Which treatment will benefit this patient best? Which substances are most promising for pharmaceuticals companies to develop? These are questions that scientists at Linköping University are seeking to answer with the aid of the tiny zebrafish embryo.
Zebrafish embryo. Image credit: Wellcome Collection, Creative Commons (CC BY-NC 4.0)
Zebrafish embryos are colourless transparent balls. We see some only a few days old, bobbing around in a plastic dish in the “zebrafish lab” at Linköping University. They still obtain nutrients from the yellow of the egg, and are not yet classified as living animals. The fact that experiments on these embryos are not animal experiments is one of several reasons that scientists Lasse Jensen and Anna Fahlgren use this particular organism, the zebrafish embryo.
“We were both frustrated that many animal experiments are carried out in drug research, while we know at the same time that many of the substances tested as possible drugs will not lead to a final product. We saw a pressing need for better screening methods in the early phases of drug development”, says Anna Fahlgren, associate professor in the Department of Clinical and Experimental Medicine.
The collaboration between Lasse Jensen and Anna Fahlgren in an example of how a common vision can bring together researchers from different fields of study. Both had independently developed new systems to investigate how human cells react to drugs. After coming into contact, it wasn’t long before they decided to work on projects together.
They are currently working along two different paths. In one, they have formed a company to help other companies test and develop drugs in zebrafish embryos. In the other, they collaborate with oncologists in research into patient-specific cancer treatment. This method is currently at the research stage, but they hope that it will eventually be used to determine rapidly which treatment strategy is most appropriate for a particular patient.
“We are both driven by a desire to help patients. My mother died from cancer during her first treatment cycle. It was incredibly frustrating to see that the tumour was growing in spite of the treatment. The problem is, of course, that we don’t yet have sufficiently accurate methods to design individual treatment regimens”, says Anna Fahlgren.
Anna Fahlgren and Lasse Jensen are collaborating closely with oncologists at six hospitals in Sweden in a research project looking at bladder cancer. After the disease has been diagnosed in a patient, most of the tumour is surgically removed. A small piece of the tumour is sent to the zebrafish lab, where the scientists label the cancer cells with a fluorescent dye. The cells are injected into zebrafish embryos and a tiny fluorescent tumour of the patient’s cancer cells forms, and can spread. In as short a period as three days, the researchers can see how a drug affects the spread and growth of the tumour.
“We test the particular treatment regimen that the doctor is considering for the patient, and thus the results from the zebrafish tests can provide information on which to base a decision about how to treat the patient”, says Lasse Jensen, senior lecturer in the Department of Medical and Health Sciences.
For bladder cancer, the step immediately after the surgical removal of the tumour is chemotherapy, in an attempt to cause the remaining part of the tumour to shrink. After this, all patients undergo further surgery to remove the rest of the cancer. However, only around a third of patients benefit from the chemotherapy. For the remaining two thirds of patients, whose tumour did not react to the chemotherapy, the surgery has been unnecessarily delayed by 6 months. Long-term survival is lower in this group, since the cancer has often spread throughout the body during the treatment period.
“The purpose of the test is to be able to see within a week which patients will probably benefit from chemotherapy, and which will benefit from having the surgery immediately. We plan to compare the results we obtain in the zebrafish embryos with how the patients respond to treatment, in order to see whether we can use this as a patient-specific method. We hope that this will contribute to increased survival”, says Anna Fahlgren.
Using fish embryos to test the effects of drugs is particularly convenient for several reasons. One of the advantages is that the embryos are transparent, which makes it extremely easy to see the labelled cancer cells”, says Lasse Jensen.
“We can see each individual cancer cell and how it is transported away from the primary tumour through blood vessels. This is extremely difficult to do in animal models such as mice. In the zebrafish, we can not only find out how a drug affects the primary tumour, but also obtain important information about how the drug affects the formation of secondary tumours, known as metastases, which are extremely dangerous in cancer.”
The article has also been published (in Swedish) in Forskning & Utveckling, no. 1/2019
Source: Linköping University