Piecing the puzzle together – the work of a fundamental scientist

Do you think Einstein’s theory of relativity or the understanding of how bacteria fight viral infection to be interesting topics but not that important? Well, let’s not be too hasty.
Researchers piece the puzzle together to understand chromosome dynamics ©️ Márcia Alves, IGC 2022

Although you might not have imagined – the scientists behind these discoveries sure did not, at that time -, the accuracy of the GPS on your phone relies on Einstein’s theory, and bacteria’s ancient defense mechanism is the basis for gene therapies that are now being used to treat cancer. And that is just to name a few of the scientific breakthroughs that stemmed from curiosity.

Scientists have always strived to fill in gaps in knowledge by asking essential questions. But, in contrast with those working on applied research, fundamental scientists are not moved by the practical applications of their findings, but rather by their eagerness to learn. Although this is the driving force behind many technological advances, applications of fundamental science can take decades, if not centuries, to see the light of day. And sometimes, new findings do not even lead to huge advancements other than the progress of knowledge itself.

For these reasons, fundamental science is often questioned. Some argue that these curiosity-driven questions are insignificant to society as they do not provide quick solutions to urgent problems. However, we should bear in mind that scientific breakthroughs are not simply stumbled upon but built on years and years of discoveries.

Over the years, many researchers have contributed with key pieces of evidence, putting together our current body of scientific knowledge. Little by little, new pieces were added to this puzzle, allowing scientists to see clearer, and inspiring new findings and applications. If you were to remove essential pieces, that is, pieces of fundamental knowledge, from this puzzle, scientists would lose sight of the bigger picture. In short, our current vision of science and technology would fade away.

An essential piece of this puzzle is the structure of DNA. This long molecule is the basis for life: it provides the necessary instructions for the development, function, and reproduction of all living things. Had its structure not been unraveled back in the 1950s, our current understanding of genetic diseases and heredity would vanish. In addition, technologies that rely on the manipulation of DNA, such as the production of insulin and gene therapy, would not exist. In sum, had this piece of scientific knowledge been removed, scientists would not have seen this far.

 

A puzzle with no limits

Although our current understanding of living systems and the world is quite astonishing, there are still a lot of mysteries to be solved. New insights inspire new questions, and this is why, despite having been discovered more than 100 years ago, there are still a lot of blank spaces to fill in regarding DNA.

The long strands of DNA fold into compact structures in our cells – the chromosomes. These structures resemble wool yarns that promptly disentangle when the genetic information is read. This information can then be transcribed into instructions to synthesize proteins necessary for cell function. When cells divide, to guarantee the development of organisms, or to replace old or dead cells, they need to distribute DNA equally not to lose any genetic information. But it is still not quite clear how cells can do that so precisely.

This “chromosome dance” is the focus of research of Raquel Oliveira, principal investigator at the Instituto Gulbenkian de Ciência (IGC) who has recently been elected EMBO Member in recognition of her outstanding achievements in the life sciences. Raquel got caught up in the process of cell division (mitosis) during her PhD in Experimental Biology and Biomedicine. She was observing mitosis under the microscope when she experienced that “love at first sight” feeling. Since then, she has devoted her career to “studying cell division, in particular, the changes that occur in the structure of chromosomes to ensure faithful segregation of the DNA”.

After her postdoc at the University of Oxford, she returned to Portugal and established the Chromosome Dynamics Laboratory at the IGC, in 2012. The multidisciplinary environment and the opportunity to openly engage with other scientists were decisive for her return. That and, of course, the desire to contribute “to the development of science” in her own country.

Awarded with their first European Research Council (ERC) grant in 2014, Raquel’s team was off to a good start to explore a myriad of mysteries around chromosome architecture and its influence on mitosis and genome stability. The group posed several questions, from the way the long strands of DNA quickly go from a diffuse configuration in the cell to the tightly-packed X-shaped chromosomes to how problems in this process impair genome stability or organism development. Despite having been visualized under the microscope for over a century, how exactly these drastic changes in chromosome shape occur is still a mystery, Raquel explained.

 

“So what?”

Only by studying the mechanisms behind chromosome dynamics at a very basic level, can we then address the consequences that arise from their malfunction. Cell division “is such a fundamental process that it has, of course, implications in many diseases”, says Raquel.

By studying how cells, tissues, and organisms deal with mitotic errors, the group might be able to identify new routes to aneuploidy – the presence of abnormal numbers of chromosomes in cells. Aneuploidy has severe consequences: in most cases, it is not compatible with life, and when it is, it is usually associated with diseases, such as developmental disorders, infertility, and cancer. Without understanding how genetic information segregates properly, it is rather difficult to understand how failures in this process occur and how to fix them. “It is the fundamental knowledge that allows us to think about novel therapeutic approaches and novel diagnostic tools”, the researcher recalls.

