Tuesday, March 27, 2012

The phenomenon of the fleeing flu

Why is the common flu more deadly for some than it is for others? Everybody’s thought about it. How is it that some people can die from something that begins as a measly running nose, while others barely notice it come and go?

The vague answer would be ‘immunity’. At least that’s how I’ve always shut my brother up when he’s feeling inquisitive. But it’s always nice to understand ambiguities. Immunity is not a switch that can be at ‘good’ or ‘bad’ but a complex system governed by millions of pathways, enzymes, anatomical and external factors.

Researchers from a whole bunch of Universities and labs in the US and UK published an article in Nature on the 25th of March that might just have made a breakthrough of sorts in bringing some certainty into the hugely murky world of personalized medicine. Scientists from the Sanger Institute in Britain claim to have discovered the “crucial first line of defense” against the flu.

What they had to work with
In 2009 the journal Cell published a paper that established a protein called IFITM3 as having a crucial role in restricting viral replication, proving to be particularly hindrant to influenza, dengue and the West Nile virus. IFITM3 does this by inducing an immune agent called Interferon to prevent viruses from emptying their poison into cells, and consequently barring replication of the viral DNA in their host. See this for details.

However the study published in Cell was only demonstrated in-vitro, meaning in lab conditions. Usually an observed result only gains enough credibility to be applied once it is sufficiently replicated within a living system, or in-vivo.

It pays to play mice
The recent study from Nature have taken the IFITM3 study to the next level and proved that the IFITM3 does indeed play a highly significant role in determining how severely a flu virus affects its host. They did this by using one of the most efficient strategies to determine the functions of a gene/protein in a body. This involves deducing the role of substance ‘X’ in subject ‘Y’, for example, simply by observing the effect of Y in the absence of X. Since human subjects are not an option, the most commonly used animal model is Mus musculus or the house mouse(The mouse DNA is almost 85% similar to ours). Usually when the function of a gene, or its product -- a protein is to be determined, scientists genetically engineer mice with that particular gene absent or inactive so as to observe the effects. These mice are called knockout mice.

So these researchers used knockout mice which had an inactive IFITM3 gene and infected them with a low-pathogenicity (relatively mild) flu virus. They did the same for wild-type mice (normal variety) as well to compare the effects. They found out that the knockout mice suffered a great deal more than it’s wild cousins. The wild-type mice was tested and found to have increasing levels of the IFITM3 protein following infection, compared to the knockout mice which were unable to produce the protein. Similar results were seen when these two groups of mice were infected with the H1N1 virus which was recently responsible for the swine-flu pandemic.

The lungs of the mice without the protein (-/-) and with the protein (+/+) Image from Nature


From mouse to man
After collecting sufficient evidence of the protective role of IFITM3 in mice, the scientists proceeded to test their theory on human beings. How they did this is by examining influenza-ridden patients who have had to be hospitalized.

Now all human beings have the IFITM3 gene; the main differences lie within the gene itself. We’re all different from each other despite being more than 99% genetically similar. A large chunk of that variation is due to something called SNP’s or Single Nucleotide Polymorphisms.
SNP into it

Picture two chains of colour beads, each about 1200 beads long. The two chains are almost exactly identical except for example the 500th bead which is red in one chain but blue in the other. This would now be called rs500 (rs stands for reference SNP). And snp500 has two variants or alleles ie. R (red) and B (blue). In this analogy, the chain = IFITM3 gene, a bead = a nucleotide. Our cells are diploid, meaning we have two sets of each gene. So a person can either be RR (both red), BB (both blue) or RB (one of each). Of course in reality, our DNA is made of not color beads but nucleotides named A (adenine), G(guanine), C(cytosine) and T(thymine).

Example of an SNP. Image from Riken research.


Sometimes the type of SNP, or the variant that you have on a particular gene will markedly affect the kind of protein that gene produces. One particular variant (‘CC’) of an SNP called rs12252 on the IFITM3 gene, results in the formation of a shortened version of the usual IFITM3 protein. This ‘CC’ variant of this SNP is much less prevalent than the more popular ‘TT’ and ‘TC’. Now if the IFITM3-flu virus hypothesis is true, the shorter protein produced in people with ‘CC’ in their IFITM3 gene will not be enough to resist the flu virus, and such a person would be more likely to have a severe attack than a person who is able to produce the usual protein.

