Field of Science

Allotrope is moving

Today the Allotrope is moving to a new home at I have been a blogger on this network for a little over two years and it has been a pleasure to write here. I am grateful to the community and to Edward, the moderator, for this opportunity. But it is time to move on. On Allotrope's new home you can expect a lot more variety in the science writing that I do. The first post about how to stop aging related cognitive decline is already up. I hope you will come with me.

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The magical role of the doormen

Half of all pharmaceuticals work because of a family of proteins that sit on the boundary of cells in the human body. This year’s Nobel prize in chemistry was awarded to Robert Lefkowitz and Brian Kobilka for their work on a family proteins called G protein-coupled receptors (GPCRs). Nearly every function of the human body from smell and sight to heart rate modification is dependent on GPCRs. Dr Lefkowitz and Dr Kobilka have helped us understand their chemical structure and mode of action to help create better means of manipulating them to our advantage.  

Robert Lefkowitz
Credit: Wikipedia
Embedded in the fatty membranes of cells, GPCRs act as doormen to a mansion. They detect chemical signals that reach the cell and convey messages through creation of G proteins inside the cell. These G proteins that take on the role of maid servants then act on the message by activating the necessary response.

But this was not known until the 1960s. All that was known then was that hormones communicated with cells in someway but no one knew how. Dr Lefkowitz started probing these hormones by attaching radioactive isotope Iodine on to them. This revealed that the cell membrane had special proteins that acted as telegraph operators relaying information from one side to the other. He was able to identify one class of these proteins called beta-2 adrenergic receptors. These are interesting because they are now implicated in responding to the neurotransmitter adrenaline known to control the fight-or-flight response.

In 1984 when Dr Kobilka arrived in Dr Lefkowitz’s lab, the lab was working on duplicating the gene sequence that made beta-2 adernergic receptors. If they could, then it would enable them to know more about the role of these proteins and how they work. When they eventually managed to do it, after a lot of failed attempts, they realised that this protein was very similar to rhodopsin, a protein that sits in the retina and is responsible our perception of light. Rhodopsin was known to activate G-proteins in the cell and that is it was thought that these could be a class of proteins, now known as GPCRs.

We now know that human body has about 800 GPCRs splayed across different cells performing some of the most critical functions. About half of these are predicted to be pharmaceutically useful, but less than 10% of that have drugs targeting them today. A major hurdle in creating pharmaceuticals for them is because little is known about the chemical structure of these proteins.

Brian Kobilka
Credit: Stanford
A way to shine light on the chemical nature of proteins is by using X-ray crystallography. To do that though, a protein first needs to be crystallised (lots of molecules arranged in a regular fashion in a tiny space). Proteins, in general, and GPCRs, particularly, are notoriously difficult at doing that. Of the 63 million proteins registered in the database of the Chemical Abstracts Service, only 600 have comprehensive structural data available for them. But in 2007 after decades of work Dr Kobilka managed to tame the beta-2 adrenergic receptors and published its structure in Nature.

The pharmaceutical industry has only started scratching the surface when it comes to designing drugs that affect GPCRs. And that has been the result of many decades of efforts by structural biologists and medicinal chemists in academia and industry. The work of Dr Lefkowitz and Dr Kobilka has opened the possibility of better understanding what one scientist calls cell biology—an alien world that has the most profound impact on humanity.

Main references:
  1. Rasmussen et al, Nature, 2007
  2. Buchen, Nature, 2011
  3. Sansom, Chemistry World, 2010

A more powerful but less sensitive explosive

Pharmaceutical companies exploit a process called co-crystallisation to optimise the physical properties of drugs. Now scientists developing new explosives have done the same. As I report in The Economist, researchers from the University of Michigan have developed a method to lower the sensitivity of an explosive without losing its explosive power. 

Explosive power depends on two factors: detonation velocity (the speed at which the shock wave travels on explosion) and oxygen value (number of oxygen atoms per carbon atom). The higher the detonation velocity the more destruction it will cause. Oxygen value matters because when the explosion occurs carbon atoms within the explosive would like to react with oxygen atoms to form carbon dioxide. But because there is little time for carbon atoms to find oxygen from the air. Instead it has to rely on oxygen atoms within the explosive. Thus the closer the number of oxygen atoms per carbon atom is to two, the better the explosive.

