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The crooked path of science – Fundamental science

by Tarciso Velho

Songbirds don’t have “bad cholesterol”, and we discovered this by accident.

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Scientists often believe that time and dedication solve everything. If the problem persists, the researcher’s technical skills come under suspicion… He then seeks help and digs deeper into the specific literature. When a solution offers itself, he breathes a sigh of relief. In hindsight, the view of science 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 engineered strains of songbirds in order to understand which genes would be involved in learning to sing.

We started by trying to replicate a well-established technique for rodents: using viral vectors to infect embryos. Generated in the laboratory and unable to reproduce, these vectors enter the cell when one of their proteins binds to another one present on the surface of the target cell: the famous key-lock 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, responsible for capturing cholesterol from the LDL fraction, the bad cholesterol associated with cardiovascular diseases. The viral genetic material enters the nucleus, inserts itself into the cell’s DNA and is then inherited by its daughters. Some of the infected cells will form sex cells and generate gametes, and therefore the offspring generated will carry the gene of interest. In other words, they will be genetically modified or transgenic animals.

As one of those balls indeed, the task of generating transgenic birds has given us several surprises. A few thousand eggs were injected, and no transgenic birds. Anyway, using a highly concentrated virus, we were successful. That same virus, however, at much lower concentrations, could infect cells of many organisms. Would we be using the wrong key?

Along with prof. Claudio Mello, from Oregon Health & Sciences University, went to spy on the genome of the songbirds and found that the receptor for the key used by the virus was significantly modified. This was the first unexpected result, because the LDLR, the lock, was until then considered common to all vertebrates. Changes in it decrease cholesterol uptake, increasing blood cholesterol levels. The famous high cholesterol.

The LDLR of birds had gaps in relation to that of other animals. A comparison showed that the virus infected chicken cells very well and birds very poorly. When we put an intact LDLR into these two species, we confirmed that it facilitated viral entry into bird 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. What is great for the bird and bad for generating transgenic animals.

Well, birds don’t fly around having heart attacks because of high cholesterol… Then came the second surprise. Since changes in LDLR increase cholesterol in humans, rodents and fish, we needed 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 revealed that there was no LDL in the bird, the bad cholesterol. This is surprising, because LDL particles are considered the main carrier of cholesterol. But it had a lot of high-density cholesterol (HDL), the saying of good. It appears then that the receptor diverged, but the cholesterol transport system has also changed. Not necessarily in this order.

Interestingly, songbirds seem to have solved the problem of bad cholesterol with a different transport mechanism, very healthy, with high levels of HDL and no LDL. How this happened we don’t yet know, but we will continue to follow this ball in effect and see where it takes us. The explanation may bring new insights into the relationship between cholesterol and cardiovascular disease, and how this issue might have been resolved in nature.

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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