Monthly Archives: January 2011

UK Biotech world

In Cambridge, anyone will point you to Eagle pub. Reason: It was in this pub that on 28th Feb 1953 one of the greatest discoveries was announced. Crick and Watson declared that they had discovered “the secret of life”. They were talking about the structure of DNA. It revolutionized biology.

I know about this piece of information because I visited the city of Cambridge to inspire me and to find out a little bit more about the subjects that I am passionate about. It does help the date of the announcement of the structure of DNA coincides with my birth date.

It doesn’t stop there. In 1997, Dolly, the sheep, was born as a result of the first mammal clone using an adult cell. In 2003, the human Genome project was completed! As of 2010, there are ~500 dedicated biotech businesses with over $ 10 billion revenue. UK has developed nearly a quarter of the top 100 medicines being utilized now.

So, what really is the relationship between India and UK in the biosciences sector?

To answer that, it is a growing relationship. India and UK are both strong in biosciences. The British market is very ‘friendly’ for the Indian investors. (Recently, many companies like Avesthagen, Ocimum biosolutions, Ranbaxy, Shasun Chemicals and drugs etc have established their offices in UK). In Britain, it is easy for a scientist to translate scientific research into a commercialized business as compared to India. There is one business spin off for every 27 million pounds worth of research on an average in UK.

India now has a good intellectual property law coupled with great skills in the clinical trials sector. We still lack good R&D facilities. We need to start working on being more practical when training our students. But, for that there are numerous obstacles which I am not going to deal with in this blog. Just so you know, it is important to be a “Lab ready” candidate when you are searching for a job.

Since I did my degree in Scotland, I can tell you a little bit about the way things go on in that part of the country.

When I selected Scotland as my study destination, I had read several articles from genuine sources which provided statistics and such which convinced me that Scotland region is indeed a genuine centre of excellence. The birth of Dolly, in fact was in Edinburgh, Scotland. I had the opportunity to do part of my degree in University of Aberdeen and the rest from the University of Edinburgh. Both the Universities provided me every facility that I would need to complete my master’s degree successfully (Which I utilized to the best of my abilities).

I have done a very crude pie chart to explain how the life science organization is divided in Scotland. Recently, a company called Haptogen (Opened by one of my course coordinators at University of Aberdeen) was taken over by another company called Wyeth. Wyeth was later bought by Astra Zeneca for multimillion pound upfront money. These kinds of major moves by pharmaceutical giants have brought small companies like Haptogen on the map of biotech world.

Now that you have understood how UK biotech world is growing at an ever increasing world, what you should do to get into it and be a part of the system?

For one, you should be sure of what you want to do. If it is research, then try to get atleast a PhD in your relevant field. Highly educated candidates are always respected all over UK and the world. If you can get some experience working in your field, then that would be good for you. I personally feel, there is no substitute for good experience.

I hope I have explained how the biotech world is divided in UK and what they expect out of you. If you still have queries, I will be glad to answer them. Remember, hard work definitely pays off, but it is also important to do some smart work and look out for opportunities.


Why vaccines work…

Right, this post will be about the very fundamental reasons for the success of vaccination as a procedure to prevent infections and epidemics of infectious diseases. Before we get started I want to introduce you to one or two terms that will be used in the remainder of the article, the first one is antigen, and the other one is pathogen. Pathogens are things like viruses and bacteria and in some cases toxins that cause disease, antigens are things the body uses to recognize things like pathogens (and other foreign bodies too, but that is not of consequence to this post)

Then of course we have the other part of the equation, the Immune System, which works to get rid of foreign bodies, these bodies being bacteria viruses et cetera, from the body, the functioning of the immune system, which mounts an immune response, can be arbitrarily divided into two parts, a nonspecific immune system (which produces innate immunity and does not distinguish between what foreign bodies it encounters) and an adaptive immune system (which is specific to the antigen and is acquired)

Acquired how? One might ask, well, to cut a long story short, phagocytotic cells digest a pathogen and present bits of it on their surface coupled to MHC proteins, other cells of the immune system process the antigen and this triggers the production of B cells which produce antibodies and T cells which facilitate a cellular response to said antigen specifically, thus allowing the body to get rid of the antigen.