One such explosive that has a higher detonation velocity and a better oxygen value than any of the commonly used explosives is CL-20. But it suffers from low sensitivity, which means that it will explode very easily if dropped or rubbed. This has meant that despite its early development it has mainly remained on the army barracks shelves.

Not anymore. Adam Matzger and colleagues have now made a hybrid explosive that has the same explosive power of CL-20 with reduced sensitivity. Find out how they made it here.

List of main references:
  1. Matzger et al, Crystal Growth & Design, 2012
  2. Matzger et al, Angew Chem Int Ed, 2009
Free image from here.

Fixing broken voices and how polymers are coming to the rescue of our medical needs

A team at MIT has developed a polymer gel that can mimic human vocal cords. Although vocal cords don't make it to the news very often, they are a serious problem for millions of people around the world. They can be a problem for celebrities, too. Julie Andrews, who once had a rare, four-octave voice, lost the range after a vocal cord injury. I wrote about the polymer gel in The Economist this week.
Laboratory tests have shown that when air is blown through a model of the vocal cords made from this material, the model responds in the way that real cords do. The new polymer gel is not intended to heal scarred tissue, but rather to make the whole tissue flexible enough to restore vibrations to normal. To achieve this Robert Langer, a biomedical engineer at MIT, proposes to inject the gel under the tissue membrane (a thin layer of cells that covers the vocal cords), forming an additional layer within... read more
Note: It's not what The Telegraph, who has happily jumped to the exaggeration bandwagon, would like you to believe. The gel isn't replacing scarred tissue. Instead, it is hoped that it will help restore flexibility in the vocal cords.

This is not the only innovation from Dr Langer’s lab that may make it into the human body. InVivo Therapeutics, an American medical devices company, with help from Dr Langer and his colleagues have developed a treatment for spinal cord injury. They use a scaffold made out of PLGA, a biodegradable polymer, to help patients recover from an injury that, if not dealt with properly, is infamous for causing paralysis. The scaffold is inserted at the point of the injury after removing dead tissue and is programmed to degrade within 21 days, the amount of time needed for the body to rebuild lost tissue. Although this treatment is not a cure either, the scaffold helps to make the most of the body’s repair systems. Work done on monkeys has shown that the technology works. This, too, will go into human trials next year, says Frank Reynolds, chief executive of the company.

Other work still in Dr Langer’s lab is looking at building intestinal, pancreatic and heart tissue using a range of materials. Touted as the next big frontier of medical technology, biomaterials are finally coming to the fore.

  1. A material to rejuvenate aging and diseased human vocal cords (Press release)
  2. Karajanagi et al, Annals of Otlogy, Rhinology and Laryngology, 2011
  3. InVivo therapeutics

Fish, schooling and video games

Much is said about why fish group together in schools. But there is little direct evidence for why that happens. Now, with the help of a video game, researchers know at least one reason why schooling is a good idea. I wrote about this in The Economist's Babbage blog.
Testing the theory requires manipulating the behaviour of real fish—trickier even than herding cats. Now, though, Christos Ioannou, from Bristol University, may have found a way around it. As the researchers report in Science, he and his colleagues have developed a video game for piscine predator to play. They put their gamer, a hungry bluegill sunfish, into a tank and projected computer-generated prey on one of its walls... read more.
Dr Ioannou worked with Iain Couzin, an evolutionary biologist at Princeton University, who has been working for quite sometime on understanding collective animal behaviour. He speaks about his other work here and here. From the likes of it, it seems there is much we need to learn from animals.

