Intro to Schizo

A while ago, I saw an Indian movie in which the female protagonist was afflicted with visual and auditory hallucinations, bizarre paranoia and delusions. Of course, there was a song and dance sequence to accompany it. This movie spurred me to go online and look for more information regarding this ‘madness’. I learnt about Schizophrenia and later about Autism spectrum disorder. There is a TED talk by Jill Bolt Taylor who talked about the most fascinating things in a very interesting manner. You can find that here.

Ever since, I have made an effort to know more about this interesting disorder and today, I wish to introduce this topic to you. Before we do, I believe it is important to understand the structure of the brain. You can find some information here which has a fun, interactive way of learning about the basics of brain and its function.

It is important to know that Disassociative identity disorder (Usually referred to as split personality or multiple personality disorder) is different from Schizophrenia. People afflicted with this disorder, as described above, suffer from hallucinations, delusions, behavioural problems etc. which makes it difficult for them to be accepted in the society.

Most medications prescribed for patients with this disorder belongs to the class of molecules which have a capacity to suppress the activity of dopamine (sometimes serotonin as well) receptors. Clinical studies relating schizophrenia to brain dopamine metabolism have ranged from controversial to negative, with HVA levels in the CSF the same for schizophrenics and controls. There is a dopamine hypothesis theory on the internet, have a look.

Dopamine receptors (D1-D5) are G-protein coupled receptors meaning they work through secondary messenger system (like Adrenalin). Serotonin receptor aka 5-HT receptors are ion gated channels. I remember writing a post about ion channels. Check it out!

Let us see where dopamine is present in high quantity and what it does to the system. The ventral tegmental area (VTA, situated in mid brain) contains the largest group of dopamine neurons in the human brain. The main function of dopamine is to set a threshold for executing behaviors. Meaning, if a certain high level of dopamine activity occurs, a lower impetus is enough to evoke a given behavior. As a consequence, high levels of dopamine lead to high levels of motor activity and “impulsive” behavior; conversely, low levels of dopamine lead to torpor and slowed reactions. Another function of dopamine is to ‘teach’. If an action is followed by an acitivty, it alters the brain in such a way that same action becomes easier to execute if performed at a later time. There are several theories surrounding how this occurs. Most of them involve basal ganglia modifications.

In my next post, I shall talk about the controversy surrounding usage of anti – psychotic drugs for treatment of Schizophrenia.

Till then,
Ciao
Avi

Ion Channels – a brief overview

I have been reading a book called “Principles of Neural Science” by Eric Kandel. I thought it would be a good idea to write a summary of a chapter that I read recently and tell you all about one the most important structures present in the cytoplasmic layer – Ion Channel. Ion channels allow the movement of ions across cell membranes, and therefore fundamental physiological processes such as muscle contraction.

Ion channels are membrane protein complexes. They are embedded in the lipid bilayer which is made up mostly of phospholipids, which have a hydrophilic head and two hydrophobic tails. The lipid bilayer is the barrier that keeps ions, proteins and other molecules where they are needed and prevents them from diffusing into areas where they should not be. They make good barriers because they are only a few nanometres thick, they are impermeable to most water-soluble (hydrophilic) molecules and are particularly impermeable to ions.

Definition: Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane by allowing the flow of ions down their electrochemical gradient.

Concept of Open/Close

Ion channels provide a high conducting, hydrophilic pathway across the hydrophobic interior of the membrane. The channel, or pore structure, is said to catalyze the ‘reaction’ of transporting charged molecules across a low dielectric medium. The ‘catalytic site’, the central channel, is either open or closed. The conformational change between closed and open state is called gating. Channel gating is controlled by external factors like enzymes are controlled by modulators and effectors.

Types of Ion channels

There are over 300 types of ion channels in a living cell. Ion channels may be classified by the nature of their gating, the species of ions passing through those gates, the number of gates (pores) and localization of proteins.

• Ligand gated channels
• Voltage gated channels transmembrane potential
• Second messenger gated channels
• Mechanosensitive channels
• Gap junctions

Structure of a channel

Channels differ with respect to the ion they let pass (for example, Na⁺, K⁺, Cl⁻), the ways in which they may be regulated, the number of subunits of which they are composed and other aspects of structure. All ion channels are complexes of transmembrane proteins, sometimes they contain cytoplasmic subunits, often they are glycosylated. The 3-D structure of most ion channels is not known, with two notable exceptions, porins and a K-channel, both of bacterial origin. There exists, however, a multitude of biochemical and functional data, combined with mutagenesis experiments that give information about the transmembrane topology of these proteins, dividing it into transmembrane segments and extramembraneous loops/domains. Often size and location of loops on one side or the other of the membrane can be determined by chemically modifying the protein and analyzing which amino acids have been modified.

For example: Nicotinic Acetylcholine Receptor – nAChR

The structure of nicotinic acetylcholine receptor, has been determined to 0.9nm resolution by cryo-electron microscopy. The nAChR is a heteromeric glycoprotein complex composed of five integral membrane proteins in a stoichiometry of α₂βγδ.

The five subunits are arranged in a circular fashion around a central hole that provides an ion pathway across the post-synaptic cell membrane. The pentameric complex has a fivefold pseudo-symmetry because its subunits are not identical. Acetylcholine binding induces the opening of the channel.

Fig: Pentameric arrangement of nAChR subunits

Problems associated with Ion channels

There are a number of chemicals and genetic disorders which disrupt normal functioning of ion channels and have disastrous consequences for the organism. Genetic disorders of ion channels and their modifiers are known as Channelopathies.

For example:

1. Human hyperkalaemic periodic paralysis (HyperPP) is caused by a defect in voltage dependent sodium channels.
2. Dendrotoxin is produced by mamba snakes, and blocks potassium channels.

That is it for now. I hope you liked what you read. If you are interested, I could always find more references and papers to support the above data.

Cheers

Avinash

Stop! Think for a moment with both your cognitive brain parts

Sometimes in life we are going too fast. We don’t know how to slow down and take a breather. It is like we are trying desperately to be one step ahead of everyone. What we don’t understand is that they are trying the same thing. We go at 100 miles an hour and yet, we are followed by others. The race to succeed never really goes away. You know that wonderful retirement stage where you envision yourself sitting on a rocking chair drinking a tall glass of iced tea looking at the scenery around you from the porch of your house while your great grand children play in the backyard? Well, let’s just say that will never happen.

