The winding path of science – basic science

from Tarciso Velho

Songbirds do not have “bad cholesterol” and we discovered this by accident.

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Scientists often believe that time and dedication will solve everything. If the problem persists, the researcher’s technical abilities come under suspicion … He seeks help and digs deeper into the specialist literature. When a solution presents itself, he breathes a sigh of relief. In retrospect, the scientific point of view seems clear, but the path to building scientific knowledge can be fraught with unforeseen events, as I once experienced.

About ten years ago, in Prof. Carlos Lois, then at the Massachusetts Institute of Technology, MIT, tried to produce genetically modified strains of songbirds to understand which genes play a role in learning to sing.

We began by trying to replicate a well-established technique for rodents: using viral vectors to infect embryos. These laboratory-generated and non-reproducible vectors enter the cell when one of their proteins binds to another on the surface of the target cell: the famous lock-and-key relationship between a ligand and its receptor. In this case, the key was the VSVg protein, which binds to the low-density lipoprotein receptor, the LDLR, which is responsible for separating cholesterol from the LDL fraction, the bad cholesterol that is involved with cardiovascular disease -Diseases is associated. The virus’ genetic material penetrates the nucleus, inserts itself into the cell’s DNA, and is then inherited from its daughters. Some of the infected cells form sex cells and produce gametes, and therefore the offspring produced will carry the gene of interest. In other words, they will be genetically engineered or transgenic animals.

As one of these balls, the task of creating transgenic birds gave us some surprises. A few thousand eggs were injected and not transgenic birds. In any case, we were successful with a highly concentrated virus. However, the same virus could infect cells of many organisms at much lower concentrations. Would we use the wrong key?

Together with Prof. Claudio Mello from Oregon Health & Sciences University examined the genome of songbirds and found that the receptor for the key used by the virus was significantly changed. This was the first unexpected result, because the LDLR, the sluice, was until then common to all vertebrates. Changes in this decrease cholesterol absorption and increase the level of cholesterol in the blood. The famous high cholesterol.

There are gaps in the LDLR of birds compared to other animals. A comparison showed that the virus infected chicken cells very well and birds very poorly. When we applied an intact LDLR to these two species, we confirmed that it made it easier for the virus to enter avian cells and made no difference to chicken cells, which already had their own intact receptor. The bird’s altered receptor appears to offer protection against the virus. Which is good for the bird and bad for the generation of transgenic animals.

Well, birds don’t fly around with heart attacks from high cholesterol … Then came the second surprise. Because changes in LDLR increase cholesterol levels in humans, rodents and fish, we had to measure this rate in songbirds. We measured the cholesterol of the two birds (bird and chicken) and compared it with that of humans. The blood test showed that the bird did not contain LDL, the bad cholesterol. This is surprising because LDL particles are considered to be the main carriers of cholesterol. But it had a lot of high-density cholesterol (HDL), the saying for good. So it seems that the receptor is diverging, but the cholesterol transport system has also changed. Not necessarily in that order.

Interestingly, songbirds seem to have solved the bad cholesterol problem with a different transport mechanism, very healthy, with high HDL and no LDL levels. We do not yet know how this came about, but we will continue to follow this ball and see where it leads us. The explanation could bring new insights into the relationship between cholesterol and cardiovascular disease and how this problem in nature could have been solved.

This is the process of many scientific discoveries: full of surprises and not always following a straight line.

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Tarciso Velho is a neuroscientist and professor at the Federal University of Rio Grande do Norte.

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