ResearchBlogging.orgIoannou CC, Guttal V, & Couzin ID (2012). Predatory Fish Select for Coordinated Collective Motion in Virtual Prey. Science PMID: 22903520

Lenna at the highest resolution possible

Lenna, a 70s playboy girl
Among the many playboy girls there is one who is very famous in a geeky group of programmers. Her name is Lenna. And her image is used by the programmers to test their algorithms. Now researchers at Singapore's Agency for Science, Technology and Research have developed the smallest image of Lenna at the highest resolution that is permitted by the laws of Physics. I've written about in The Economist's Babbage blog.
Dr Kumar and his team start with a plate of silicon. The electron beam carves bits of this away, leaving a pattern of cylindrical posts each about 140 nanometres (billionths of a metre) across and 50 nanometres apart. That “about” is important, though. The exact diameters of the posts and the distances between them are crucial. Varying them changes the colour that forms between the posts... read more.
The colours are achieved by coating this plate with noble metals. This is not cheap, but they are already working on replacing them with cheaper metals or looking at the use of polymer. Furthermore, they want to use this technique for data storage.

Data on CDs, DVDs and Blu-Ray discs is stored in the form of 0s and 1s represented by pits and troughs on the disc's surface. With the new technique the pits and troughs will still be there in the form of cylindrical posts and spaces between them, but they will be able to reflect back light of a particular frequency. As this no longer limits them to a binary system, they could encode a whole string of 0s and 1s in just one "pit".

References for The Economist piece:
  1. Kumar et al., Nature Nanotechnology, 2012
  2. Lenna Image
  3. Retina Display Kumar K, Duan H, Hegde RS, Koh SC, Wei JN, & Yang JK (2012). Printing colour at the optical diffraction limit. Nature Nanotechnology PMID: 22886173

Oceanic carbon sinks

So nature deals with increasing carbon dioxide emissions by sucking up more of it. Plants take more and grow faster. The increased partial pressure of COcauses more of it to be absorbed by the oceans. On land more plants is a good thing, but in the oceans more COleads to increased acidity which can be devastating for the flora and fauna.

Recently there were two interesting papers, one in Nature and the other in Nature Geoscience, that looked at Earth's carbon sinks. I've written about the studies in The Economist's Babbage blog. I took the chance to speak to some of the leading researchers in the field: Ashley Ballantyne at the University of Colorado, Corinne Le Quéré at the University of East Anglia (and not involved in the climate scandal), Jean-Baptiste Sallée of the British Antarctic Survey and Jorge Sarmiento at Princeton University. The conversations helped me learn a number of things. I'm sharing those here:
  1. The ocean in the southern hemisphere take up most of the CO2 because of their large unbroken waters. But this absorbed gas is not evenly spread out. Some pockets have a lot more of it than others.
  2. This ocean also absorbs a lot of the heat that is getting trapped because of excess greenhouse gases. By one estimate almost 70% of it. As oceans warm up, their capacity to hold COreduces. These carbon sinks could become carbon sources at some point.
  3. The lack of an ozone layer leads to localised cooling in the Antarctic. Global warming causes most of the heating in the tropics. This temperature difference causes stronger winds which could whip up deeper ocean layers bringing up CO2-rich waters which won't be able to absorb as much of it as they do now.
  4. Land carbon sinks could become carbon sources, too. Increased temperature leads to growth of microbes in the soil. These will then consume more of organic matter and convert it into CO2, which they do already but the plant consumption of CO2 is able to keep that in check.
Climate change is a very complex phenomenon. I knew that but these conversations made me realise just how much we don't know (PS: this is not to doubt that humans are causing global warming). Only after a few questions, all researchers started answering the question by first saying 'We don't know, but one theory is...'. Oceanic carbon sinks, in particular, are a big area of debate, mostly because of the lack of hard data. Things are changing, but are they changing fasting enough?

A list of main references for The Economist piece:
  1. Ballantyne et al., Nature, 2012, 488, 70
  2. Salée et al., Nature Geoscience, 2012, ASAP
  3. Climate change: What lies beneath - The Economist
  4. Argo project, UK Met Office
  5. Climate Variability and Predictability (CLIVAR) Ballantyne AP, Alden CB, Miller JB, Tans PP, & White JW (2012). Increase in observed net carbon dioxide uptake by land and oceans during the past 50 years. Nature, 488 (7409), 70-2 PMID: 22859203

Sallée J-B, Matear RJ, Rintoul SR, & Lenton A (2012). Localized subduction of anthropogenic carbon dioxide in the Southern Hemisphere oceans. Nature Geoscience DOI: 10.1038/ngeo1523

Squirrels and climate change

Credit: Jeffrey Lane
Jan Murie, emeritus professor of biology at the University of Alberta in Canada, is passionate about squirrels. He has even written a book: The Biology of Ground-Dwelling Squirrels. Even after retiring he keeps up with his interest. With the lead author Jeffrey Lane, a biologist at the University of Edinburgh, he has published a paper in Nature on the effect of climate change on Columbian ground squirrels. I've written about it in The Economist's Babbage blog.