When a car spins out of control a bystander can often tell how the car might spin but when a person spins out of control, you can never tell anything until the shit hitting the fan has finally had the chance to settle down on some part of the room.

This is what happened to me. No, I didn’t meet with an accident. But, I caught the flu. I was careless enough to play in a river all day long and uninhibitedly walked around in wet clothes. Add to that, a sick friend who exposed me to a possible influenza virus and I am a very sick man. Being sick and having someone fuss around you leaves two things for you to do: Sleep and think. I did the most rational thing a person can do. I slept for 24 hours in 2 days. Rest of the time, I thought about how difficult it must be for people who are invalid for the rest of their lives to deal with it and this brought to my mind a TED talk that I watched way back about a woman who suffered a stroke. Her name is Jill Bolte Taylor. She is quite famous for her book – My Stroke of Insight. She was also on The Oprah Winfrey Show to promote her book.

If you haven’t listened to her TED talks or read her book, this is what she went through.

Jill Taylor was a neuroscientist who worked on schizophrenia (a kind of mental disorder – more on this later, I promise you). In 1996, a blood vessel in her brain exploded in the left half of her brain. It is important to understand that the left hemisphere is an integral part of everyday life. In fact, it is the dominant of the two hemispheres and is responsible for things such as walking, talking, reading, writing, recalling etc. Basically, without the left part of your brain, you will be an infant. That is not a nice thing, I assure you. Diapers and drool all day long!

So, why bring up Jill Taylor and her stroke. I wanted to talk to you about an exciting thing inside your brain. Wait! Make that two exciting things: The left and the right hemispheres. Before you get disappointed, let me assure you, this is one of the best things nature has created. Can you believe that the two parts of our brain process differently? They think about different things, care about different things and in fact come up with different solutions for a single problem. The two parts are connected in the middle through the corpus callosum and this is a medium for connection and contact with each other.

Jill Taylor thinks that the two parts of the brain have different personalities.

Let me give you a few things that the right and left hemispheres do. Our right hemisphere thinks in pictures. It understands different the situation kinaesthetically (smell, feel, hear) and makes a mosaic picture on where we are standing, what we are doing etc. In fact, it is concerned about the present. The “this moment” of my life is what right part understands and cares for.

On the other hand, the left side of the brain is more logical. It is linear in its thinking. It recalls the past, thinks about the future keeping the present mosaic that the right builds up as a base for its thought process. It is detail oriented (sounds like something you find on a CV. Next time you can write, my left part of the brain is my real boss. So, I am more interested in details, futures and not repeating past mistakes). More importantly, our left hemisphere contains the memory for words and language. So, it thinks in language and words (Again, a CV pointer. Are you noting it down somewhere?).

“Did you watch what she said? OMG” did a small voice inside your brain tell you this when you listened to someone on the TV or on the road? That small voice is a weapon created by the left part of the brain not only to give you sane advice but also to make your life miserable with guilt. But, it is also a distinguishing feature. Do you remember the day you recognized that small voice in your mind as yours? No? Because, it has been there always and it is responsible for your self – identification. “I am not like that. I am a better person than that. I am the way I am” all things that can be found on slogan T – shirts as well as the things that the left brain instils in you.

So, the next time you find yourself in a situation where you have that “Aha – moment” think about this: We are not just minions of the world who have opposing thumbs (dexterity, if you will), capacity to stand on two legs (Bipedal) and can feed ourselves. We are the ultimate creatures that nature created. We may not be the fastest or strongest or even the loudest but we are definitely the smartest. Case in point, we don’t have one but two cognitive minds. Power to choose our identity and lead our lives. Think about it: use both parts of the brain this time.

Peace

Avinash

The immune system – a brief overview

There are a lot of posts in this blog that require at least a minimum awareness of immunology. So, I decided to tell you what immunology really deals with and how you can understand previously discussed topics with this knowledge.

So, what is immunology? Basically, it is studying body’s defence mechanism. It is important to understand this in both healthy as well as diseased conditions because the body has different components “active” in different scenarios.

What are the different things involved in the immune system? Many components of the immune system are actually cellular in nature and not associated with any specific organ but rather are embedded or circulating in various tissues located throughout the body. There are some organs which are responsible for the production of these cells. They include thymus, bone marrow (Bone marrow, the soft tissue in the hollow centre of bones, is the ultimate source of all blood cells, including lymphocytes), spleen, tonsils, lymph vessels, lymph nodes, adenoids etc. The cells are in turn responsible for the production of different kinds of biomolecules (Eg: Antibodies)

The key to a healthy immune system is its remarkable ability to distinguish between the body’s own cells, recognized as “self,” and foreign cells, or “nonself.” The body’s immune defences normally coexist peacefully with cells that carry distinctive “self” marker molecules. But when immune defenders encounter foreign cells or organisms carrying markers that say “nonself,” they quickly launch an attack.

In abnormal situations, the immune system can mistake self for nonself and launch an attack against the body’s own cells or tissues. The result is called an autoimmune disease. Some forms of arthritis and diabetes are autoimmune diseases.

Where are the cells concentrated? Lymph nodes, which are located in many parts of the body, are lymphoid tissues that contain numerous specialized structures.

• T cells from the thymus concentrate in the paracortex.
• B cells develop in and around the germinal centers.
• Plasma cells occur in the medulla.

Lymphocytes can travel throughout the body using the blood vessels. The cells can also travel through a system of lymphatic vessels that closely parallels the body’s veins and arteries.

Cells and fluids are exchanged between blood and lymphatic vessels, enabling the lymphatic system to monitor the body for invading microbes. The lymphatic vessels carry lymph, a clear fluid that bathes the body’s tissues.

The immune system stockpiles a huge arsenal of cells, not only lymphocytes but also cell-devouring phagocytes and their relatives. Some immune cells take on all intruders, whereas others are trained on highly specific targets. To work effectively, most immune cells need the cooperation of their comrades. Sometimes immune cells communicate by direct physical contact, and sometimes they communicate releasing chemical messengers.

Why are we using proteins and cells of the immune system for research purposes? If evolution is so perfect and we are the ultimate answer to all animals, why are we being plagued by so many diseases and disorders?

