Genes in our body should work like harmonious orchestra, but it happens that individual performers get out of balance and play out of harmony. It makes us sick. In this case, the orchestra consists of over 20 thousand genes carried by 40 trillion cells, and scientists are developing tools with which we can dissect each cell separately, says Vilnius University Life Sciences Center (VU LSC) researcher Prof. Linas Mažutis.
"Research in the field of life sciences often does not produce immediate results applicable in practice, but it generates knowledge and a much deeper understanding of molecular processes in biology," says the researcher who returned to work in Lithuania from Harvard University about the importance of fundamental research. The inDrops technology created by him and his coworkers is already being used around the world, but the work does not stop there – a new generation of tools is being developed that may help us to better understand how our bodies work and how diseases develop.
Q: The term "gene expression" is found in your works. How would it be correct to explain what role gene expression plays in our body? Comparisons have been made that gene expression is like a conductor in an orchestra. Is it true?
A: No, not quite. Imagine an orchestra, but in this case, each member of the orchestra is a gene. When one or another piece is played, the performers play at different times, setting a different tone. For example, the genes are the same, but in some cells some genes play one type of music, in others they are silent and other genes with a different musical note join the composition. It is also possible to imagine that in an unhealthy cell, one or more genes start playing music so loud that it surpasses all others, while in healthy cells the music of genes is balanced.
Q: Why is gene expression important for understanding diseases? For example, you mentioned cancer.
A: Cancer is a very complex disease. Some forms of cancer are determined by genetic mutations. Therefore, we can inherit certain mutations from our parents and be prone to certain diseases. Likewise, if a mutation occurs during our lifetime due to external factors, cancer can also develop. Let's say this is one category.
Another category is complex diseases, where it seems that the genes do not have known mutations, but the cells are still malignant. And we still don't understand these mechanisms - why this happens, why cells get malignant. One such factor may be unbalanced gene expression.
Going back to the orchestra example, let's imagine if the orchestra is playing a certain piece of music, everyone is playing properly, and then one of its performers gets out of balance. In other words, the cell begins to respond inadequately to the environment and its neighbors, and begins to behave malignantly and differently than it should.
Q: Is this also the case with other diseases to which people have a genetic predisposition. For example, prone to diabetes?
A: Yes, it is.
Q: What other molecular cancer puzzles are you trying to solve?
A: One of the goals is to better understand the biological mechanisms that determine certain functions and phenotypes of human cells. To use the orchestra example again, one of those phenotypes would be that the cell's "melody" becomes disharmonious. We are trying to understand this lack of balance. When we understand what determines the imbalance, we can postulate and raise other problems, for example, what if we throw out an inharmonious performer or replace him with another artist, maybe then all the harmony will return? Or maybe the whole orchestra will fall apart without that performer?
Research success often depends on collaboration. Therefore, our work is not an exception. We would hardly achieve anything alone. We always try to find common points of contact with clinicians, biologists, and scientists from other fields, identify important problems, and provide technologies, and solutions.
Therefore, our research is not only fundamental. We are developing technologies and methods that allow us to conduct research beyond what can be done with traditional methods.
Work at the laboratory
Q: What technologies are these?
A: These are microfluidic technologies. We have developed single-cell transcriptomics technology…
How to explain it in a simple way… If, for example, you are flying on a plane and you look at the National Philharmonic Society building from the window of the plane, it would probably be impossible to tell how many and what kind of artists are inside the building? Well, we have created a tool that allows you to see through that window how many performers there are and what instruments they play.
Q: As with a microscope?
A: We can say that this technology is a kind of lens or a microscope that allows us to look inside human cells. A human is made up of about 40 trillion cells, where each cell carries around 20 thousand genes We are developing technologies that would enable us to look at each cell individually and tell what biological function they perform, whether they are playing harmoniously or not. With the help of these technologies, we can study the expression of genes in individual cells, gene expression.
Q: Where is the knowledge of transcriptomics applied in general? What do you learn from such studies?
A: It is used in biomedicine, cell biology, and other life sciences. More specifically, the knowledge can be applied, for example, in the research of human diseases, Alzheimer's, cancer, or others. We are trying, in cooperation with other researchers, to understand how individual cells function as a whole when there are many of them - what is the function of individual cells, how do they "talk" to each other, why some cells respond to external stimuli, while others do not.
In some cases, the changes in gene expression hint towards important insights about a certain response of cells or their tendency to metastasize. For example, human cells are specialized and their gene expression (transcriptome) is strictly regulated. However, there are scenarios when cellular gene expression is misbalanced, and cells turn on the genes that should remain off.
Suppose, lung cells turn on the genes responsible for brain development. Then such a cell, having lost its identity, can either die or cause serious problems for the whole organism, metastasize. Therefore, we aim to better understand why the cell's gene orchestra gets out of balance, and what the consequences are.
Q: Is inDrops already used in the world?
A: Yes, it is. A couple of years after we published a scientific article about it in the journal Cell, it was successfully adopted by a US company called 10X Genomics, which offers equipment and molecular biology facilities to study gene expression in single cells. This company seems to be worth billions already and employs over 1,000 people. But this is just one nice example. Now, together with Atrandi Biosciences, we are developing new technologies that may be as successful as inDrops was a few years ago. The future will tell, and our work does not stop.
Q: What unites the technologies you develop?
A: If inDrops allows us to look at gene expression, we are now developing such technologies that we can simultaneously look not only at gene expression but also at the same time at epigenetics of cells that control gene expression.
If you ask epigeneticists, they will tell you without batting an eyelid that epigenetics determines everything! And they will be almost right. But those who study protein will say that protein is everything! And they will be almost right, too. However, there is a direct link between gene expression and epigenetics, so we are moving in that direction.
Q: How did you start developing such technologies?
A: The number of mechanisms by which a cell can control its biological functions is limited. However, those mechanisms can be very complex, and intertwined, and deciphering them is extremely difficult.
One mechanism is, for example, if we use a drug, the chemical compound binds to a cell receptor, then the signaling system is induced, and gene expression is triggered. Then we think about key principles governing life functions, there are not so many of them. The challenge is that biology is very complex - in this case, there can be hundreds of receptors to which a chemical compound can bind with different affinity. And they can respond to ligand with different efficiency.
Q: Why is it important to find out?
A: It is very important for us, researchers, to have such tools that allow us to extract as much information as possible from a cell so that we can evaluate and predict the function of those cells as accurately as possible.
We want to create a technology that would allow not only the determination of gene expression but also their epigenetic profile in cells at the same time. This is important for any disease, for a better understanding of biology and cell function in general.
However, scientific research takes time and often does not immediately produce a result that one can touch or carry in the pocket. But it provides important knowledge, on which other stages are built, new ideas emerge, and a much better understanding of human biology is gained.
For example, the development of the inDrops technology took about 3–4 years, because it was necessary to accumulate a lot of knowledge, to solve technical and other problems that arose during the work. Persistence often pays off, it's important not to give up.
Q: Thank you for the answers and I wish you success in your research.
A: Thank you.
Interviewed by Goda Raibytė-Aleksa
Photo credits: Prof. Linas Mažutis personal archive