Here's the blurb:
Winter is a pain in the animal kingdom. Birds can flee it by migrating to warmer climes but grounded beasts, including mammals, have no choice but to stick around. To cope, many species have learned to hibernate. Some, like the Columbian ground squirrel, spend up to nine months of each year in their alcoves. This conserves energy but leaves them with only three months to plump up for the next winter and, crucially, to procreate. To make matters worse, climate change is leading them to emerge from hibernation later than usual... read more.
While chatting with him about the paper he told me that these squirrels in captivity live up to the age of 13 years, while in the wild their average is 6 years. Adult squirrels tend to cope well, but it's the juveniles that get hunted down. Although there's nothing surprising about that, it was a reminder of what can happen when you live in the wild. Especially, if you happen to be at the bottom of the food chain.

  1. Lane et al., Nature, 2012, ASAP  
  2. Lane et al., J. Evol. Biol., 2011, 1949 Lane JE, Kruuk LEB, Charmantier A, Murie JO, & Dobson FS (2012). Delayed phenology and reduced fitness associated with climate change in a wild hibernator Nature DOI: 10.1038/nature11335

A silent healer

I have an article published in The Economist's Babbage blog.
Carbon monoxide gets a bad rap. The gas, produced by incomplete combustion of hydrocarbons, causes hundreds of deaths every year by poisoning and sends many thousands to hospital. But there is more to the “silent killer”, as CO is sometimes called. Exploiting this insight, researchers have successfully used CO to treat a number of ailments in lab animals and most recently in humans... read more.
Here is a list of main references:
  1. Romao et al., Chem Soc Rev, 2012
  2. Motterlini et al., Nat Rev Drug Discovery, 2010
  3. Montogomery et al, US Patent 7523752
  4. National Safety Council data
  5. Winslow et al, US Patent 20120094912A1

Publishing on preprint servers... do you do it?

In following up the arsenic in DNA story for The Economist, Rosie Redfield has brought some interesting issues to light. Dr Redfield, who blogs on this network, has recently published a paper in Science showing that NASA's claims about finding an organism that has arsenic instead of phosphorus in its DNA weren't true. Interestingly, her paper was available on arXiv, a preprint server, since February this year.

Before making it available on arXiv, she got in touch with Science to know if she can do this. Of course, physicists do it all the time. But Rosie figured that if Science publishes physics, then it must allow it too. To that end she asked and got this answer:
Posting of a paper on the Internet may be considered prior publication that could compromise the originality of the Science submission, although we do allow posting on not-for-profit preprint servers in many cases. Please contact the editors for advice about specific cases. We provide a free electronic reprint service to authors that allows visitors to the authors' web site free access to the published version of the Science paper on Science Online immediately after publication. 
 Interestingly, Nature says the same thing but with more clarity than Science:
Nature journals do not wish to hinder communication between scientists. For that reason, different embargo guidelines apply to work that has been discussed at a conference or displayed on a preprint server and picked up by the media as a result. (Neither conference presentations nor posting on recognized preprint servers constitute prior publication.)
Our guidelines for authors and potential authors in such circumstances are clear-cut in principle: communicate with other researchers as much as you wish, whether on a recognised community preprint server, by discussion at scientific meetings (publication of abstracts in conference proceedings is allowed), in an academic thesis, or by online collaborative sites such as wikis; but do not encourage premature publication by discussion with the press (beyond a formal presentation, if at a conference).
How many people in the biological and chemical sciences really know about this? How many actually practice it? The only example I am aware of is Rosie's. Do you know of others?

