It’s brain awareness week!

Hello all!  I wanted to take a few minutes to write something for the brain awareness week. This is important to me because my research focusses on understanding the role of the immune system in the brain. For a very long time, the brain was thought to be an “immune privileged” organ i.e., it was thought that the brain is protected from all the peripheral insults and that it is “divorced” from the rest of the body. In 2015, it was shown that there exists certain lymphatic vessels that connect the CNS to the rest of the body (1). The lymphatic system carries immune cells through a network of vessels and tissues; it connects the bloodstream and tissues in order to remove dead cells and other debris. The discovery of the new “glymphatic system” has opened new avenues to study the connection between the brain and the rest of the body. This is especially helpful in understanding the role of the peripheral immune system on the CNS during infections, injury, and other disease insults.

glymphatic system
Old lymphatic system (left) and newly discovered lymphatic system in the CNS (right). Source: University of Virginia Health System

My work focusses on a specific cell type in the brain known as microglia which are are the resident macrophages of the CNS (they eat up and clear out the bad stuff in the brain like dead cells and mis-folded proteins). Microglia are the only known immune cells of the brain. Compared to all that’s known about the cells of our body’s immune system (B cells, T cells, NK cells, neutrophils, basophils, Treg cells, MDSCs, TH1, TH2, and many many more with several subtypes of each cell), it is safe to say that cells of the CNS are poorly understood. My efforts are focussed towards understanding the role of microglial cells in neurodegenerative diseases such as Alzheimer’s Diseases (AD) , Parkinson’s Disease (PD), Multiple Sclerosis (MS), etcetera. These diseases are characterized by mis-folded proteins that aggregate in the different regions of the brain tissues causing the neurons to degenerate and eventually die. The microglial cells in these disorders play a major role in disease progression by regulating many pathways involved in cell-cell communication, cell survival, and cell death. This is a relatively new and an exciting area of study with many missing links and questions to be answered. I will try my best to keep this space alive with updates and stories! In the meantime, here’s a fun read on Leonardo da Vinci’s contributions to neuroscience: http://www.sciencedirect.com/science/article/pii/S0166223600021214

And here’s a 1504-1506 drawing of the human brain by da Vinci:

Leonardo da Vinci's contributions to neuroscience
In the upper figure, the three ventricles are labeled imprensiva (anterior ventricle, corresponding to the paired lateral ventricles), senso comune (third ventricle), and memoria (posterior or fourth ventricle). Below the ventricles, seven pairs of cranial nerves are shown. The lower figure shows a human head in an exploded view, with the skull raised over the brain and from the head. Source: 

Sources:

  1. Louveau A, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337–341. doi: 10.1038/nature14432.
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Thoughts on lab rotations

The thing with first-year rotations in a Ph.D. program is that anxiety starts kicking in somewhere along the way when you consciously identify the lab that you want to join and want to get started right away. Having realized that this is going to be a long journey and rushing into things may not help, I am now gaining patience and perspective, and hope to make the most of the remaining time of my first year.

Rotations are a great way to learn about a lab and get involved in the nitty-gritty of research. I was warned at the beginning by a few seniors that I would either love a lab or reject it within the first few weeks of the rotation. Mind you – this has nothing to do with the science pursued in the lab (one wouldn’t decide to rotate in a lab if they didn’t find the research interesting in the first place). This is more about getting comfortable with the way a lab functions and deciding if the environment is a good fit for you. An eight-week lab rotation is really like an eight-week long interview with a potential PI and the lab! It is essential to identify the kind of relationship you foresee having with your advisor for the next couple of years (and beyond). This is perhaps one of the most important aspects of a rotation for me, next to the research work. A good mentor-mentee relationship can go a long way and can be extremely beneficial to one’s academic/professional career. I prefer having an open channel of communication with my mentor and learn as much as possible from him/her.

Not all graduate programs require laboratory rotations. Many departments or programs accept or reject students simply based on their application and/or an interview. In the UK for example, students are recruited to work on specific projects and grants as a part of their Ph.D. for the time period of around 3 years. This may not benefit the candidates who wish to propose their own ideas and develop their own thesis based on their individual research interests. In the US, for most graduate programs in the life sciences (mainly biology and chemistry), the average time for graduation is around 5-6 years. I believe that the freedom and independence of this system trump the short graduation time of the other systems. Although I am certain that both sides have their set of merits and demerits, at the end of the day, the journey is unique to each one of us and what we make of the experience matters the most.

I got a grant!

I got a grant for my ion channel research project! Receiving the graduate research grant award has immensely boosted my morale, and has encouraged me towards the scientific career path that I wish to pursue.

