts about the effectiveness of the treatment. If a virus gets you well, your body will be bursting with viruses. I therefore wonder if the bacteria can grow enough in the lungs of the chickens to form the protective layer that the team is talking about.”
“In addition, I wonder whether the bacteria can make nanobodies at a therapeutic level, that is, sufficient to be effective against the virus.” Van Bergen en Henegouwen, however, gives the team the benefit of the doubt: “These are questions that are difficult to answer in advance. To find out the effectiveness of the treatment, you have to test it. I have my doubts, but the team is optimistic. Then I always give the opportunity to those with optimism.”
A battle against mutations
In addition to a large amount of bacteria that produce sufficient nanobodies, it is necessary that they can disable the bird flu virus. Virologist Xander de Haan, also from Utrecht University, has been researching different types of viruses for about twenty years. This gives him a good overview of this part of the project: “I find the idea of the team interesting, but there are still snags.”
As with corona, the treatment will have to be adjusted based on mutations of the bird flu virus.
“If the nanobodies work against the bird flu virus, it will only be temporary. As soon as the virus starts to mutate, there is a chance that the treatment will no longer work,” explains De Haan. This has to do with the antigens of the bird flu virus: the molecules to which the nanobodies bind, so that the virus is switched off. De Haan: “The structure of the nanobodies therefore needs an adjustment for every mutation, so that they can again bind well to the viral antigens. You also see this with human viruses, such as influenza and corona, where the vaccines need regular updates.”
In order to be prepared for virus mutations, the Groningen students are working on a computer program with which they can determine the necessary adjustments to their therapy. In this computer program they make a model of the viral antigens and the nanobodies. When the virus mutates, they want to use this program to determine how to change the structure of the nanobodies so that they fit the antigens like a puzzle piece again. Van Bergen en Henegouwen is working on a comparable computer program, but De Haan wonders whether such a program is cost-effective against bird flu: “For each mutation, modified nanobodies would then have to be sprayed again. That is probably very expensive.”
Attack multiple targets
However, there is a solution where you don’t have to adjust nanobodies for every virus mutation. De Haan: “If you only have one target, the virus can easily become resistant to it through a process we call ‘viral escape’. It is therefore more effective to have multiple targets, attacking multiple components of the viral antigens. You see this, for example, with AIDS, where a single drug does not work, but a cocktail of drugs is effective.” The team recognizes that their treatment will probably work best in combination with other treatments. In this way they hope to build a wall. strong enough to stop the virus.
In addition to the number of targets, the piece of antigen to which the nanobodies bind also plays a role in the effectiveness of the treatment. De Haan: “The frequency with which different pieces of antigens mutate differs. It is more effective to target pieces that mutate less, because then your therapy is effective for longer. However, it is more difficult for nanobodies to bind to pieces that mutate less. .” A balance must therefore be found in which the targets mutate as little as possible, but where they are still accessible to the nanobodies.
Nanobodies in chicken feed
The bacteria can end up in the chicken’s intestines by processing them in food.
Finally, De Haan indicates that the bacteria must also form a protective layer in the chicken’s intestines, because the bird flu virus can also multiply here. But the team has also taken this into account: the bacteria they use naturally occur not only in the lungs of the chicken, but also in its intestines. The team therefore expects that their therapy will also be effective in the chicken’s intestines.
It is still unclear whether the modified bacterium also ends up in the chicken’s intestines via the spray. Another option for getting the nanobodies into the intestines is by processing them in the feed of chickens. This is already happening, for example, with natural probiotics, which can be used to enrich the intestinal flora of chickens. In this way, both the lungs and intestines of the chicken are protected against the bird flu virus, and the situation of these animals may finally be improved.