Mountains are for climbing

Guess what? I successfully powered through my first year of grad school! My first year was all about rotating from one lab to another in hopes of finding a permanent home where I would metamorphose from being a timid first-year grad student into a fearless, hopeful, and an optimistic researcher powered by data and caffeine.

I cannot believe how much I underestimated the process moving forward. Between taking courses (and therefore preparing for exams and working on assignments), attending seminars, teaching two labs (and two recitations, one office hour, plus all that grading), writing grants and fellowship applications, AND doing my own research in any time that I find in between, it has been a CRAZY semester so far. One of the most disheartening things is how much behind I am on my reading. I am usually so tired by the end of the day that my brain freezes and will not take in any new information that’s thrown at it. My eyes burn down, my legs become numb, and my back starts yearning to crash on my cozy bed as soon as I get home. The papers keep piling up, experiments haunt me in my dreams (the night before every rat dissection, episodes of drug treatments and protein assays flash before my eyes!) and I dread the 1:1 meetings with my PI having no data to report or no hypotheses to discuss. Is this normal for a second-year grad student? I don’t know. I am trying to make up for all the research time lost due to coursework and teaching by working till late evenings and on the weekends. There is no difference between a Friday and a Saturday or a Sunday anymore. Is this grad life? Are we more than just grad students?

A faint silver lining amidst this craziness has been the fact that I have started to formulate the research direction I want to pursue my main Ph.D. thesis on. Of course, I have been working on other projects on the side, but I have now started to connect the dots and evaluate my main project in terms of its novelty, idea, and the required experimental framework. I realized that the more I write about my work in grant/applications or the more I attempt to justify it, I start to identify the gaps in knowledge that needs to be filled. This is truly exciting. The funny thing is, I sometimes wish there was a guidebook that could tell me exactly what I need to think or how I should approach a problem. Unfortunately, there isn’t one. There is so much knowledge out there, but no guidelines for using it. Maybe this is what its all about?

Picking my permanent lab

Almost a year has passed since I started my Ph.D. journey in the land of snow and maize. After four long lab rotations across three departments and hopping from one project to another, it is time to pick a permanent lab and a research direction.

IMG_6374.JPGI am happy to announce that I have officially joined the distinguished Department of Chemistry at my university and have begun my research at the Institute for Drug Discovery where I will work for the remaining period of my doctoral degree. I couldn’t be happier with my decision which was mainly determined by three aspects – my advisor/mentor, the research area and the lab (environment and members). It feels good to finally know where I am headed towards and not feel lost or uncertain. Every one of my rotations was unique and helped me learn the nitty-gritty of grad school. Moving forward, I will focus on brain-related disorders like Alzheimer’s Disease and work towards understanding a tiny piece of a large puzzle which may aid in finding a cure/prevention/slow down the progression of the disease. Specifically, the overarching theme of my work will be to identify and test compounds predicted for the disease by taking into account all the possible interactions between biomolecules in the protein universe (aka the proteome). Traditional drug discovery methods involve targeting a specific protein or a specific pathway and thereby limiting the possibility of finding successful leads. In reality, we know that one biomolecule interacts with several other biomolecules in several different pathways. Interactome-based drug discovery is promising because of its broader and quicker approach compared to the other mainstream pipelines that exist today.

One other major factor that helped me decide my major lab was the computation aspect involved in drug discovery research. Taking the challenging Computational Chemistry course this semester helped me take the first step towards learning about some of the components of computer-aided drug discovery. It is amazing how the two channels of research (wet lab and dry lab) finally come together in solving some of the major challenges in health and medicine. Anyway, I will continue to update here more on my day-to-day lab rat adventures. I am excited to start this new chapter of my life and see where it takes me! :)

The Human Kinome

The entire set of 518 protein kinases in the human genome makes up one of the largest of all human gene families. These enzymes catalyze the phosphorylation of proteins, specifically serine/threonine and tyrosine residues – an important reaction that regulates key cellular functions like cell division, metabolism, and apoptosis in normal and disease states. This makes kinases key therapeutic targets in several diseases such as cancer, neurodegeneration, behavioral disorders, diabetes, and cardiovascular diseases. Interestingly, both the labs that I’ve been in so far are focussed on kinases involved in pancreatic/prostrate cancer and GPCR signaling in the light of alcohol/drug addiction. Leaving this nice phylogenetic tree here as a reminder and reflection of kinome research!Map of the Human Kinome

Stress – it’s all in your head!