Unfortunately, we are not the only products of evolution. Viruses, bacteria and other harmful microbes have also had similar treatment from nature and they are equipped with arsenals that have the capacity to evade our immune systems. As for why we need to do research on the immune system, for the simple reason that we will have more information on how to tackle the diseases and disorders that are life threatening.

What kind of research is going on? Scientists are now able to mass-produce immune cell secretions, both antibodies and lymphokines, as well as specialized immune cells. The ready supply of these materials not only has revolutionized the study of the immune system itself but also has had an enormous impact on medicine, agriculture, and industry.

Read about monoclonal antibodies here. Ankur has provided a good description of its use and production.

Research into the delicate checks and balances that control the immune response is increasing knowledge of normal and abnormal immune system functions. Someday it may be possible to treat autoimmune diseases such as systemic lupus erythematosus by suppressing parts of the immune system that are overactive.

Scientists are also devising ways to better understand the human immune system and diseases that affect it. For example, by transplanting immature human immune tissues or immune cells into SCID mice, scientists have created “humanized” mice, a living model of the human immune system. Scientists are manipulating the immune system of humanized SCID mice to discover ways to benefit human health. Humanized mice are also being used in research on transplantation and autoimmune and allergic diseases, and to manufacture molecules that help regulate immune system function and immune tolerance.

In pioneering experiments, scientists are removing cancer-fighting lymphocytes from the cancer patient’s tumor, inserting a gene that boosts the lymphocytes’ ability to make quantities of a natural anticancer product, then growing the restructured cells in quantity in the laboratory. These cells are injected back into the person, where they can seek out the tumor and deliver large doses of the anticancer chemical. This is called cell therapy.

Now that you have enough information for understanding the immune system, you can appreciate all its myriad applications. There are several ways by which the cells, organs and even protein molecules of the immune system can be manipulated for the betterment of the society.

Hope you enjoyed this. If there is something you have difficulty understanding or you would like us to give you information on a specific topic, please don’t hesitate to ask.

Peace

Avi

Top myths about brain and its ability

Recently, I was seeing cartoon network. Yes, I know it is cartoon network. Are you telling me you haven’t seen it recently? Boy, you are missing a lot!

Anyway, coming to the point, I saw Jerry whack Tom with a saucepan and Tom loses all his memories! Amnesia has really got the short end of the stick. I wanted to tell that doesn’t really happen to my father (Yes, I know! He was watching it with me). This gave me a brilliant idea. There are so many myths about the brain and its capacity. When it comes to the brain, everybody miraculously transforms into a neuroscientist. So, here is my article on the top myths about the brain and the reality behind it. Hope you enjoy it. Oh and by the way, don’t forget to catch up with Tom and Jerry.

We use only 10 percent of our brains. 
I have heard this time and again. For brain’s sake stop spreading this. It has been repeated in popular culture so many times, that people are compelled to believe this. The myth implies there is a huge reserve of untapped powers that can be utilized to perform extraordinary feats.

I want you to think about this before I give you the actuality behind this. Do you think evolution will be stupid enough to give humans a chunk of the brain without any use? Will it really allow us to carry around a mass of expensive tissue just in case we find a way to utilize it? In evolutionary terms, that 90% or whatever percent of brain which isn’t used is called as a vestigial organ.

There are multiple examples of vestigial organs in the human body. You can read more about this here.

Brain is an expensive organ. Not merely due to its activities but because it takes a huge amount of energy and complex compounds during foetal and childhood development to make it into the organ it is today. In that case, it would make no sense to completely utilize so much energy on a mass of tissue that may or may not be utilized in the course of the human life. Common, look around you, there are millions of people struggling to do normal stuff. How is it going to be for them to have 90% extra power in their hands? It is like giving a 5 year old kid keys to the Kohinoor diamond (Oh wait, has this been made into a movie? Movies these days, pfft)

Experiments using PET or fMRI scans show that much of the brain is engaged even during simple tasks, and injury to even a small bit of specified point in the brain can have profound consequences for language, sensory perception, movement or emotion.

True, we have some brain reserves. Autopsy studies show that many people have physical signs of Alzheimer’s disease (such as amyloid plaques among neurons) in their brains even though they were not impaired. Apparently we can lose some brain tissue and still function pretty well.

The older you get, your brain becomes inactive

This is partially true. Many of our cognitive skills decline as we age. Have you played a game of concentration against a 10 year old? Well, don’t! It isn’t worth the humiliation and you will have to be his slave for the next 100 years he is alive.

Young adults are faster than older adults to judge whether two objects are the same or different; they can more easily memorize a list of random words, and they are faster to count backward by sevens.

What we tend to forget is that the brain is responsible for every single thing we do. There are millions of things that old people can do that the youngsters aren’t very good at. For example, older people are better at vocabulary. They know more words and understand subtle linguistic distinctions. Given a biographical sketch of a stranger, they’re better judges of character. They score higher on tests of social wisdom, such as how to settle a conflict. And people get better and better over time at regulating their own emotions and finding meaning in their lives.

Brains are like computers. 

Repeat after me. The brain is not a computer.

We speak of the brain’s processing speed, its storage capacity, its parallel circuits, inputs and outputs. The metaphor fails at pretty much every level: the brain doesn’t have a set memory capacity that is waiting to be filled up; it doesn’t perform computations in the way a computer does; and even basic visual perception isn’t a passive receiving of inputs because we actively interpret, anticipate and pay attention to different elements of the visual world.

There’s a long history of likening the brain to whatever technology is the most advanced, impressive and vaguely mysterious. Descartes compared the brain to a hydraulic machine. Freud likened emotions to pressure building up in a steam engine. The brain later resembled a telephone switchboard and then an electrical circuit before evolving into a computer; lately it’s turning into a Web browser or the Internet. These metaphors linger in clichés: emotions put the brain “under pressure” and some behaviors are thought to be “connected like an electronic circuit.” Speaking of which…

The brain is hard-wired

This is one of the most enduring legacies of the old “brains are electrical circuits” metaphor. There’s some truth to it, as with many metaphors: the brain is organized in a standard way, with certain bits specialized to take on certain tasks, and those bits are connected along predictable neural and communicate in part by releasing ions (pulses of electricity).

But one of the biggest discoveries in neuroscience in the past few decades is that the brain is remarkably plastic. Brain plastic doesn’t mean brain is a fake piece of organ. It means it has the ability to change remarkably based on the situation.