However, doing all this takes some time, ranging from at least two days to two weeks, so if a pathogen gets into the body it can cause disease in that period, before the immune system is able to clear the inection out. If the person survives the infection, the primary immune response that had been induced in the aforementioned timeframe then leads to the establishment of immunological memory (the immune system basically ‘remembers’ the pathogen, the next time the same pathogen is encountered, the immune system is ready to get rid of it extremely rapidly, and this is why most people (those with normal immune systems) don’t get infected by the same pathogen twice, this secondary response is called, um, a secondary response.

The next question when one is looking to prevent disease is to ask if one may somehow prime the immune system against the pathogen so that the first encounter with the pathogen triggers a secondary immune
response…and vaccines do this, here is how…

1) Various things that belong to a pathogen can trigger an immune response, such as proteins on the surface and polysaccharide capsules.

2) These antigens can trigger immune responses without causing disease, as long as they are disjunct from the pathogenicity of the organisms.

3) By supplying antigens to the immune system without the risk of associated pathogenesis, it can be taught to recognize those antigens and mount an immune response against the antigens, and the pathogens that have those antigens.

4) QED.

This is just a very brief introduction for laymen to the world of vaccines, in the near future you may expect to see various posts on the nitty-gritties of this critical field of medical science.

Say hello to someone else too.

I am pleased to let everybody know that this blog will now have one more contributor, Avinash Chalam, he is also a biologist and is interested in science education and career development as well as science per se, and we share common views and interests regarding the aforementioned issues, I’d also like to officially welcome him to the blog with this post.

What this means for readers is that you can now expect a lot more content.


Concept – here comes RNA Interference, just as promised.

The behaviour of genes can be affected by other genes and other elements that interact with genes, ranging from transcription factors to antisense transcripts that operate post-transcriptionally, and today the focus of my post will be something called RNA Interference (RNAi in short)

If one were to look at what happens to genes in terms of the central dogma of molecular biology, you will find that the biochemistry of genes can be written down as follows.

DNA ————-> RNA (Transcription) ———–> Protein (Translation)

RNAi acts on genes following transcription but before translation, and it does so by breaking down mRNA that would have been translated otherwise, and this is mediated by the RNA Interference pathway, something that is conserved in Eukaryotes (with the exception of certain fungal lineages, the interesting thing is that the loss appears to be independent in fungal lineages) and is, as I will elaborate later in this post, of much practical utility.

The next part of my post will deal with the RNAi pathway per se. But before we venture there, it would be prudent to have a brief outline of the components required, to put it extremely simply, we will need double stranded RNA and a set of enzymes to use double stranded RNA as the reference for destroying target RNA and then something to cleave the target RNA.

Double stranded RNA does the trick well, and basically long chains of double stranded RNA are cut into smaller double stranded RNA fragments  of a length that is 20-25 base pairs long by an enzyme called, funnily enough, Dicer. These shorter double stranded fragments, that come with a two base overhang, are called siRNA (short interfering RNA).

siRNA then binds to Argonaute proteins to form what is called an RISC, a multi-protein complex that is involved in the final part of RNAi, the identification of complementary mRNA and the breakdown thereof. RISC stands for RNA Induced Silencing Complex, by the way.

A very good video of the process can be found below.

Organisms may use RNAi for gene regulation through the function of miRNA (microRNA) , here a long noncoding chain of RNA (pre-miRNA to be precise) is produced first by transcription, and this undergoes self-base pairing within the ssRNA strand to form a structure with loops and stems, further processing by enzymes like Drosha and Pasha help in the conversion of the long transcript into a double stranded form, which is mature miRNA, after which the RNAi pathway functions as described above.

That is about the jist of what RNAi is, but what about the implications? And what empirical standing do the proposed applications of this system have?