They tested the hypothesis by selecting patients from various hospitals who were struck with severe influenza and testing their DNA to detect whether they were TT, TC, or the rogue CC. Then they compared this distribution to the normal frequency of these alleles in the population and concluded that the faulty variant CC is indeed more prevalent in severe flu patients than it is in normal circumstances.

A pie chart representing how the rogue allele CC is more likely to occur in hospitalised flu patients than in the general European population Image from Nature.


Frankly my dear, should I give a damn?

This not only favours the hypothesis that the IFITM3 protein does indeed play a role in the progress of the flu, but also gives us a potentially useful way to predict a person’s susceptibility to a killer flu.

This also can explain why during the swine flu pandemic for example the virus was deadly for some and barely perturbed others.

With more confirmation, perhaps there could be a day when people can take informed decisions on whether or not he/she should take extra precautions like vaccines against the disease.

Even more in the future is the possibility of developing a drug that is similar to the IFITM3 protein so that it can curb the flu virus the same way.

But hold your horses…
There’s still a lot more to be done. The number of patients studied was only fifty three, hardly a large enough sample. The researchers themselves emphasise on the need for these results to be replicated in larger studies to hold good.

Another fact to keep in mind is that a living body is too complex for simple cause-effect relationships. Though the role of IFITM3 stands out, it is not the only gene that plays a role in our overall susceptibility to the disease. Other genetic and environment factors too interfere.

Other references
http://www.bbc.co.uk/news/health-17474197
http://healthland.time.com/2012/03/26/study-why-flu-hits-some-people-harder-than-others/
http://cmbi.bjmu.edu.cn/news/report/2005/flu/78.pdf

Wednesday, March 21, 2012

How is a painkiller curing cancer?

Cancer has been one area of science that the Indian media is willing to spend space on. Sadly, I couldn’t come across too many reports -- forget Indian reports -- that would lure a lay-reader to go beyond the ‘Aspirin a Cancer killer’ headline and bother to find out what was actually done here.

What is Aspirin?

Aspirin belongs to a class of drugs called nonsteroidal anti-inflammatory drugs or NSAIDs which is usally called ‘Dispirin’ in India. The main use of Aspirin is as a pain-killer, though more recently it has shown to prevent cardiovascular (heart) problems and now cancer.
How does it work?

Aspirin blocks the activity of an enzyme in our body called cyclo-oxygenase. Cyclo-oxygenase is needed to produce various chemicals in our body like prostaglandins, prostacyclins and thromboxane.

Pain: Prostaglandins are chemicals produced during injuries because of which we get swellings, inflammation and thereby pain. A high dose of aspirin (300mg and over) prevents the enzyme cyclo-oxygenase from producing these prostaglandins. And Voila! No pain.

Cardiovascular diseases: A lower dose of aspirin blocks cyclo-oxygenase too, but not enough to prevent prostaglandin production. At lower doses, aspirin prevents cyclo-oxygenase’s role in the production of another chemical called thromboxane. Thromboxane is usually produced by blood cells called platelets (with the help of cyclo-oxygenage) to help clot our blood and prevent too much bleeding, when you hurt your knee for example. But clotting of blood within your blood stream can obstruct free flow of blood and result in a stroke or a heart attack. So by preventing the production of thromboxane, blood is less likely to clump together in your blood vessels and cause complications.

Cancer: While the above two uses of Aspirin are relatively well established, it’s role in cancer prevention/cure has been debated since the 70’s by Bennett and Del Tacca. But three recent studies on the topic conducted by Peter Rothwell of the Oxford University however have silenced some skeptics. They conducted a randomized, controlled trials and concluded that a daily low dose of Aspirin for just 3 to 5 years is enough to lower risk of certain cancers, particularly bowel cancer in people who are at risk.