On behalf of the Graduate Studies Office, I am pleased to inform you that you are a recipient of a Graduate Research Grant for the 2014-2015 Academic Year. Those who evaluated your proposal were impressed with the project.  We congratulate you and look forward to your successful completion of the proposed research. We will be interested in your progress as you move along in your research, and look forward to hearing your presentation at Student Research Day next spring.

The Graduate School seeks, through such awards, to encourage the highest standards of scholarship among its graduate students and we are extremely gratified to provide this opportunity for you to pursue your theory.

***

Our lab finally got a new fluorescence/chemiluminescence imager and it has been great for our investigations so far. I have also been getting many positive western blot results. Evaluating the right antibody concentrations for the blots and tweaking the immunoprecipitation protocols to fit my experiments was a considerable amount of work. My next goal is to quantify the protein bands and figure out the statistical significance of GIRK channel subunit interactions. I am so glad to have had worked on it during the fall semester. I can now concentrate on putting my findings together by the time I graduate in spring(!).

Besides this, I am looking forward to working on the electrophysiology rig with my lab mates next semester. We have been concentrating on the biochemical experiments since the past couple of months. It would be interesting to perform preliminary patch clamping experiments on the cells expressing the mutated and wildtype channel subunits.

I finally got down to updating this space after a long break. I have been very busy with the research work, classes and teaching. It feels great to finally break the writing dry-spell.

Giraffe and Evolution – Not just a long (neck) story

Feeding on acacia leaves
Feeding high up on acacia leaves

In the early 19th century, Lamarck proposed a theory of evolution by studying the behaviour of giraffes. He believed that giraffes evolved to have long necks as they began reaching for higher leaves on trees. He called this “change through use and disuse”. According to this theory, an organ or a character that is used more often becomes stronger and better. Therefore, over the course of history, giraffe’s neck got longer as it began stretching it a lot more than usual. Lamarck also proposed the “law of inheritance of acquired characteristics” according to which the improved characteristics of an organism are passed on from one generation to the next. These improved features persists and the disadvantageous features disappear.

The Lamarckian theory was eventually abandoned* as it could not explain the genetic basis for inheritance of acquired characteristics (traits obtained after birth due to environmental changes, accidents, use and disuse; these traits are not inheritable). Lamarckism also predicts that simpler life forms will disappear from the earth once organisms become more complex. While we see some organisms evolving into more complex systems with intricate functions, the simpler life forms like the single celled prokaryotic cells still exist to this day.

Darwin’s theory of evolution on the other hand, can account for the continued existence of the simpler life forms on earth. Darwin believed that complexity is a result of adaptation to the environment from one generation to the next. In the Origin of Species, Darwin proposed a theory of evolution driven by natural selection. According to this theory, there is variation seen amongst individuals. Certain environmental conditions favours certain variations and the species exhibiting these variations adaptsurvive. The unadapted species which do not exhibit the favoured variations do not survive and become extinct over generations of time.

Applying this to giraffes, the long neck species are considered dominant and have greater chances of survival during harsh drought conditions compared to the short neck species that have to rely on ground habitation for food. This of course is just one theory amongst many other. The long necks are also used to reach deep inside trees that other competing animals cannot reach, and is therefore more advantageous. One of the latest proposal is the theory of sexual selection. Male giraffes fight with other males by “necking” to compete for female partners. As it turns out, females prefer males with longer and stronger necks. Natural selection again, favours long neck males.

“Animal Autopsy”, a show on National Geography channel dug deep into giraffes – quite literally! – to explore the physiological and anatomical features of this intriguing mammal to unravel some of its evolutionary secrets.

During the autopsy, Richard Dawkins talks about one of the evolutionary disadvantages caused due to the long laryngeal nerve that starts off in the brain and ends in the larynx (which is in fact situated very close to the brain). This nerve runs all the way down the neck, loops around one of the arteries in the chest and returns to the larynx on top. Why does the nerve take such a long route when it can simply connect from the brain to the larynx directly without having to pass through the entire neck? Also, consider this – giraffes with a long necks must also bend much lower to drink water from the ground. The contracting of the muscles along with the tension in the elastic tissue in the neck utilises way more energy, and is considered to be another evolutionary flaw. Another interesting fact to chew upon is that due to its long neck, giraffes have to pump blood to the brain that is ~2.5 meters above the heart – against gravity – by using extremely high blood pressure. How does the long neck favour such distant positioning of the heart and the brain?

Biologists consider different perspectives to understand the evolutionary reasoning behind the advantages as well as the flaws caused due to the long necks of giraffes. As more pieces of this puzzles are put together, it is quite remarkable to think about the imperfections that are caused due to evolution. Imperfections that somehow adds up to the making of such a marvellous mammal on our planet.

*New research reveals the epigenetic basis for the inheritance of acquired characteristics. In the article “A Comeback for Lamarckian Evolution?”, Emily Singer of the Tufts University School of Medicine provides evidence for the largely abandoned Lamarckian theory of evolution. Read article on MIT tech review here.

