‘The Biggest Challenge Is To Find Out How 98% of DNA Regulates The Rest of It’

A young geneticist, Dr Rais A Gania was surprised to see his takeaways from his PhD were part of the text well before he entered the classroom as a teacher. Credited for identifying a particular enzyme that helps in crucial DNA copying, he is serving the IUST’s molecular medicine centre. In a freewheeling interview, he opens up about his research and future plans

KASHMIR LIFE (KL): You studied in Kashmir and worked in different universities all over the world. How was your learning curve and what were the challenges you faced?

DR RAIS A GANAI (DRAG): I was born and brought up in the Posh-Kirri village of Anantnag. I did my primary schooling at Government Primary School in the same village. Later, I went to the Government Middle in the nearby Hugam village. Later, my father suggested me to complete further studies in Srinagar, as he was working at the University of Kashmir. Then, I went to the Starland High School Zakura and completed my matriculation there.

In Srinagar, I found it very difficult to compete with students because of the language barrier, as the medium of instruction was different. It was a challenging task to learn English and Urdu languages. It took me a lot of time to cope with the level of the students.

Then I completed my 10+2 from Soura Higher Secondary School. Afterwards, I went to the Islamia College of Science and Commerce, where from I completed my graduation. Even though there was not an ample structure at that time but the laboratories were well established. Attendance of labs was mandatory, due to which my scientific temper got developed.

After that, I was selected at the University of Kashmir for a couple of courses but I chose to study Biotechnology. After completing the Master’s degree in Biotechnology, I went to the Indian Institute of Science (IISc), Bangalore, where I worked under the mentorship of Prof Umesh Varshney and worked intensely on various Biotechnological challenges. He invested a lot of money, time and effort and taught me many new things due to which my interest in the research further deepened. During this time a few of my research papers were published.

Then I went to Sweden in 2009 for my PhD and completed it in 2015 and later got an international Postdoc fellowship offer in Sweden amounting to Rs 2.5 crore. I used that fellowship and immigrated to the USA. There I joined the NewYork based Howard Huges Medical Institute. I did research there for almost 2-3 years under the well-known researcher Danny Reinberg.

Then I came back to Kashmir as a Ramanujan Fellow. Initially, I joined the Central University of Kashmir and later moved to the IUST’s Watson-Crick Centre for Molecular Medicine in 2020.

KL: The work on genetics has been going on in all major universities throughout the world. However, we still have not understood the gene fully. What are the various challenges in understanding the gene, and what are the different goalposts we still have to reach?  

DRAG: The gene is actually a small DNA sequence made of sugar bases like Adenine, Guanine, Thymine, and Cytosine (A, G, T, C). They are about 3 billion sugar bases called Nucleotides (made of Deoxyribose sugar, the Phosphate group, and the Nitrogen base) in a DNA molecule arranged in a chain structure. All the Nucleotides in a DNA molecule do not constitute genes, but only 1-2 per cent makes the genes and the rest 98-99 per cent of the base pairs do not attribute to the genes.

Scientists have identified most of the genes in our body and their functioning but the functioning of the rest 98 per cent of the non-genomic sequences (regulatory sequences) is still not known. We only know that these contain non-genomic sequences that regulate the genes, but the biggest challenge is to find out how 98 per cent of DNA regulates the 1 per cent of DNA.

The other major challenge was to understand the three-dimensional structure of DNA and its arrangement inside the cell. The chromosomes are arranged in compartmental structures. How and when these compartments are formed is yet to be discovered. How these genes are activated and repressed in the cells is still a challenge.

The actual structure of a DNA molecule has a three-dimensional chromatin architecture. These DNA molecules are present on the chromosomes. Our body contains 46 chromosomes in each cell that are intertwined inside the cell. The intertwined structure of chromosomes helps in the better expression of genes during cell division and cell formation. All the required genes express together and activate simultaneously in order to form a complete cell.

KL: What was your PhD all about and what were the major takeaways from your research?

DRAG: As I mentioned that DNA is a small molecule contained in a cell. A cell contains two meters of intertwined DNA, which if stretched is equivalent to at least four times the distance between the sun and the earth. During cell division and cell multiplication, this DNA is replicated/ duplicated which has to be very accurate. Genetic defects during cell division cause mutations/errors, which lead to genetic diseases, metabolic disorders, or even cancer.