In blind people, parts of the brain that normally process sight are instead devoted to hearing. Someone practicing a new skill, like learning to play the violin, “rewires” parts of the brain that are responsible for fine motor control. People with brain injuries can recruit other parts of the brain to compensate for the lost tissue.

A conk on the head can cause amnesia. 

Those bloody serials. How I would like to conk them in the head. Switching babies at birth and re-emerging from a tragic death. All shite that are shown on the tele nowadays. Along with that comes this: Someone is in a tragic accident and wakes up in the hospital unable to recognize loved ones or remember his or her own name or history. (The only cure for this form of amnesia, of course, is another conk on the head)

In the real world, there are two main forms of amnesia:

1. Anterograde (the inability to form new memories) and

2. Retrograde (the inability to recall past events).

Science’s most famous amnesia patient, H.M., was unable to remember anything that happened after a 1953 surgery that removed most of his hippocampus. He remembered earlier events, however, and was able to learn new skills and vocabulary, showing that encoding “episodic” memories of new experiences relies on different brain regions than other types of learning and memory do. Retrograde amnesia can be caused by Alzheimer’s disease, traumatic brain injury (ask that sports player who didn’t have enough marbles not enter the violent game to begin with) thiamine deficiency or other insults. But a brain injury doesn’t selectively impair autobiographical memory—much less bring it back.

“Flashbulb memories” are precise, detailed and persistent. 

We all have memories that feel as vivid and accurate as a snapshot, usually of some shocking, dramatic event—the assassination of a President/Prime Minister, the explosion of the space shuttle Challenger, the attacks of September 11, 2001.

People remember exactly where they were (On 9/11 I was sitting in my Grandma’s house), what they were doing (eating dinner), who they were with (with grandma duh), what they saw or heard (She asked me to change the channel so that she can catch on with her daily serial).

But several clever experiments have tested people’s memory immediately after a tragedy and again several months or years later. The test subjects tend to be confident that their memories are accurate and say the flashbulb memories are more vivid than other memories. Vivid they may be, but the memories decay over time just as other memories do. People forget important details and add incorrect ones, with no awareness that they’re recreating a muddled scene in their minds rather than calling up a perfect, photographic reproduction.

We have five senses. 

Sure, sight, smell, hearing, taste and touch are the big ones. But we have many other ways of sensing the world and our place in it.

Proprioception is a sense of how our bodies are positioned. Nociception is a sense of pain. We also have a sense of balance—the inner ear is to this sense as the eye is to vision—as well as a sense of body temperature, acceleration and the passage of time.

Compared with other species, though, humans are missing out. Bats and dolphins use sonar to find prey; some birds and insects see ultraviolet light; snakes detect the heat of warm blooded prey; rats, cats, seals and other whiskered creatures use their “vibrissae” to judge spatial relations or detect movements; sharks sense electrical fields in the water; birds, turtles and even bacteria orient to the earth’s magnetic field lines.

Happiness is in our hands we can do something to get it

In some cases we haven’t a clue. We routinely overestimate how happy something will make us, whether it’s a birthday, free pizza, a new car, a victory for our favorite sports team or political candidate, winning the lottery or raising children.

Money does make people happier, but only to a point—poor people are less happy than the middle class, but the middle class are just as happy as the rich. We overestimate the pleasures of solitude and leisure and underestimate how much happiness we get from social relationships.

On the flip side, the things we dread don’t make us as unhappy as expected. Monday blues? Oh please, there is a survey done and people predict that Monday mornings aren’t that unpleasant. So, suck it and get back to work.

Seemingly unendurable tragedies—paralysis, the death of a loved one—cause grief and despair, but the unhappiness doesn’t last as long as people think it will. People are remarkably resilient.

Our perception is always right 

We are not passive recipients of external information that enters our brain through our sensory organs.

Instead, we actively search for patterns (like a Dalmatian dog that suddenly appears in a field of black and white dots), turn ambiguous scenes into ones that fit our expectations (it’s a vase; it’s a face) and completely miss details we aren’t expecting.

In one famous psychology experiment, about half of all viewers told to count the number of times a group of people pass a basketball do not notice that a guy in a gorilla suit is hulking around among the ball-throwers.

We have a limited ability to pay attention (which is why talking on a mobiles while driving can be as dangerous as drunk driving), and plenty of biases about what we expect or want to see. Our perception of the world isn’t just “bottom-up”—built of objective observations layered together in a logical way. It’s “top-down,” driven by expectations and interpretations.

Men and women are different 

Some of the sloppiest, shoddiest, most biased, least reproducible, worst designed and most over interpreted research in the history of science purports to provide biological explanations for differences between men and women. Eminent neuroscientists once claimed that head size, spinal ganglia or brain stem structures were responsible for women’s inability to think creatively, vote logically or practice medicine. Today the theories are a bit more sophisticated: men supposedly have more specialized brain hemispheres, women more elaborate emotion circuits. Though there are some differences (minor and uncorrelated with any particular ability) between male and female brains, the main problem with looking for correlations with behavior is that sex differences in cognition are massively exaggerated.

Women are thought to outperform men on tests of empathy. They do—unless test subjects are told that men are particularly good at the test, in which case men perform as well as or better than women. The same pattern holds in reverse for tests of spatial reasoning. Whenever stereotypes are brought to mind, even by something as simple as asking test subjects to check a box next to their gender, sex differences are exaggerated.

Women college students told that a test is something women usually do poorly on, do poorly. Women college students told that a test is something college students usually do well on, do well. Across countries—and across time—the more prevalent the belief is that men are better than women in math, the greater the difference in girls’ and boys’ math scores. And that’s not because girls in Iceland have more specialized brain hemispheres than do girls in Italy.

Certain sex differences are enormously important to us when we’re looking for a mate, but when it comes to most of what our brains do most of the time—perceive the world, direct attention, learn new skills, encode memories, communicate (no, women don’t speak more than men do), judge other people’s emotions (no, men aren’t inept at this)—men and women have almost entirely overlapping and fully Earth-bound abilities.

I will leave you with some of my wisdom. This is a precious piece of information and I hope you treat it with the respect that it deserves. Watch Tom and Jerry and get enlightenment.