Stress is an interesting body response that is stimulated by our brain due to incoming auditory, visual and/or somatosensory signals. It is how we feel and how our body reacts when we encounter an imbalance in the normal rhythm of life. Watching a horror movie, coming face to face with a deadly creature or simply feeling overwhelmed due to daily tasks may all evoke stress. How does our brain respond to a stimulus that elicits fear and anxiety?

The key areas of the brain that are involved in stress are the thalamus, hippocampus, amygdala, and the prefrontal cortex. The thalamus located in the forebrain processes the incoming visual and auditory signals and relays them to the prefrontal cortex and the amygdala. The prefrontal cortex is the hub for executive function. With respect to stress, it gives meaning to the relayed signals and makes us conscious of what we see and hear. This part of the brain is also critical for ‘turning off’ the stress response once the condition is passed.

The Neurobiology of Stress - Brain regions involved in stress response
The Neurobiology of Stress – Brain regions involved in stress response

The amygdala is the emotional center of the brain and is responsible for triggering the stressful response. It is a part of the limbic system and is located deep within the temporal lobes of the brain. The amygdala also drives the body’s sympathetic nervous system to initiate anxiety that is associated with stress. This includes increasing the heart rate, blood pressure, hyperventilation of the lungs and increasing perspiration.

Finally, the hippocampus located in the medial temporal lobe stores the memory linked to a particular stress response and allows the brain to access these memories when the same visual and auditory triggers of stress are encountered later on.

It is also essential to mention the role of the hypothalamus and the linked pituitary gland that pumps out high levels of cortisol – “the stress hormone”. Recent studies suggest that cortisol can damage and kill brain cells, especially that in the hippocampus. (The hormonal response of stress is in fact a huge area of study with lots of factors involved.)

A critical question in this area of study that interests me is, “How much stress is bad for us? Can a little stress actually be helpful?” It turns out that acute stress (short-lived, unlike chronic stress) may actually be good for us. New research suggests that it conditions the brain for improved performance by inducing an increased level of alertness, behavioural and cognitive performance. This may explain why we get most of work done when we’re under pressure!

Scientific data representation

As a graduate student, one is asked to read and interpret quite a few research and review papers every week. Usually, most of the articles represent data in the form of mundane tables and histograms, which can get tedious. Recently, I read this nature review article on zoonotic diseases (diseases spread between humans and animals, for example, malaria, west nile virus infection, ebola, H1N1 flu, etc) and was really impressed by the unique and creative way the data is represented in it.

NOTE: All images and image captions copyrighted to – Bean AG, Baker ML, Stewart CR, Cowled C, Deffrasnes C, Wang LF, Lowenthal JW. Studying immunity to zoonotic diseases in the natural host – keeping it real. Nature Reviews Immunology. Published online 25 October 2013. doi: 10.1038/nri3551

Figure 1: Emergence of zoonoses. / Tombstones representing number of deaths!

Over the past century, humanity has witnessed the emergence of numerous zoonotic  infections that have resulted in varying numbers of human fatalities. Influenza viruses that originate from birds account for  an important proportion of these deaths, and recently many new zoonotic viruses that originate in bats, such as Hendra  virus, Nipah virus and severe acute respiratory syndrome (SARS) coronavirus, have caused outbreaks with high mortality  rates. Hyperlinks to World Health Organization disease report updates are provided in BOX 1. MERS, Middle East  respiratory syndrome coronavirus.
Over the past century, humanity has witnessed the emergence of numerous zoonotic
infections that have resulted in varying numbers of human fatalities. Influenza viruses that originate from birds account for an important proportion of these deaths, and recently many new zoonotic viruses that originate in bats, such as Hendra virus, Nipah virus and severe acute respiratory syndrome (SARS) coronavirus, have caused outbreaks with high mortality rates.

