The Spanish woman who has managed to portray the enzyme of immortality

La española que ha logrado retratar a la enzima de la inmortalidad - Investigación, Innovación

She has done it again. Eva Nogales photographed for the first time in 2016 the CRISPR-Cas 9 genomic edition system. Now the graceful has been the telomerase, whose structure has revealed this paparazzi of cell biology. A task of precision that nobody had managed to execute to date. The blissful 'enzyme of longevity' has resisted any attempt to portray it with a decent resolution, but has succumbed to the technical charms of Nogales and to a work done with exquisite care.

The tool used for this meticulous work has not been a camera, but a technique known as electronic cryomicroscopy that was awarded in 2017 the Nobel Prize in Chemistry to Jacques Dubochet, Joachim Frank and Richard Henderson. They laid the foundations for this method, whose application is pioneered by Nogales. "I started working with cryomicroscopy at the end of the 80s, when I was still in my childhood," she told XATAKA, a scientist born in Madrid, who was then in the UK doing her doctorate. Now, Nogales runs his own laboratory at the University of California at Berkeley (USA).

During all this time, the scientist has perfected her approach to the technique of electronic cryomicroscopy, which she has used to study many different biological systems and know their structure. "Among them, microtubules, which are an important target against cancer," says Nogales. That is, a structure to attack to destroy cancer cells. Now, Nogales stars - along with other researchers also associated with Berkeley - an international impact study published on Wednesday in Nature.

Beyond the limits

The focus of the article is telomeres: a repetition of DNA sequences that exist at the end of each chromosome [structures that contain most of a person's genetic information] and protect it. Without them, Nogales explains, the cells would think that they are broken chromosomes that should repair and fuse with each other, "which would be terrible." The problem is that every time a cell divides it has to copy the genome - replicate the DNA - and, in this process, chunks of the end of the chromosome that are not copied are lost. This causes the telomeres to be increasingly shorter, to a point where the cell realizes that something is not working and decides to commit suicide or stop dividing, which leads to aging.

The study by Nogales and his colleagues "provides an unprecedented view of how the enzyme complex is organized and establishes a framework for drug discovery," says Nature. Although some image of the structure of telomerase had already been obtained, its resolution was very poor. In contrast, the one obtained by the Berkeley researchers is three times better, taken at a scale below the nanometer.

The problem was double. On the one hand, the difficulty of isolating many copies of telomerase and getting those that are active. On the other, the flexibility of telomerase, which makes it difficult to know its structure. To overcome these barriers, the researchers developed an improved purification procedure. "We needed two things: to improve the amount of active telomerase we were able to obtain and to force the limits of what electronic cryomicroscopy is capable of," he explains. And they did it.

Hence the relevance of the study. "The media have not stopped calling us in the last 24 hours," he says. And, in the scientific field, telomeres are a hot topic because of their relevance to cell biology, human aging, the development of cancer, etc. And, until now, nobody has been able to obtain information about their structure. "This study has crossed many limits in what was technically possible," says the Spanish.

The research is also interesting for other reasons, beyond the telomeres. Nogales points out that, thanks to this, a process not previously described is known, that can be extrapolated to other biological systems and that is critical, for example, in the regulation of gene expression or epigenetics [what determines which genes are expressed and which ones do not, and with them the human capacity to adapt to the environment].

What this means

One of the first things that can be done once we know these structures - explains Nogales - is to map the genetic mutations that promote the development of different diseases within the structure of telomerase, which provides a better understanding of the reason why that mutation causes this disease. "This is critical to thinking about how to treat affected patients," he says.

The development of drugs directed to a specific point in the cell is another fundamental application of this finding. "Knowing the structure of telomerase as a fundamental actor in human health is a first step for the design of this type of drugs," says the scientist. The possible uses of these medicines are multiple, starting with cancer, since they would prevent the destruction of healthy cells that occurs with current chemotherapy drugs.

On the other hand, anticancer treatments against telomerase are also interesting. As Nogales explains, this enzyme is what makes cancer cells immortal. For this reason, the Spanish says that we must be cautious in the anti-aging strategy based on telomeres, since trying to make them immortal in all cells can be a double-edged sword. "Cancer is still an immortal cell that has lost its identity and reproduces uncontrollably, and if telomerase were always functional, it could facilitate its development." Somehow, making telomeres shorten is a way to maintain half sure to try to prevent it, "he explains.

The researcher Mariana Castells, professor at the Harvard Medical School, points out another useful field of the study published in Nature: cloning. The ignorance of telomerase - says Castells - was one of the reasons for the early death of the Dolly sheep. "In cloning processes you have to make sure that the telomeres are functional, that they are in good condition," says Nogales, who admits that she is not an expert in this field.

Multidisciplinary science, and in feminine

Nor is telomerase the Nogales fort, that's why it allied with other scientists from different fields. "This is a job that could not have been done alone in Katty Collins' laboratory or mine," he says. In his opinion, it is a sample of the importance of multidisciplinarity in research between fields that are complementary and that a laboratory can not do in isolation. It is a work of years, involving the collaboration of experts in different fields.

Nogales also highlights that the two laboratory directors and the young researcher who did most of the work (Kelly Nguyen) are all women. "We are not afraid of the risk, we see something important and we go for it, whatever the cost," he says. This - he maintains - gives an idea of ​​where the research is going: toward collaboration and toward female leadership in 'risk science'. "Women increasingly have a more relevant role in science that is leading, in which the chances of something not going well are very large but that, if it does, has a lot of impact," he says.

And, since we are talking about pioneering scientists and telomerase, we could not fail to mention the Spanish María Blasco, director of the National Center for Oncological Research (CNIO). In 2008, his research group at the CNIO was one of the first to discover some telomeric components called Terra. Since then, they have proposed deciphering their function. Recently they have taken an important step in this. As a study published this month in Nature Communications shows, Terra play a decisive role in the assembly of telomeric heterochromatin. That is, they are important epigenetic regulators.

Source: Xataka