Peace

Avinash

A sad sad world

This is my 8th attempt at writing today’s article. I must have written almost 5000 words before I restarted my computer to write again from scratch. Every single time I thought I had written enough, electricity flickers (Monsoon time, I can’t help it) in my home and my computer shuts down without me saving the article. I have written so many versions of the same topic because I cannot remember how I introduced the topic to you all. It is quite depressing really. Ahhh!! There it is: my opening. I’m going to talk about a touchy subject – depression.

I’d appreciate it if people took an open mind to what I’m saying, rather than defensively saying ‘I had depression, it is not like that and you don’t know what the hell you are talking about’. I’m not claiming to be a saviour or guru; I’m just writing my opinion based on my personal experiences.

If somebody greets you, you always greet them back with a positive message. Fine, good, great, awesome etc, even if you aren’t. Even if you are sad, depressed, unhappy, in pain, you never let it through and usually try to hide it. So, I thought I will write something about depression and sadness. It is important to know the reason for such things and ways of overcoming it. Did you know there are genes associated with depression? I will tell you more about finding “the gene” later on. First, we will see some of the reasons and factors pushing us towards depression.

Society today through the use of mass media especially TV, movies and magazines gives the impression to young people (more so girls but males as well), that life is going to be one big picnic, you are going to find the partner of your dreams, you are going to be the coolest person around at school, basically that life is going to be one big fairytale.

Now when people reach the mid-teenage years, they begin to discover that the world isn’t everything it’s made out to be. Their parents are just people with the same faults and inconsistencies as anyone else, with the ability to hurt them just the same as anyone else. They read magazines and find that they are not as attractive as the models they read about, begin to discover that the guy of their dreams is possibly not going to ride in and sweep them off their feet (The Twilight guy, whatshisface? Robert Pattinson? Tall, dark, handsome and a rich man), people in their lives are going to do things that upset them, and their grand fairytale plan for life isn’t going to fall into their arms. It isn’t just body issues.You can read more about the body issues here

I think when people begin to realise that the real world is a very different place than what they have been led to believe. Some people are brought up thinking that the world owes them happiness. That their family/friends/teachers are responsible for them feeling bad, and they get stuck in a rut which leads them to be sad about the situation and frustrated at their helplessness.

Recently, an article was published in the Guardian which claimed that depression can be good for you! Here is an extract from that article. I don’t know if it is true, but it sure gives something to think about.

Dr Paul Keedwell, an expert on mood disorders at the Institute of Psychiatry in London, has written how Sadness Survived in order to understand why something that causes so much pain and disability has withstood evolutionary changes and still occurs so commonly. ‘We see it as a defect – often patients see themselves as broken in some way – whereas I think of it as a defence mechanism. It has simply adapted in the human species to actually give us some long-term benefits.

‘Essentially, depression can give us new and quite radical insights – it can give us a way of responding effectively to challenges we have in life. In its severe form it is terrible and life-threatening, but for many it is a short-term painful episode that can take you out of a stressful situation for a while. It can help people to find a new way of coping with events or your situation – and give you a new perspective, as well as making you more realistic about your aims.’

Keedwell says there is good evidence from long-term studies, particularly a recently published population survey of Dutch adults, to show that, after their depression, many patients seem to be able to cope better with challenges. ‘For most, their vitality, their social interaction and their general health actually improved on recovery – and so did their work performance. I know from patients that it can also make you more realistic in your outlook; you develop more empathy to those around you.’

Going deeper into depression:

Much of what we know about the genetic influence of clinical depression is based upon research that has been done with identical twins. Identical twins are very helpful to researchers since they both have the exact same genetic code. It has been found that when one identical twin becomes depressed the other will also develop clinical depression approximately 76% of the time. When identical twins are raised apart from each other, they will both become depressed about 67% of the time. Because both twins become depressed at such a high rate, the implication is that there is a strong genetic influence. If it happened that when one twin becomes clinically depressed the other always develops depression, then clinical depression would likely be entirely genetic. However because the rate of both identical twins developing depression is not closer to 100% this tells us that there are other things that influence a person’s vulnerability to depression. These may include environmental factors such as childhood experiences, current stressors, traumatic events, exposure to substances, medical illnesses, etc.

How people process positive and negative stimuli is central to theories of emotion, and may be the key component in vulnerability factors governing risk for depression and anxiety. Depression and anxiety are commonly experienced in the general population and may significantly impair psychosocial function. In their extreme form these negative affective states develop into clinical depression and anxiety – the most commonly experienced psychiatric disorders today. While these disorders are often characterised as distinct phenomena, they co-occur in up to half the cases with either disorder. Here is an article to read if you are interested in knowing the neurosciences behind depression.

How to overcome it?

STOP WORRYING, FOR EFF’S SAKE.

Here is a cycle that might give you an idea what is happening during depression. I forgot where I got this article (Remember the 8 power cuts I had to deal with), so I am sorry I cannot refer this properly, but anyway, it gives a good picture about depression and the “escape route”.

While sadness will always be part of the human condition, hopefully in the future we will be able to lessen or eradicate the more severe mood disorders from the world to the benefit of all of us. This can be done by doing research in this progress. And for that, the government and funding bodies have to provide money for the researchers. A long process and umpteen number of convoluted bureaucracy to deal with. It is quite depressing, really.

Woes and delights of being a counsellor

I am not a career counsellor. Counselling someone is a dangerous job. You can persuade a person to do something that is totally the wrong thing for them to do. But, you can also guide that person to make some amazing choices which they will always remember as the best moment of their lives. Typically, when a person comes to you and asks your opinion about something, they are not looking for you to give them a different option. They will already have made up their minds and want some form of acceptance.

I am not a career counsellor. Sometimes, students who require some advice on their chosen path reject interventions made by a professional career counsellor and prefer to rely on the advice of peers or superiors within their own profession. They feel that the advice given by peers/superiors is reliable because they have been through the exact situation that they are facing.

I am not a career counsellor. Being one of the few in my family to hold a Masters degree in Science, I am approached by not only my family and friends but also from my friends’ relatives. It is a responsible job and I try to make full justice to it because they have come to me and are confiding their fears and apprehensions. I want them to leave with lessons that I have learnt through my own experiences and ones that I hold most precious. I help them understand the concept of “calling” as I call it. Others call it passion, professional interests, whatever. As long as they are sure of what they want to do for the rest of their lives and are happy doing it, my job is done. There will be many a days when you will be bone tired but still you will go to your place of study/work because it is not just a job anymore but something more.