Well, we already know that RNAi can turn genes off, which means it is great when we are looking to target the mRNA of viruses et cetera, identify target sequence, find sites that are unique only to the viral mRNA, design dsRNA, introduce that into cells, and watch as the RNAi apparatus goes about marmalizing the viral genome. The very fact that some regions of viral genomes are conserved, even in highly variable strains like Influenza viruses means that broad spectrum therapies could be developed utilizing this process.

Want to study gene function and what happens if you knock a gene out? Same principle more or less, put in your dsRNA sequence, watch as the gene is silenced, observe for phenotypic changes, the very fact that one is now able to silence genes directly instead of generating knockout organisms by traditional mutagenesis and breeding is certainly very attractive.

Want to study or control gene regulation? Not a problem, you can just add in extra copies of miRNA or target miRNA for cleavage, either using other antisense approaches (antagomirs) or using complementary dsRNA. I hope you are now able to appreciate the scope of this technique.

There have been recent advances, too, such as the development of a technique called dicer substrate RNAi , wherein, instead of using long dsRNA which has to be processed by dicer, it is possible to introduce 25-28 nucleotide long double stranded RNA directly for integration with Argonaute, and this method, according to reports in the scientific literature, can greatly increase the efficacy of RNAi.

I am not sure that we have many RNAi therapies in active clinical use at the moment, but it sure does look promising. You may want to peruse the following resources for further information.

Wikipedia article on RNA interference.
RNAi Therapeutics: Principles,Prospects & Challenges (peer reviewed paper)
RNAi as a means of controlling lipid levels (peer reviewed paper)
Science : RNAi Collection (A collection of peer reviewed research papers)
Science: miRNA Collection (A collection of peer reviewed research papers)

Antagomirs et cetera and case studies of RNAi application will be parts of future posts somewhere down the line, until then, have a happy Interfering time :P.

PS – work on RNAi won the 2006 Nobel for Dr.Andrew Fire and Dr.Craig Mello, the apposite press release can be found here
& Dr.Fire’s Nobel lecture is here and Dr.Mello’s Nobel Lecture is here

These are always entertaining to watch because they give you an opportunity to ‘connect’ with these researchers in a way that research papers themselves do not. Happy viewing.

Paper Review – Alzheimer’s Disease and RCAN1

This is the first of my paper reviews and today I will be explaining the paper “Regulator of Calcineurin-1 (RCAN1) facilitates neuronal apoptosis through caspase 3 activation” that is fresh off the pages of the JBC.

I know that the title is a mouthful, but I will try to simplify the work that was done and explain the inherent beauty of it all.

At the outset, please remember that Alzheimer’s disease is a neurodegenerative disorder (it kills brain cells, basically, and in doing so impairs brain function), this of course is a product of various pathogenic factors, the most famous of which is a protein that is called Beta-amyloid, the formation of plaques of which is a defining feature of the disease, the disease leads to neurons becoming sticky, getting all tangled up, and dying, if one were to stick to the very basics.

Scientific breakthroughs, in my opinion, often entail the application of insights that are drawn from other works of research into testing hypotheses, and in this case the insight came from a well documented facet of observational reality, that patients with Down’s syndrome (with three copies of Chromosome 21, a condition known as trisomy 21) inevitably suffer from Alzheimer’s disease while only being middle-aged.

This led the authors to hypothesize that genes that are overexpressed in Down’s syndrome may have something to do with it, and the candidate gene they studied,and its protein output, of course, and have reported here in the paper, happens to be a gene called RCAN1 (Regulator of Calcineurin 1).

They found there is a version of RCAN1 with a unique regulatory region, which is called a promoter, and promoters basically control how active a gene is, they determined that RCAN1 is upregulated by one or two other substances firstly, confirming that this was part of a signalling cascade (a signalling cascade consists of proteins working like Dominoes, if a laymen’s analogy were to be used) , thus indicating that the involvement of this particular gene and its protein in the pathogenesis of Alzheimer’s may have something to do with its regulation.