Her most recent study with Sara Carvalhal, a former researcher at Raquel’s lab and now a junior group leader at Algarve Biomedical Center Research Institute, is a clear example of this. Using fruit flies as a model organism, they discovered that when cohesin, the molecular glue that holds chromosomes together, was partly lost, there were erroneous chromosome movements and unexpected problems in mitosis. With this basic knowledge, Sara, the first author of this study, wondered if similar problems happened in human diseases associated with the malfunctioning of this chromosomal “glue”. So, she switched from fruit flies to human patient cells to study the impact of cell division errors and loss of chromosome cohesion in development. And she ended up learning a lot more than she was expecting. The scientists were very surprised to discover that two of the patients involved in the study had mutations in both copies of a critical gene for cell division – BUB1. This was, until then, thought to be incompatible with life. The researchers went on to explore how the pathological variants of this gene affected cell division and how the resulting mitotic defects could underlie the patients’ rare neurodevelopmental disorder. Importantly, what they uncovered in the lab could prevent the misdiagnosis of patients with the same mutations in the future, with direct consequences for their treatment, prognosis, and follow-up. And it all started with a curious question.

Of course it gets easier to explain the relevance of Raquel’s work when we think of all the applications it could have down the line. But not all curiosity-driven research has this obvious practicality just around the corner. The truth is that the knowledge we are producing today may, in the long term, “become important to humanity (…) for unforeseen reasons”. There are several examples of basic discoveries that were made “without any expectation” of practical benefits “that are nowadays used in the clinic”, the researcher pointed out. One example is the finding that cancer cells divide at a higher rate than normal ones. With this in mind, scientists are now developing cancer drugs that target proteins that operate in mitosis to selectively kill dividing cells, Raquel explained.

But the value of fundamental science goes beyond its eventual applicability. As Isaac Newton once said: “if I have seen further, it is by standing on the shoulders of giants”, meaning that scientists can only make new discoveries by working in the light of the ones made by their peers. All the tiny puzzle pieces are needed to create an intelligible image, and even the simplest questions can advance our understanding and inspire a scientific revolution.

Defying the limits of knowledge

Apart from curiosity, a cross-disciplinary environment and cutting-edge technologies are key to challenging the limits of knowledge.

Being in a stimulating and interdisciplinary environment is “absolutely crucial” for the groups to achieve their goals. According to Raquel, the open-space laboratories at the institute promote interaction and discussion, making the IGC the perfect place for new ideas to pop. In fact, a substantial part of the work now conducted at Raquel’s lab was highly influenced by a fruitful and interdisciplinary collaboration with Diogo Castro, a former group leader at the IGC and now a principal investigator at Instituto de Investigação e Inovação em Saúde (i3s). At the time, the teams joined forces to understand how the expression of genes is regulated when neurons are formed. Their findings revealed that, surprisingly, some transcription factors, that drive the expression of specific genes, remained bound to chromosomes during cell division. They also figured that some of these did not actively drive gene expression throughout cell division, but rather promoted their timely expression at the end of it. This mechanism could ensure that some genes are reactivated before others, with consequences to the fate of the cells, for example, during neurodevelopment, Raquel explains. This has been challenging long-term dogmas since, for many years, “it has been assumed that all of the transcription machinery was evicted from chromosomes when cells entered mitosis”.

Simultaneously, Raquel was collaborating with Rui Martinho, also a former principal investigator at the institute, and now at University Aveiro. They were screening for genes involved in the “gluing” of chromosomes when they stumbled upon something they believed to be involved in the silencing of transcription. Ultimately, these two independent lines of research stirred up the curiosity of Raquel’s team and led them to pursue the molecular mechanisms behind this unexplored process: the silencing of chromosomes during cell division. When cells are not dividing, their DNA behaves like an open book, so the cell can read the genetic information and transcribe and express all the necessary genes”. But when cells divide, “it is almost like the book closes and most of the transcription is switched off”, the researcher explained. Although this is a well-established phenomenon in cellular biology, it is still very unclear how and why this happens. This is now the focus of their most recent ERC grant, awarded in late 2020.

But studying chromosome structure or transcriptional inactivation during mitosis is not easy, given that these processes are essential to cells. To unravel the role of different mediators, scientists need to make sure that these are depleted from the cell only when mitosis takes place. Raquel Oliveira’s lab came up with a method to switch proteins on and off “within minutes”. This system can be applied in the fruit fly, allowing the researchers to understand the functional consequences of disabling certain proteins in a developing organism, Raquel explains.

The presence of well-established scientific support units at the IGC makes the implementation of novel techniques and protocols like this a lot easier. Raquel assures that their “work would not have been so smooth” if it were not for these expert services that assure, among other things, the maintenance of fruit flies and quantitative imaging analysis.

In fact, the availability of technology is often a limitation to science development, the scientist remarked. “The questions are out there: we all want to know how to kill cancer, we all want to know how to prevent diabetes, but the knowledge that we have is, at the moment, limited by technology”. Raquel believes that advances in technology development are on the horizon, with the potential to impact a “wide range of scientific fields”.

Curiosity, imagination, scientific know-how, and a lot of teamwork are, for sure, some of the most important tools to thrive doing basic science. But we cannot undermine an essential asset of this toolkit: funding. Despite the importance of generating knowledge, applicable or not, the translational potential and the impact of research projects are still some of the strongest prerequisites to obtain funding. As society becomes more and more skewed towards short-term goals, we are losing sight of important discoveries that could lead to huge advances in the long term. The steady decrease in funding for basic science is something that Raquel, as a fundamental scientist, is “very worried about”: if we cannot “explore ideas” we will be “shortening knowledge generation”. Although practical advances that solve society’s global challenges quickly are necessary, without basic science we would not have the groundwork for applied research, she recalls. “It is called fundamental for a reason: it is really the foundation and the basis of everything”.

Updated on 18 august 2022

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