I am not a career counsellor. But, I take a lot of effort to help young students who are confused about their future. Making money might be one important factor of your career. I understand, everyone should do something to make a living but it is also important to find that spark which makes you happy. So, I take immense pleasure in speaking to young people about such things. Their minds are fragile so, it requires a lot of subtle touches to help them move in the right direction. This is not just confined to my family and friends. It is a global issue. Each one of you has your own platform. Actors and actresses have a stage and you have yours. Maybe it is 20, 30 or 40 people. Wherever you are, that is your circle of influence and that is where your power lies. Every day you are showing people exactly who you are and who you can become. The power is the same with people with big platform and also people with a small community. Some people get paid to listen and it aligns with their job but not everybody is lucky. But, everybody is called. It maybe your skill at listening, empathising or nurturing. People often get confused between fame and service. So, it is your duty as a person of influence to help young people see their potential and understand what they can do for themselves and for others in the society.

I am not a career counsellor. But, I always tell people how important it is to own up to their responsibilities and not live someone else’s life and dreams. Children, especially look up to their parents. They understand the struggle the parents have gone through to keep them as a family and want, desperately to fulfil their dreams. Somewhere down the line, they forget their own identity and become an image of their father/mother. I am not saying it is wrong but it is not right either. A person who is artistically inclined being forced to study science isn’t a good thing. He/she should be left to make their own choices and live with the consequences. You might think that this point is contradictory to career counselling efforts. If you think about it, career counselling is not persuasion. It is giving options and telling the people what they can become, if they are interested. This is where choices and consequences come into the picture.

I am not a career counsellor. But, I understand the importance of validation. When young people come to you for guidance, as I mentioned earlier they are looking for acceptance. It is your duty to validate them. Tell them “I see you; I hear you and what you say means something to me. I see your dreams and I believe you can achieve it”. There are so many people who have a common thing – they want validation. They have a sense of unworthiness which can be an impediment in their lives and barricade them from dreaming big and achieving them. There should be least amount of judgement from your side (well, I can’t say I am saint. I judge, I do, but I keep it to myself).

Try it, with your friends, family, your boss, your colleagues.. Just try to listen, validate them, give them options (if they want) and try being a career counsellor.

Peace

Avinash

Exciting world of neurosciences

Hello everybody,

Today, I am going to write something about a subject that is very dear to me. I am fascinated by this subject so I hope a little of my fascination rubs on to you. I am new to this subject, so I am not an expert. I hope that you will learn and come to appreciate this subject just as I have.

The subject that I am going to talk about is THE BRAIN. Yes, I know. There are a million different things that can be said about this one “master organ”. It is a 3 pound jelly (you can hold it in the palm of your hand!), made of 100 billion neurons. Neurons are a class of cells which make up the brain and nerves. The brain is such a wonderful organ that is can contemplate the vastness of the universe, contemplate the meaning of infinity, God… In fact, it can even contemplate itself contemplating the meaning of infinity. Self – awareness, according to me is the holy grail of neurosciences.

All these neurons together constitute the spectrum of human activities. To understand how the brain works, there are several different methods. One such method is to study the brain which has been damaged. If the damage is confined to a small region of the brain (either due to genetic change or a physical damage), then the brain itself doesn’t stop working altogether. There is no reduction in the cognitive ability on the whole. Instead, there is a highly selective loss of one function while other functions are preserved intact. This makes it easy to map the function onto the structure and understand how the structure contributes for the overall activity.

Here are a few examples which help you understand this process:

Example number 1: Capgras Syndrome

According to wiki, the Capgras delusion theory (or Capgras syndrome) is a disorder in which a person holds a delusion that a friend, spouse, parent, or other close family members have been replaced by identical-looking impostors. This is due to the damage to a very specific part of the brain called fusiform gyrus. It is also called discontinuous occipitotemporal gyrus. In layman terms, it can be called the face area of the brain. If there is damage to this particular part of brain you can no longer recognise people just by seeing their face. Mind you, you can still recognise them by hearing them. In fact, you won’t be able to recognise yourself in a mirror. Of course, you know it is you because it imitates your actions.

In this rare syndrome, the person will be completely lucid but still will not be able to recognise his own friends and family members. In the olden psychiatry textbooks, this can be explained by a Freudian principle – Oedipus complex in men and Electra complex in Women. According to this explanation, young children will have a strong sexual attraction to their parents (“father-fixated” and “mother-fixated”). As they grow up, the cortex develops and inhibits these latent sexual feelings. If there is a damage to the part of the brain which suppresses these feelings then the sexual arousal returns.

You have to understand that I don’t necessarily believe in this principle. It just happens to be one of the explanations that could successfully resolve the capgras delusion. But, this principle cannot explain why a person with capgras delusion has difficulty recognising his own pet. The whole Freudian explanation (Oedipus and Electra) don’t really work for pets, do they?

To explain it, scientists looked at visual areas in the brain (all 30 of them). The object is processed and sent to a small structure in the brain called fusiform gyrus where faces are perceived. From this structure, the message cascades into another structure called amygdala in the limbic system which is involved in gauging the emotional significance of the object that has been visualised.

The patient (With Capgras delusion) might  have a problem in the area where the neurons connect the fusiform gyrus with the amygdala. So, he recognises his friends, parents etc, but the emotional significance of it is lost. So, the patient starts thinking of his own friends and family as imposters. (Scientists determined this based on galvanic skin response)

You can read more about this methodology here.

How is this complex neural circuitry set-up in the brain? What is the reason for it? Is it nature, nurture or genes?

Example number 2: Phantom Limb

                Recently, an uncle of mine had an amputation done on his leg (above the knee) because the doctors found giant cell tumours below his knee cap. I started reading up about this peculiar feeling that he had post surgery. It was a vivid compelling experience for him. Of course, I knew what a phantom limb was but I never appreciated the severity of the situation. He was bed ridden for several months before the operation and experienced severe pain (due to a fracture to the same leg). His brain sent signals to his leg to move but it gets back visual feedback saying “NO”. This is called learned paralysis because it gets wired into the brain that even after sending a command, there is no appropriate result.

