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The fish helping scientists to understand the human brain
Scientists use a range of model organisms to understand human biology, from basic single-celled yeast to more complex animals such as flies and mice. Dr Camila Esguerra at the University of Oslo is a major advocate for an alternative model: the zebrafish.
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Dr Esguerra’s neurology research group is based at the Centre for Molecular Medicine Norway (NCMM), where they use zebrafish to study the human central nervous system, meaning the brain and spinal cord, and related diseases such as epilepsy, schizophrenia, and autism.
By improving our understanding of the mechanisms that lead to these diseases, the group hopes to identify new drugs that could be used for treatment.
Like zebrafish, like human
“The greatest advantage of zebrafish is the fact that they are transparent during the first weeks of development”, explains Dr Esguerra.
“This means researchers can easily view internal organs such as the brain, and monitor its activity using non-invasive imaging in live, freely-moving animals. This makes it possible to monitor neural activity patterns associated with specific behaviors in the fish; for example, during prey capture or even when they are having convulsions as a result of seizures.”
Studying zebrafish then, helps researchers to understand human brain function, health and disease.
“Zebrafish and humans are actually quite similar when it comes to genetics and neurology”, says Esguerra.
Indeed, you may be surprised by how much zebrafish and humans have in common. In terms of physiology, zebrafish have all of the same organs as humans, with the exception of lungs and a uterus. Genetically, scientists now know that around 70% of human genes have an equivalent in zebrafish. Furthermore, if you compare genes linked to disease, the degree of overlap is even higher. For example, 88% of all human schizophrenia risk genes have equivalent copies in zebrafish.
Adding and removing genes to understand epilepsy
Dr Esguerra has been involved in a range of studies using zebrafish to investigate neurological diseases.
“Prior to starting my group in Oslo, I co-led a study that used zebrafish to identify a new gene involved in fever-induced seizure susceptibility, which affects 2-4 per cent of all children and is also linked to epilepsy. When this gene is switched on it produces a protein called ‘Syntaxin 1B’, and forms part of a larger multi-protein complex essential for the release of neurotransmitters – the chemical signals that nerve cells use to communicate with one another. We found that deleting (knocking-out) this gene caused the same symptoms in fish as seen in humans, with spontaneous seizures that increased in severity when we simulated fever-like conditions”, she says.
This indicated that faulty Syntaxin 1B might be involved in inducing seizures in humans – an idea that was supported by other factors. Dr Esguerra continues:
“The zebrafish and human Syntaxin 1B genes are almost identical in sequence. We were able to cure the Syntaxin 1B knockout zebrafish of their seizures by switching on production of human Syntaxin 1B in their cells. Conversely, when we introduced the Syntaxin 1B gene from one of our seizure patients into the knockout fish, this could not rescue the fever-sensitive epilepsy symptoms”.
These findings strongly indicated that the patient’s Syntaxin 1B was faulty and causing disease symptoms. Therefore, it may be that Syntaxin 1B is a good target for therapy to treat these seizures.
“Here in Oslo, we are building upon this work by using zebrafish to investigate a range of other genes linked to causing epilepsy in humans. This will help us to understand the relative involvement of these genes in different aspects of disease - for example, do mutations in certain genes make an individual more susceptible to epilepsy, or perhaps make certain symptoms more severe. In parallel, together with collaborators at the University of Luxembourg, we are using fish epilepsy models to test whether certain genes make people resistant to specific types of seizures. Some of our new data indicates that we may be able to identify genes that protect individuals from seizures.”
Assessing drugs to treat a rare infant syndrome
Another approach utilized by the Esguerra group involves introducing known disease-causing patient mutations into zebrafish genes to model different human disorders, then screening these fish using a range of drugs. Any drugs that appear to relieve disease symptoms in the fish models could therefore provide useful tools for treating patients.
In a recent study, the Esguerra group investigated the potential of certain drugs to treat Dravet syndrome, a very severe and devastating type of epilepsy occurring in infants and children.
“We were able to show that several drugs work just as well in our fish model as they do in human patients participating in clinical trials. One drug, called fenfluramine, is pending FDA approval and we have shown that it has ‘disease modifying’ activity in our fish models. In other words, it not only significantly reduces the number of seizures but, when given early enough during brain development, it corrects the brain defects associated with seizures.”
Such studies are difficult to assess in human patients, as these types of epilepsies are rare, meaning it is difficult to recruit the numbers of patients required. Also, data must be collected over very long periods of time – often several years or longer. Of course, patient-based safety and efficacy studies should nevertheless be carried out at later stages. Dr Esguerra hopes that her group’s findings in zebrafish will help guide future human patient studies.
Using zebrafish to study cancer
Zebrafish are not only a useful tool for the neurology research field.
“The small size of zebrafish embryos and larvae make them a great tool for large-scale screening approaches commonly used to answer a range of fundamental biological questions”, says Esguerra.
For example, using just a few small culture plates it is possible to simultaneously test hundreds of different drugs for their overall toxicity and/or effects on specific organs.
“As an alternative to testing drugs, we can also screen many different genetic mutations to assess which genes are involved in the growth, development, health and disease of the zebrafish. Again, many studies have shown that genes identified in this manner play similarly important roles in humans”, she says.
This versatility means zebrafish are nowadays used by researchers from across the world to study many different human diseases including muscular dystrophy, deafness, Parkinson’s disease and even type 1 diabetes.
Zebrafish can also be used to model one of the biggest human killers – cancer. One example comes from so-called ‘patient-derived xenograft’ (PDX) zebrafish models. Here, zebrafish are injected with human cancer cells, which form tumors within the fish. Researchers are then able to see how fully formed tumors respond to various treatments administered to the zebrafish, for instance new drug leads for cancer therapy. Compared to experiments performed in a cell culture dish, PDX models enable scientists to study cancer cells in an environment that is more similar to the ‘real life’ tissues and organs in which they reside in human patients.
Will become more popular
Dr Esguerra believes zebrafish will grow in popularity as a tool for studying human biology. Discussing the future potential for zebrafish-based research, Dr Esguerra says:
“Due to their many practical benefits, I believe zebrafish will become an increasingly favoured model for studying health and disease. I also believe a greater number of drugs that were discovered using zebrafish-based screening techniques will be entered into human clinical trials.”
Other model organisms have their own individual benefits, but Dr Esguerra’s group hopes that more and more scientists will realize the fantastic opportunities afforded by zebrafish and add this model organism to their toolkit to help answer important questions in biology.
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