Genetic research on liver fattening and cardiovascular disease
‘Over 50% of the population in the Netherlands is overweight. That is a big problem since it can cause accumulation of fat in the liver and, consequently, increase the risk of cardiovascular disease, liver damage, and liver cancer. The increased risk of cardiovascular disease is mainly due to increased levels of different types of fat in the blood, such as cholesterol and triglyceride. Despite the National Prevention Agreement and all the information provided to tackle excess weight, we are not seeing a decrease in the number of people who are overweight.
‘The costs associated with cardiovascular disease are a huge burden on society. There are medicines, such as statins, that help to reduce blood cholesterol levels, but some people have side effects. Furthermore, it has been shown that statins are not effective in reducing specific fats, such as triglycerides. Unfortunately, other good medicines to reduce blood cholesterol levels are very expensive. Besides, reducing blood fat levels must be started early to reduce the risk of developing cardiovascular disease later in life. This means that it would be best to start monitoring the fats in your blood at a relatively early age.
‘Due to this significant societal and economic problem, animal experiments to study fat homeostasis are justified. Mice are very suitable for detailed studies of fat homeostasis. Many processes and genetic components that are involved in fat homeostasis are the same in humans and in mice. Mice are also very suitable for modifying their genetic material to increase the comparability with humans. Genetic modifications can be used to inactivate certain genetic characteristics or, conversely, to make them more active. You can then find out what the effect is on fat homeostasis. This allows you to acquire knowledge that can be used to develop new medicines.
‘A genetic predisposition is not always sufficient to simulate a disease process. That is why the mice are sometimes also given a high-fat and high-sugar diet. You can compare this to a diet of hamburgers, chips, and fizzy drinks. The animals can cope with this very well; they enjoy such a diet, just like people do. They subsequently develop liver fattening and cardiovascular disease, but these are conditions that do not bother the animals. The discomfort that they experience during an experiment is moderate, comparable to the pain or stress that you experience when receiving a vaccination or having a blood sample taken.
‘We use a relatively new technique, CRISPR/Cas, for the genetic modification. You can compare this technique to scissors, with which you cut a piece from the DNA to then stick it back together in the way you want. This allows you to alter the genetic information very specifically. We use this technique in mouse embryos that are subsequently born and that pass on the genetic modification to their offspring. This results in a mouse strain that has a specific, hereditary genetic modification. But this means that you have to keep the strain alive. You must keep breeding these animals, even if the study is temporarily stopped because you are still analysing the data from previous experiments.
‘To avoid this problem, we have increasingly often used somatic genetic modification—an even newer method—over the past few years. This method also uses CRISPR/Cas, but this technique is used on adult animals. The genetic modification is then not passed on to the offspring. The advantage is that you can already see within six months whether the genetic modification influences the process that you are studying. This means that you can decide quickly whether you wish to continue studying this specific genetic modification in your research. In our department, we are using this method already in almost half of all research projects. Because it is quick and efficient, but also because you can save a large number of mice. The total number of animals that is required for the research decreases because you no longer have to keep various mouse lines alive.
‘Everyone—including every researcher—welcomes fewer animal experiments. Cell cultures are often mentioned as an alternative: growing cells in a cell culture flask in the laboratory. We are also increasingly often using this alternative to animal experiments; however, the way in which processes in the cells in a cell culture flask are regulated is not always the same in a living organism. It is a fact that cells develop differently inside a living organism than they do in a cell culture flask, partly because they are in contact with other cell types, organs, and blood that contains nutrients and hormones. Furthermore, our fat homeostasis is also regulated by the day-night rhythm, which is absent in cell culture. Unfortunately, to improve our knowledge and the development of medicines and treatment methods, we still need animal experiments… that is a reality we must face.’