Even after the operation, he continued to feel that pain in the same place. He knew his limb was amputated. He could see it, but still he felt the pain. The learned paralysis allowed him to feel the pain. The phantom limb also behaves like a paralysed limb. The only way of dealing with this is to allow the brain to see that the phantom limb is moving according to the command. This can be done using a mirror box. A simple but ingenious creation by Vilayanur S. Ramachandran. You can read more about this here.

Example number 3: Synaesthesia

                Synaesthesia is a neurologically-based condition in which stimulation of one sensory or cognitive pathway leads to automatic, involuntary experiences in a second sensory or cognitive pathway. In short, it is mingling of the senses.         

In one common form of synaesthesia, letters or numbers are perceived as inherently coloured. 5 is red, 3 is green, 1 is white, 2 is blue so and so forth. These people are completely normal in other ways. Sometimes, sound and colour gets mixed up. C sharp is yellow, perhaps?

Did you know that synaesthesia is 8 times more common in artists, poets, novelists and other creative people?

In the brain, the “colour area” and the “number area” are next to each other. In people with synaesthesia, there is a crosslink between these two areas. This is because the gene which causes the changes in interneuronal connection. Usually, artists have a way of perceiving seemingly mundane things in a different way. (Her lips were like a volcano that’s hot – Elvis Presley). There is a link between these things. You can read more about this here.

Just a few more things to say: Each neuron makes 1000 – 10,000 contacts with other neurons in the brain. That is a lot! This blog is not a review of any one particular paper. I will leave that to someone who is an expert in that particular field. What I want to achieve by posting this blog is to create an interest in neurosciences amongst budding scientists. There are a lot of things being done in this particular area and yet, we have only taken baby steps in our understanding of the brain and its functions. If we join this research, then we will surely be able to understand more about ourselves and our behaviour.

Peace

A

Success Story of Gleevec (Imatinib): a product of rational drug design

I know Ankur recently posted a short essay on Gleevec.

I am writing something on the same drug. I did an essay on Gleevec during my Masters programme. This post has some parts of my old essay. I hope this gives you all a good idea on rational design, in particular the “magic bullet” drug.

Introduction

During the early 1990s, George Daley, R Van Etten and David Baltimore successfully induced Chronic Myeloid Leukaemia in mice using the p210^bcr/abl gene present on Philadelphia Chromosome¹. This experiment confirmed that the genes Bcr/Abl gene expression is the major reason for the pathophysiology of chronic myeloid leukaemia (CML) in most cases. CML is a haematological stem cell disorder characterized by myeloid cells hyperplasia in the bone marrow. After studies on the gene, they found out tyrosine kinase was highly active in the cells and this lead to CML. The next logical step was to find a drug which has inhibiting capacity for the Bcr and Abl genes. After a series of screening processes, a highly effective drug was found out called Imatinib. The drug was highly successful in eliminating the disease symptoms and helped the patients live a better life even after diagnosis with CML.

To begin understanding the discovery process of Imatinib, it is essential to understand the disease.

Chronic Myeloid Leukaemia (CML)

CML is characterized by the reciprocal translocation between chromosome 9 and 22, resulting in Bcr-Abl fusion. This can be cytogenetically visible if we look at the shortened state of chromosome 22².

When a patient is suffering from CML, there are three stages:

• The first stage is named chronic stage. In this stage 50% of the patients do not even have symptoms. Few complain about fatigue, pain and feeling full (loss of appetite). The blood workup of the patient will show 10% of abnormal white blood cells in the plasma and more than usual WBCs inside the bone marrow.
• The second phase is called accelerated phase, where up to 20% abnormal white cells are found in the blood. During this phase, patients generally complain about fatigue, bruising, fever, night sweats, infection, bone and abdominal pain.
• Third phase is blast crisis phase where the symptoms become much more noticeable. They include fatigue, bleeding, fever, weight loss, complications from infection and gout due to rapid cell turnover.

For Patients who were diagnosed with CML, the median survival was estimated to be about 5 to 6 years (before using Imatinib). Some patients, however, have an aggressive course from the outset and die within a year of diagnosis; other patients survive for 20 or more years³.

By the numerous experiments and studies done on this disease it is now clear that the Bcr-Abl gene fusion protein product is responsible for CML (90%).

Biology of Abl gene and Bcr gene

The Abl gene is responsible for production of a protein which works as a non-receptor for tyrosine kinase. The Abl gene is ubiquitously present in hematopoietic cells, but usually decreases with myeloid maturation. Tyrosine kinase is an enzyme which phosphorylates a substrate using phosphate group from ATPs. The Abl phosphorylation is tightly regulated process. If this controlling region is lost (as in case of fusion with Bcr), then it will lead to uncontrolled kinase activity.

Bcr gene is much more complex because they have many functional motifs. It is also involved in phosphorylation and GTP binding. The first exon present on this gene has oncogenic property because they have the codons responsible for production of proteins involved in Bcr-Abl fusion. It also has serine and threonine kinase enzymatic activity and it has autophosphorylation capability⁴.

Biology of Bcr-Abl gene

Studies on p210^bcr/abl shows that they are pleiotropic molecules critical for the development of CML and they have effect on DNA repair leading to instability (might lead to disease progression) (Razelle Kurzrock, 2005).

Inhibition of tyrosine kinase activity

After the detailed study of Abl tyrosine kinase activity, medicinal chemists started working on inhibitors for this enzyme. They worked on several possible compounds which showed inhibitory effect. Some of the molecules that showed inhibition included benzopyranones and benzothiopyranones and the tyrphostin classes of compounds. However, they showed limited selectivity (affected normal tyrosine kinase present in the rest of the body) or showed less potency at cellular level (Michael Deininger et al, 2005).

Discovery of Imatinib

After working on many compounds the chemists landed on a 2-phenylaminopyrimidine derivative. This compound had low potency and poor specificity, inhibiting both serine/threonine and tyrosine kinases⁵.

Using this as the parent molecule, they started designing a specific tyrosine kinase inhibiting molecule.

• By addition of a 3’ pyridyl group, they found out the molecule will have enhanced cellular activity inside the cell.
• Introduction of Benzamide  will increase the “anti-tyrosine kinase” activity.
• If “flag methyl” group is added to the 6 –position instead of anilino phenyl ring, it will lead to enhanced activity against tyrosine kinase.
• To overcome problems of oral bioavailability and water solubility a highly polar molecule called N-methylpiperazine  was added.
• This drug was initially called CGP57148B (changed to STI571) later it was called Imatinib {IUPAC name 4-[(4-methylpiperazin-1-yl) methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl) amino] phenyl] Benzamide} or Gleevec as it is more commonly known.