Figure 2: The severity of emerging infectious diseases is influenced by the host-pathogen interaction. / Organisms in the innermost circle (bats) show no sign of symptoms at all and the signs increase as one moves to the organisms in the outer circle (humans) – leading to high mortality rates. Mainly, animals in the inner blue circle are the transmission hosts. Read ‘The curious case of MERS-CoV‘ for more on MERS transmission hosts.

Many  zoonotic agents cause little or no signs of disease in their natural hosts, such as wild birds and bats, but transmission hosts  might present with disease symptoms ranging from moderate (for example, pigs infected with avian influenza virus) to  severe (for example, horses infected with Hendra virus). The terminal or spillover host can present with severe symptoms  and high mortality rates (for example, in the case of humans infected with H5N1 influenza and Hendra virus). For some of  the most recently identified emerging infectious diseases, such as H7N9 influenza and Middle East respiratory syndrome  (MERS) coronavirus, natural and transmission hosts have not been conclusively identified (indicated by a question mark).  SARS, severe acute respiratory syndrome.
Many zoonotic agents cause little or no signs of disease in their natural hosts, such as wild birds and bats, but transmission hosts might present with disease symptoms ranging from moderate (for example, pigs infected with avian influenza virus) to severe (for example, horses infected with Hendra virus). The terminal or spillover host can present with severe symptoms and high mortality rates (for example, in the case of humans infected with H5N1 influenza and Hendra virus). For some of the most recently identified emerging infectious diseases, such as H7N9 influenza and Middle East respiratory syndrome (MERS) coronavirus, natural and transmission hosts have not been conclusively identified (indicated by a question mark). SARS, severe acute respiratory syndrome.

Figure 3: The host immune response to an infection influences the disease outcome. / The difference in immune response to H5N1 in different spillover hosts.

Infection with H5N1 influenza  virus can cause very different disease outcomes in different reservoir and spillover host species. Waterfowl, such as wild  ducks, are the natural host for this virus and develop a limited inflammatory response that is associated with low levels of  cytokine expression. Intermediate hosts, including mice, pigs and ferrets, are often used to study this infection and display  mild to severe disease symptoms (depending on the H5N1 virus strain used) that are associated with increased levels of  pro-inflammatory cytokines. By contrast, spillover hosts such as chickens and humans display a rapid and strong  inflammatory response, often referred to as hypercytokinaemia (or cytokine storm) and the infection becomes systemic,  causing severe disease symptoms and high mortality rates.
Infection with H5N1 influenza virus can cause very different disease outcomes in different reservoir and spillover host species. Waterfowl, such as wild ducks, are the natural host for this virus and develop a limited inflammatory response that is associated with low levels of cytokine expression. Intermediate hosts, including mice, pigs and ferrets, are often used to study this infection and display mild to severe disease symptoms (depending on the H5N1 virus strain used) that are associated with increased levels of pro-inflammatory cytokines. By contrast, spillover hosts such as chickens and humans display a rapid and strong inflammatory response, often referred to as hypercytokinaemia (or cytokine storm) and the infection becomes systemic, causing severe disease symptoms and high mortality rates.

I think it is really important to represent scientific data in a simple, straightforward and an efficient fashion. Many researchers disregard this fact and don’t acknowledge it well enough.  A really good diagram or data representation is one which contains all important facts or information required to infer the purpose of the diagram itself. One must be able to simply look at it to make interpretations and get the general idea without having to go too much into the depth of long procedures and discussions in the paper. (Sometimes exceptions exists w.r.t. the kind of paper & data, of course.)