The next step was to verify if RCAN1 is indeed upregulated, and the evidence that they present in the paper suggested it is the case, not only are levels of RCAN1 mRNA elevated, as per previous studies they quote) but the protein product is also elevated in patients with Down’s Syndrome + Alzheimer’s.

The next bit of their work, dealing with the actual relationship between RCAN1 and caspase activation, involved an ingenious bit of work. They had noticed that dexamethasone, a chemical, triggers cell death (apoptosis) in cell cultures, and if caspase inhibitors were concurrently used, this would not happen. Now the question to be answered is “Is RCAN1 a mediator in the pathway between dexamethasone and caspase activity?”

If RCAN1 was essential for dexamethasone to cause apoptosis, knocking it out would result in Dexamethasone activity not being able to cause apoptosis, and they verified if that was true using antisense oligomers (which can be used to silence a gene) to turn RCAN1 off , the results confirmed the integral role of RCAN1 in apoptosis since Dexamethasone couldn’t trigger apoptosis with RCAN1 switched off.

Now we have Dexamethasone ——-> RCAN1 ———->Apoptosis,  and
Dexamethasone ——-> Caspase ———> Apoptosis

The next question to ask would obviously be if the correct pathway was RCAN1 ——>Caspase —–>Apoptosis.

But wait! There are many caspases, and caspase 3 is perhaps the most important of them, going by this line of reasoning, the authors reformulated their question as , to paraphrase “Does RCAN1 cause apoptosis through Caspase 3?”

They first identified a correlation by seeing what happens to Caspase 3 levels when RCAN1 was overexpressed, they found that these levels shoot up, indicating that the two are related statistically, next question, was there a causal relationship?

To check this out, they used a test system that used mutant cells without Caspase 3, and found that RCAN1 couldn’t cause apoptosis in this case, thus establishing that Caspase 3 was also essential for RCAN1 to cause apoptosis. Great work so far.

There are again three upstream activators of Caspase 3 (that is, these have to be activated first before they carry out the activation of caspase 3) namely caspase 9,10 and 8, to identify the correct upstream activator, they again used the correlation approach, seeing which of the two candidate caspases would be expressed more if an excess of RCAN1 was present, the results pointed towards Caspase 9.

They also wanted to see if the activation of Caspase 9 was specific, or whether other caspase families were also activated in some kind of broad effect, they used levels of Caspase-11 as a measure for this and found that the activation involved was indeed specific to the caspase-9 pathway.

The authors note, from previous literature, that Beta amyloid can increase RCAN1 expression and also that Caspase 3 can increase Beta amyloid expression, combine this with the fact that RCAN1 expression can increase Caspase 3 expression, we have a tirumvirate for Alzheimer’s

They also noted that an ortholog of RCAN1 in Drosophila, called Nebula, could be associated with severe memory impairment in that subject species if it is not regulated properly.

The work is significant because breaking the circle could lead to better therapeutic strategies against what is a very devastating disease.

The paper itself, for the discerning reader, can be found here at

More useful information may be obtained by means of the following links.

I hope you enjoy this and do not doze off.

Hello there.

This is my first post on the blog (well, obviously) and I would just like to lay down the intended objective(s) of starting this blog, it is to share some of my creative pursuits, firstly and to develop a platform for the dissemination and discussion of my ideas and thoughts.

I will be posting photographs that I’ve taken, including micrographs in an effort to try and popularize the field of biology, to try and do my part to encourage young people to take up biology as their pursuit, since curricula seem to be fundamentally disconnected from the natural beauty that biology proper studies.

A Welcome to You.

I will also be posting various deliberations about whatever may happen to catch my eye, ranging from research papers, which I hope to be able to explain to laymen in a way that is accurate yet understandable (which of course most of the science media seems to be utterly incapable of doing, which is why I loathe them) to random thought patterns that deal with issues that have a direct connection to me.

I hope that you have a good time perusing this blog, and yes, although I’m a full eleven days late, I would like to wish readers a Happy 2011.