Pre-clinical tests

During the pre clinical tests, imatinib was assayed for inhibition of the enzyme.

In-vitro analysis

During the experiments it became clear that this specifically inhibited only tyrosine kinase and it did not affect threonine kinase or serine kinase or any growth receptors (Ex: Epidermal growth factor receptors or VEGF – R1 and R2).

The experiments were repeated on cell lines (containing Abl active forms). It showed inhibition with 50% inhibitory concentration being 0.1 – 0.35 µm (Buchdunger et al, 1996). Since then numerous experiments have been done using Ph+ cell lines taken from patients and the IC₅₀ values have been between 0.1 and 10 µm (showing that drug penetrated cell membrane).

	No. of colonies	% of inhibition for 1µm conc.	No. of colonies	% of inhibition for 10µm conc.
AMuLV cells	97 ± 3	71	20	94
v-sis cells	152 ± 16	83	20	94

In vivo analysis

To test the anti tumour activity of imatinib, syngeneic mice were transformed by transferring Bcr-Abl gene. Experiments done at Ciba Geigy (now Novartis) showed that imatinib is orally absorbed effectively in mice and relevant concentration in plasma is seen with half life of 1.3 hrs. Use of 160mg/kg of imatinib on mice consecutively for 11 days showed assured continuous blocking of p210bcr/abl but it did not affect any other cancer type which is Bcr-Abl negative (Buchdunger et al, 1996).

Using protein structure predictions, they found out that imatinib intimately reacts (engaging at least 21 amino acids) with Abl Kinase. This binding will create conformational changes in the enzyme leading to obstruction of ATP binding site (competitive inhibitor). Therefore, phosphorylation cannot take place and the tumour cells cannot proliferate.

Clinical Side effects that might create problems.

There were some clinical side effects observed in rats, dogs and monkeys when the imatinib was being tested. Dogs and monkeys showed reduced sperm count but there is limited data on fertility of men who have undergone treatment with imatinib.

Imatinib is also teratogenic in rats and hence women are advised to use conception and avoid pregnancies.

Clinical trials – Imatinib Monotherapy

Phase I

The phase I studies on the drug were done in June 1998, to determine the tolerated dosage level. Patients (diagnosed with CML in chronic stage and who had failed IFN treatment) were treated with 300mg of the drug and the results were very promising. Complete haematological response was shown by the patients. There were minimal side effects like Nausea, periorbital oedema and rashes.

Phase II

Phase II trials started in late 1999. Tremendous improvement was shown by patients who were treated with imatinib on a daily basis. The disease progression free survival rate was as high as 89.2%. The drug was eliminated predominantly by hepatic metabolism and had a plasma half life period of 18 hours (hence daily dosage is recommended).

Phase III

In the third phase studies, imatinib was administered along with IFN and cytarabine (anti-metabolic agent). The results were very positive showing 87% complete cytogenetic response (table 2). Imatinib not only has efficacy, but it also improved patients’ quality of life (Michael Deininger et al 2005).

Table 2: Imatinib versus IFN + cytarabine in patients with chronic CML (newly diagnosed)

n = 553	Complete hematologic response	complete cytogenic response	Progression-free survival, 14 months
Imatinib	95.3	87	92.1
IFN + cytarabine	55.5	8.8	73.5

After passing all the three phases of clinical trials, imatinib was approved by FDA in the year 2001.

It also was a feature article in TIME magazine as “magical bullet” curing cancer.

New problems emerge everyday regarding this drug. One such is the problem of resistance, but by using low doses and combining the imatinib dose with other forms of therapy will help in overcoming the resistance problem.

Conclusion

In 2009, Lasker-DeBakey Clinical Medical Research Award, often called the “American Nobel Prize” was awarded to Dr Brian J. Druker who shared the honour with Nicholas B. Lydon and Charles L. Sawyers for developing targeted treatments for CML and converting a fatal cancer into a manageable chronic condition⁶. The drug is a proof that targeted rational drug design is possible. It has created a major paradigm shift for patients and doctors alike.

Gleevec is an exceptional case because it is targeting a cancer type which simpler when compared with other cancers (usually influenced by complex interaction of genetic and environmental factors).  The drug has changed the way how drug designing is looked upon. By 2009, FDA had approved imatinib for many other different cancers.

Essay writing tips for Scientists in the making

1.  Understanding the Question – Comprehensive analysis of the title or question:

• Read it several times
• How many sections are there?
• Break up into key words/segments – Underline/highlight key words
• What do they mean?
• How can they be interpreted?
• How does it link to course lectures?
• What else do I need to find out?
• Discuss with others

2. Research

Make a list of:

• All the questions ideas that have arisen from analysing question/title
• All the information that needs to be found
• Where to get the answers: notes, books, library …

3. Read quickly to find information

• Use contents page, index, headings, sub headings
• Read first sentence, summary, conclusion
• Scan for key words, phrases

4. Read carefully to improve understanding of the information

• Pay attention to what you are reading
• Try to prevent your mind from wandering
• Re-read ‘missed’ material
• Be an active reader – Make outline notes, draw sketches, boxes, doodles to organise ideas

5.  Tips on Note-taking

• Develop good note-taking
• Note sources for referencing
• Put quotation marks round direct quotes
• Have a system for keeping notes ( I use endnote. Easy way to organise your references)

6. Analyse the Information

• Find links, themes, differences etc
• Cross reference the information: use a map, coloured post-its’, coloured highlights
• Draw graphs, bar charts if relevant
• Be critical – ask: which information is important, is the question being answered? – only use relevant information
• Look at the bigger picture
• Be independent and draw your own conclusions

7. Writing the Essay

• Do a rough draft – Don’t expect to it get right first time
• Use own words – Keep direct quotes to a minimum
• Include references to ALL work that is not your own
• Draw diagrams/graphs to illustrate and explain, where appropriate
• Proof read draft and edit – more than once if necessary

8. How to Acknowledge your Sources

• Word-for-word:  quotation marks and reference [i.e. make a footnote, endnote or put information in brackets if using Harvard system].
• Author’s idea in your own words (paraphrase):  no quotation marks, but reference.
• No need to reference things that are common knowledge