However, it must be noted that all these studies have been epidemiological studies. Though statistics have been proved to be immensely useful to establish correlation between two factors, is it enough? From what I have explored, not many biological reasons for this phenomenon have emerged. If they have then, nobody seems to be talking about them enough.

How is Aspirin doing this?
The biological processes involved in this correlation have still not been established. However there have been some explanations proposed.

As mentioned, Aspirins thins blood, makes it less likely to clot by its effect on blood clotting platelets. Now platelets, save us from bleeding to death no doubt, but they have been show to play a sinister role as well. They prime cancer cells for metastasis ie. They help cancer cells spread from its site of origin. How it does this is detailed in this easy-to-understand article .
So since Aspirin is anti-platelet, and platelets are pro-cancer, this could be one of the mechanisms by which Aspirin cures cancer.
Last month Australian scientists made another explanation.
Co-lead author Tara Karnezis said tumors secret proteins and compounds called growth factors, attracting blood and lymphatic vessels to their vicinity and allowing the cancer to flourish and spread. These growth factors also encourage lymphatic vessels -- or "supply lines" -- to widen, which enables the spread of cancer, she added. "But a group of drugs reverse the widening of the supply line and make it hard for the tumor to spread -- at the end of the day that's what kills people," Karnezis said. "This discovery unlocks a range of potentially powerful new therapies to target this pathway in lymphatic vessels, effectively tightening a tumor's supply lines and restricting the transport of cancer cells to the rest of the body."

Reality checks
So whatever the reason, this doesn’t mean we can simply start gobbling up pills and expect to be Cancer free. There are several concerns that haven’t been addressed.

Aspirin has been known to have side-effects, one of the more serious though rare one is stomach bleeding.

Some critics have noted that some of the doses given in the study were much higher than the 75mg dose typically given in the UK, said a BBC report (Since the article is Lancet, read Elsevier, stuck up folks aren’t letting me read it for free and verify this myself).

The benefit of Aspirin for healthy people is yet to be quantified. The lead author Prof Rothwell himself has said that for most fit and healthy people, the most important things they can do to reduce their lifetime cancer risk is to give up smoking, take exercise and have a healthy diet. Aspirin does seem to reduce the risk further – but only by a small amount if there is no risk factor.




Links

http://press.thelancet.com/aspcomment.pdf
http://www.cancer.gov/cancertopics/prevention/aspirin-cancer-prevention/Page1
http://www.bbc.co.uk/news/health-17443454
http://www.guardian.co.uk/science/2012/mar/20/cancer-drugs
http://www.nytimes.com/2012/03/21/health/research/studies-link-aspirin-daily-use-to-reduced-cancer-risk.html
http://jnci.oxfordjournals.org/content/94/4/252.long
http://www.foxnews.com/health/2012/02/14/aspirins-role-in-cancer-mystery-explained-by-scientists/

Tuesday, March 20, 2012

My First Rage Comic

It's not enough to live in Anugraha apartments or Brihadeeswar Flats anymore. Even Sunflower apartments and Fern Hill just don't cut it. THIS is the new status symbol



Fancy Flat names in India

Saturday, March 3, 2012

#100WaysToDieInIndia

As of now (03-Mar-2012, 17:48 IST), #100WaysToDieInIndia is trending on Twitter. Globally that is. So I thought it would be amusing to see what people outside of India know about India.. In fact, so enamoured did I get with this notion that I abandoned my dissertation work in this noble pursuit.

What I found out:-
1) Indian food is deadly spicy.

2) Indians hate Pakistanis

3) It is unheard of to not love SRK


4) Indian elders regularly beat kids with chappals

5) Cows, goats and elephants trample on us frequently. Cobras also.





6) Indian parents have no tolerance for their wayward (read non-engineering/medically inclined) offspring.


7) Indians are all vegetarians


8) Indians all have long names


9) Indians often sell body parts to buy cricket tickets


10) Indian men don't cheat

11) Abusing a Sardar is frowned upon.


12) We all marry our cousins. And Sanji is a real name.


13) If not that then at least we must do arranged marriage


As if all of this wasn't enough, we've got these to worry about -
whatever they are..