‘During my PhD, I Identified Four Gene’s Vital for Blood Brain Barrier Formation in Drosophila’

Neuroscientist, Dr Mubarak Hussain Syed is personally amazed by brain development and its evolution in diverse life forms. Leading a laboratory at the University of New Mexico, he is attempting to find answers to how diverse neural cell types are formed during development. Using fruit flies as a model system, his research group is investigating the neural stem cells that generate diverse cell types of the olfactory navigation and sleep-wake circuit.

KASHMIR LIFE (KL): What is the correlation between neuroscience and genetics? How it is going to impact the knowledge in future?

MUBARAK HUSSAIN SYED (MHS): Neuroscience is basically a study of the brain and the nervous system including other associated nerves and veins. It interrogates the development of the nervous system and neurons in the early growing stages of human beings and how they function in different ways.

I was at a workshop in Okinawa, Japan where we had a session about the history and evolution of neuroscience. The first person to depict the nervous system, like how we see and perceive light was Ibn Al-Haytam, who was from Iraq. The father of neuroscience, Santiago Ramon y Cajal from Spain, is the one I admire the most, for his contribution and knowledge. He is known for the discovery of the precise physical structure of brain cells. Santiago Ramony Cajal co-shared the 1906 Noble prize with Camillo Golgi on defining the basic structure of the nervous system.

What we get to know from neuroscience is what the brain is, how the brain develops, what it is made of and how brain cells or neurons and many other cells like glial cells, confabulate with each other and make us think and do things like, how we memories certain stuff, the movement of our body and how the environment affects our brain. There are different sub-specialities like, for example, molecular cellular neuroscience, neuro-technology as well as psychology, which talk about various mental functions and how certain brain disorders could be treated.

The brain is the most complex organ in our body consisting of more than a hundred billion neurons. The most fascinating thing is that these cells or neurons develop only duration of six months when we are in our mother’s womb. These glial cells and billions of neurons are born in a short frame of time, which differ from each other and regulate different functions. How neural stem cells generate this amazing neural diversity is an open question in the field. A question, we have been investigating in our research programme for a while now.

I would say the next hundred years of brain science are for neuroscience. In fact, when Barak Obama was the president of America, he started the initiative of brain science as he was well aware of the future. At one point in time, there was the genome project that was about sequencing the genome of humans. Now they are done with that project and they are aware of the facts and figures of genes or genomes. The next frontier is to understand the brain.

The mechanism of how temporal gene expression within neural stem cells governs the formation of different neuron types was first identified in fruit flies; interestingly similar temporal patterning programmes are utilised during vertebrate and human brain development as well. In our laboratory, we have identified how sleep-promoting neurons in fruit flies form during development. My graduate student Adil Wani has identified a stem cell that produces these neurons and genes that regulate their formation and function. Another, graduate student Aisha Hamid has identified neural stem cells that generate navigation neurons. A different gene regulates its specification and functions. We are excited about these results; since our findings will help the field understand how a neural stem cell generates diverse neuron types over time.

KL: How was your journey from Kashmir to New Mexico?

MHS: Well it was not that easy. I could not qualify for the examinations in my early days, especially the NEET, given the competition in those days and the fact that most of the examinations are memorization based. I was in Kashmir till 2007. I lived in Budgam’s Wahabpora village. I did my schooling from there only and I was among the first batches of Imamia Public school that had started in 1985. I spent a few years at a primary school in Wadwan followed by high school at Salafia Muslim Institute. After finishing my 10+2 education from the Government Boys Higher Secondary Budgam, I joined Amar Singh College, Srinagar for my undergraduate studies.

One of my elder brothers and uncle, whom I admire for the sacrifices he made for me, made sure that I study. Though my parents insisted that I become a doctor, I was not that interested in medicine, rather I wanted to explore nature and investigate living systems. Instead, I did a diploma in pharmacy, which also did not excite me. Eventually, I went for MSc in Biochemistry. That was the time when there were fewer resources and laboratory infrastructure at the University of Kashmir. I did the master’s but it primarily was book education without any solid laboratory research experience. I observe things have changed now. There are laboratories with good equipment and resources. In the Kashmir education system, we lack early exposure to research and other interesting career pathways. From my experiences, it seems the emphasis in our education system is on degrees for jobs, which is good as long as we provide avenues to experience how knowledge is accumulated and how one can utilize knowledge gained to advance society.

With a master’s in hand, I applied for a faculty position at Government Polytechnique College to teach biochemistry in a leather technology department. I taught there for about six to eight months. It was quite a good experience but I realised that I was not being honest with the students as I did not know much about science and teaching science.

It was during that time that I got an opportunity to take our students for a month-long training at Central Leather Research Institute in Chennai, India. That was a unique experience. I went to Bangalore for a week and stayed with my friends. At the National Centre for Biological Sciences (NCBS), I got an opportunity to see world-class research labs, and new scientific technologies and met people who were passionate about science and research. I got excited and thought that this was something I should try.

When I went back to Kashmir, I realised a need to leave my comfort zone and explore the world. It was challenging to convince my parents about my move, but I feel it was a good decision. It took me fifteen years of training, gaining experiences from travels, failures, and ups and downs to become a better version of myself. My advice to all young people is to try and go beyond their comfort zone, which is critical for personal growth.