The Biology of Vaccination

I was never too involved in the vaccination debate until I came to the United States. Back home in India, the majority of us seem to be grateful to science for being able to wipe out dreadful diseases like MMR (mumps-measles-rubella) and polio, and prevent the lifelong suffering of thousands of people. A friend recently mentioned that his mother refused to vaccinate him as a child when she observed escalated fever-like-symptoms every time he got an immunization shot. This is one small example of a widespread scientific ignorance that lures people into believing in absurd anti-vax propaganda.

Let’s talk about the biology of vaccination. A vaccine is a weakened form of a disease-causing agent that boosts the immune system and provides protection against natural infection. This “agent” may be an altered form of the infection or its less dangerous close relative. A vaccine is usually combined with an adjuvant – a chemical that enhances the immune response. Prior to vaccination, a process known as variolation remained popular in the 17th and 18th century. In this, scab material taken from a mild form of smallpox was inoculated through the skin to curb the disease. Variolation was in no way harmless and therefore ceased to be in use when safer alternatives were sought. The history of vaccination is one of the most interesting stories in the field of science and medicine. Edward Jenner (the father of Immunology) – after having observed that milkmaids exposed to cowpox were protected from smallpox disease,  treated the locals with cowpox scabs and successfully prevented the occurrence of smallpox.

So how does vaccination work? I have briefly talked about the two main kinds of immune responses in one of my earlier posts. Further, acquired immunity consists of antibody (humoral) response and cell-mediated response that involves various types of white blood cells (WBCs) like macrophages, dendritic cells, T-lymphocytes and B-lymphocytes. When an infectious agent enters the body, chemicals called chemokines and cytokines recruit WBCs to the area of infection. The pathogen is broken down into its constituent proteins by Antigen-Presenting Cells (APCs) and is then “presented” to the helper T-lymphocytes (CD4+ T cells). These lymphocytes actively mediate protective immunity.

In humoral immunity, the receptors on B-cells recognize specific antigenic proteins, get activated and multiply to make hundreds of identical cells. Upon maturation, these plasma cells release a large number of antibodies that are specific to the antigen. This rapid increase in the number of antibodies is sufficient to eliminate the pathogen. Apart from the B-cells, cytotoxic T-cells (CD8+ T cells) also induce an immune response by directly destroying antigens that are presented by the APCs.

Primary exposure to pathogen via vaccine and secondary exposure to pathogen via infection - Sequence of events.
Primary exposure to pathogen via vaccine and secondary exposure to pathogen via infection – Sequence of events with respect to humoral immunity. Cell-mediated immunity works similarly through cytotoxic T cells – Activated cytotoxic T cells directly destroys the antigen. (Not shown) — CLICK TO ENLARGE —

When the infection is cleared, the immune response reduces and so does the number of antibodies and cytotoxic T-cells. During this time, some of the T- and B-cells become memory cells and preserve their antigen-specific surface receptor. These cells stick around in our serum and wait for a subsequent attack by the same pathogen. This is the crux of vaccination.

When our body is invaded by the same pathogen again, these memory cells immediately proliferate and release surplus of specific antibodies against it. This secondary response is faster and involves a greater number of cells, and is therefore more effective than the primary response. Vaccination establishes a pool of memory cells that are specific to the antigen and prepares the body in case of future infection. Therefore, when a weakened form of the pathogen is intentionally administered to us, our body develops an “actively acquired immunity” for a quicker and a more efficient secondary response.

Antibody response during primary and secondary exposure
Antibody response during primary and secondary exposure

The milkmaids from Edward Jenner’s anecdote had acquired an active immunity for smallpox virus because they were previously infected by the cowpox virus (both poxviruses, members of the Poxviridae family) due to their occupation. Also, when my friends mother observed an escalated fever-like symptoms after the vaccine shot, it was merely the body’s primary immune response to the infection – completely normal and a sign of an actively functioning immune system.

Though the science of vaccination is pretty forthright, many concern arises regarding its safety, constituents, production and side-effects. It is important to understand that every immune system is unique due to which every person may respond differently to different vaccines. Many of the health and safety claims (with respect to autism, mercury, formaldehyde, and so on) have already been debunked extensively by reputed scientific sources. Also, parents choosing not to vaccinate their kids against the government’s decision are endangering the rest of the community. Herd immunity works when the larger part of the population is resistant to a pathogen providing protection to those without immunity thereby preventing an outbreak. And finally, if you’re against vaccination due to your religious beliefs, please pack up and leave.

Interestingness –

  1. How the anti-vaccine movement is endangering lives
  2. The dangerous consequences of anti-vaccine propaganda in one map
  3. Understanding Herd Immunity
  4. 9 vaccination myths busted. With science!