During my PhD, my research was about the role of an enzyme called DNA polymerase in DNA replication. This enzyme reads, copies, and then makes the exact copy of a parent DNA molecule. The three billion nucleotides of a DNA molecule in a cell are copied accurately without any error or defect with the help of this enzyme. Besides, it also rectifies the errors, which are caused during cell division and helps in errorless duplication. Thus, the DNA polymerase enzyme not only plays a role in DNA replication but also fixes the errors caused during DNA replication, if any.

I also studied the functioning of various other enzymes but the pivotal research was about DNA polymerase. The majority of DNA polymerase enzymes look like, if I can say, a right-hand structure, containing a thumb, a palm, and fingers. The DNA polymerase, we studied has an additional domain called the P-domain, unlike the other DNA-Polymerase enzymes which only have three domains. The majority of DNA-Polymerase enzymes require a scaffold or support (called PCNA) for DNA copy and replication, but the DNA-polymerase we studied does not require PCNA rather it has the inbuilt P-domain that helps in DNA synthesis and thus does not require an outside scaffold. This was the biggest takeaway from my PhD research.

To my surprise, I later found when I was at the Central University of Kashmir, that our work and findings were published in textbooks, and are being taught to students in different Universities all over the world.  It was a very difficult project to work on because nobody prior to us had worked on this. Our work was then published in the Journal Nature Structural and Molecular Biology, which now is a part of the textbooks and is being taught.

Dr Rais A Gania (WCCMM)

KL: What was your Post-doctorate research about, and what were your accomplishments and learnings during that period?

DRAG: I mostly studied two things during my Postdoc research, the role of epigenetic factors in the development, and the development of stem cells into the cardiomyocyte.

I actually wanted to expand and diversify my expertise, so I shifted to the field of epigenetics.

Under epigenetics, we study how the genes present in the DNA are regulated.  Let us understand it this way – if we have two monozygotic twins and one of them is raised by the adopted parents and the other by the natural parents. Technically, after 30 years of age, both should be identical because of the principle of monozygotic nature, but because of the environmental effects, they would have developed variations over time. It is because the influence of environmental conditions affects the development of an individual and that regulates the body. Thus, the effect of an environment on the development over time, beyond the genetic basis and beyond DNA is called epigenetics.

There are thousands of genes on a DNA molecule and there are specific factors that actually regulate the functioning of these genes. I also worked on these factors.

DNA is wrapped around by the histone proteins. These proteins contain chemical modifications or tags that determine the function of the DNA sequence. I worked on early embryonic development, particularly on stem cells. I studied how differentiated development takes place from a single cell into different kinds of complex organs i.e., how a stem cell is transformed into a cardiomyocyte.

KL: How could you make lawmen understand this differentiation of a stem cell into different complex organs? What really controls this differentiation of cells? Is this also part of epigenetics?

DRAG: Nobody really knows how embryonic development occurs as it is not easy to study this field. People have now started research on it.

During embryonic development, the fusion of egg and sperm results in the formation of a Zygote, which later undergoes the 2-cell stage and the 4-cell stage, and so on. From day one of development certain genes are activated which stimulates the Zygote division and this division activates other genes, which then cause muscle cell formation. More and more genes get activated that guide the muscle cells to transform into different complex organs. It is mostly like this, but there is still ambiguity on how embryonic development takes place through different stages of development.

KL: What is your role at the IUST’s Watson-Crick Centre for Molecular Medicine and what are the different domains you are working on?

DRAG: I am establishing my lab here for research purposes. Besides, I am also the coordinator of the B Voc course on the Medical Lab and Molecular Diagnostic Technology. I teach students also. I guide students on how to do diagnostic tests and the process of opening diagnostic clinics.

The primary part of my job at the Watson-Crick Centre is to do research along with my students who work with me on the continuation of my PhD research work. We are studying the role of DNA polymerase enzyme other than the role of DNA synthesis.

Secondarily, we are also studying epigenetics. Epigenetic marks at different positions of a DNA molecule, other than the normal positions cause diseases like cancer, and developmental and neurodegenerative diseases, among others. Therefore, our aim is to research epigenetics in detail in order to develop drugs for the treatment of these diseases.

Mujtaba Hussain processed the interview


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