Dr Mubarak Hussain Syed (neuroscientist)

At NCBS, Bangalore, India, after a long struggle, I worked in a laboratory for one and a half years, with a very famous scientist namely Veronica Rodriguez, who unfortunately is not living anymore. After almost a two-year of research experiences, I wanted to explore beyond India to get more exposure to international science. Eventually, I got accepted for a Max Planck PhD programme in Germany, where I worked with Prof Christian Klaembt for about four years. Initially, studying in Germany and getting adjusted to a new environment was challenging, but with time and having good mentors, and friends around helped.

Then I did my post-doc with Prof Chris Doe, who is an HHMI investigator and top developmental neuroscientist at the University of Oregon, USA. I feel lucky to have met good mentors and friends who have trained and taught me to be a responsible scientist and a good mentor. After my six years of postdoctoral training, I was lucky to find an independent research faculty position at the University of New Mexico. In 2019, I shifted to New Mexico and started my own laboratory. It was a rough start but it is getting on track now.

KLWhat was your PhD and post-doctoral research all about?

MHS: In my PhD, I worked on the blood-brain barrier (BBB), which is a specialized system of brain microvascular endothelial cells (BMVEC) that shields the brain from toxic substances in the blood, maintains ionic balance, and filters harmful compounds from the brain back to the bloodstream. Most often the BBB is a challenge when we have to treat brain disorders because it is hard to make a particular drug cross that barrier and get into the brain. During my PhD, I investigated the formation and function of the BBB in fruit flies. In fruit flies, the BBB is made by the glial cells and interestingly the molecules, which form this barrier are conserved.

In a genetic screen, I identified four new genes that are essential for BBB formation. Two of the genes, leaky and undicht are published and the other two others await to be characterized further. The gene I identified, if you knock it out, there is a leaky barrier and when the BBB is disrupted there is no barrier left. So I named it leaky and one more gene is Wular (not published), which I have named after Kashmir’s Wular Lake. If you are the first to identify and characterize gene function, you get the privilege of naming the gene.

KLDid you continue your post-doctoral research in the same area?

MHS: Yes. But I did change a bit. Actually, it is better to do a post-doc in a different field, at least, on a different topic. For my post-doc, I wanted to experience the research culture in the USA and I got lucky to get offers from all the places I interviewed. I finally decided to go to Oregon because I prefer small places with the outdoors and mountains close by. Also, Prof Chris Doeis a top scientist, and HHMI investigator with a track record of mentoring excellent scientists.

My post-doctoral work investigated the neural stem cell-specific mechanisms that regulate neural diversity. I investigated how neural stem cells make different neuron and glial cell types.

It was a challenging project and it took some time but eventually after lots of failures for about two-three years, our work identified over a dozen novel molecules that express in neural stem cells temporally. Our work showed neural stem cells express a set of early genes and at mid-age neural stem cells express a receptor for hormones to mediate temporal switch to the late expressed genes. This was the first description of extrinsic hormonal cues regulating neural stem cell temporal patterning, not to our surprise recently the thyroid hormone was shown to be important for the human eye cell type formation. We propose these newly identified molecules to be essential to make distinct classes of neurons, questions we are addressing in my independent lab at the University of New Mexico.

KLPlease elaborate on your research is going to help the society and medical science field.

MHS: As you know, our brain has BBB made primarily by the tight junctions of endothelial cells and astrocytic end feet, this barrier regulates ionic influx (groups of molecules that have an electric charge). Our fundamental work in the fruit flies has identified many genes that are conserved in humans and function similarly. This is how fundamental discoveries are made, the findings from basic science most often go to the textbooks. The genes and the processes, which we have discovered, are fundamental discoveries for understanding brain development and function. The advantage of studying fruit flies is that we can manipulate single neural stem cells, and manipulate and label neuron cell types in vivo, a kind of experimentation quite challenging in mice and other vertebrates. The basic research on fruit flies unravels fundamental principles of life, such as how genes regulate a trait, how genes regulate the development of our body, sleep and many other behaviours.

Currently, we are studying the development of sleep-promoting and olfactory navigation neurons in fruit flies. In humans, we also have neurons which promote sleep called the ventrolateral pre-optic neurons (VLPO). The behaviour we study, and the genes we work with are conserved, perhaps our discoveries will help understand human brain development and function.

Mubarak Hussain Syed carrying his son Jibran in typical traditional Kashmir style. This has been the old style of helping kids stay warm during winter. Mubarak Hussain Syed

The fundamental discoveries take time to be applied. Some of them may not be applied at all. But all these fundamental discoveries are very important in understanding the basic principles of life. I still remember when, in my post-doc, I published a paper about how hormones regulate the gene transition in stem cells and make different neurons. Maybe similar principles would occur in humans. And only a year later, there was a paper where they had shown the role of thyroid hormone in making specific subtypes of the human eye in an organoid model. The brain organoid is a new method of culturing the human brain in a dish. The scientists re-programme skin cells to make human tissue-derived brain organoids. So pursuing basic research is important not only for understanding fundamental principles but also for treating disorders.

KL: Can you tell us more about JKScientists, an organization that mentors and helps students from Jammu and Kashmir?

MHS: JKScientists is a decade-old organization that has had a tremendous impact on science and education in our part of the world. Thanks to the dedicated young scientists and scholars who volunteer to train and mentor next-generation scientists. There are various mentoring programmes such as SPROUT and SPECTRUM. I advise all interested undergrads, master, and PhD students to join these amazing programmes. Over the years, JKScientists has organized various science and education outreach events. We value diversity and have started a women’s support group, and a mental health cell as well. There is 24×7 counselling happening in our closed Facebook group, which has over 13K members. We have recently launched our newsletter and students and trainees can contribute articles or art.

(Umima Reshi processed the long interview)

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