The conduct of science

I have an article published in The Economist's Babbage blog. Here's the blurb:
Most scientific research is about incremental improvements to existing theories. Every so often, though, an anomaly shakes things up, offering upstart ideas the chance to dislodge reigning ones. Sadly for NASA, who attempted to do such a thing, the glory did not last for very long. In what has come to be known as the #arseniclife controversy, researchers around the world used blogs and Twitter to highlight the flaws of the NASA study. The implications of their actions have important lessons for the conduct of science... read more.
Here is a list of main references:
  1. Wolfe-simon et al., Science, 2011
  2. Reaves et al., Science, 2012 
  3. Erb et al., Science, 2012
  4. Scientist in a strange land, Popular Science 2011
  5. Redfield on NASA's claims, RRResearch 2010
  6. Redfield's paper on arXiv, 2012

Gas-guzzling paint

I have an article published in The Economist's Babbage blog. Here's the blurb:
Armies need to be prepared for the threat of chemical weapons. Part of that preparation means being able to decontaminate people and equipment that have been subject to attack. The suits and masks worn by soldiers can, if necessary, be thrown away once used, but heavier and more expensive equipment, such as vehicles, cannot be treated in such a cavalier fashion. It needs to be cleaned. Britain’s Defence Science and Technology Laboratory, working in collaboration with AkzoNobel, a paints company, proposes to do the cleaning job with special paint... read more.
Here is a set of main references:
  1. Halabja gas attack in 1988 - BBC
  2. AkzoNobel and DSTL patent
  3. Christopher Landry's paper - J. Am. Chem. Soc. 

When waiting is not an option

I have an article published in The Economist's Babbage blog about how some patients with a terminal diseases are second-guessing pharmaceutical companies and medicating themselves. Here's the blurb:
It takes eight years on average for a drug to receive approval from America’s Food and Drug Administration (FDA) after clinical trials have been successfully completed. Some patients of amyotrophic lateral sclerosis (ALS), with a life expectancy of two to five years after diagnosis, do not want to wait that long. Since September 2011 some of those diagnosed with the fatal disease have taken to injecting themselves with a substance whose chemical identity they deduced from published literature, and which they claim is currently being clinically tested.... read more.
Here is a set of main references:
  1. Neuraltus Pharmaceuticals press release
  2. James Heywood et al. Nature Biotechnology, 2011
  3. Eric Valor's conjecture
  4. ALS Study Shows Social Media's Value as Research Tool - The Wall Street Journal
  5. Frustrated ALS Patients Concoct Their Own DrugThe Wall Street Journal
  6. PatientsLikeMe - Lithium and ALS, sodium chlorite, NP001
  7. ALS Chlorite

Is India's new antimalarial drug worth the hype?

I have an article published in Chemistry World today discussing the hype around this drug launch. I've already written about Ranbaxy's new antimalarial drug Synriam on this blog in the two previous posts, but there are a few new pieces of information in the recent article.

Here is a full set of references for the article:
  1. Ranbaxys' press release
  2. Ranbaxy's Synriam brochure
  3. Ranbaxy, Cipla unveil malaria combo drugs - DNA
  4. Daiichi to buy Ranbaxy stakes for $4.6 bn - The Financial Express
  5. Malaria deaths are down but progress remains fragile - The WHO
  6. Jonathan Vennerstrom et al. Nature 2004
  7. Jonathan Vennerstrom et al. J. Med. Chem. 2010

The story behind Ranbaxy’s new anti-malarial drug

From the previous post about Ranbaxy’s new anti-malarial drug, we know that Synriam is a fixed-dose combination of two known molecules, arterolane maleate and piperquine phosphate. The highlight of the media coverage has been to call this India’s first new drug, which isn’t entirely correct. What makes Synriam special, though, is that it is the first ever drug based on arterolane, a cheaper and better alternative to what is currently available.

Credit: InPharma
Before we look at arterolane, let’s take a quick look at malaria and anti-malarial drugs. According to a World Health Organization (WHO) report, every year 250 million new cases of malaria are reported and it causes 800,000 deaths. It is the biggest killer among the diseases that affect children less than 5-years of age. Anti-malarial drugs have existed for over 300 years, but it is only in the last century that there has been a rise in drug-resistance among the parasites responsible for the disease. This spurred research into developing new drugs and therapies.

One key finding from the increased attention that malaria received was the role of combination therapy. It was found that a judicious combination of drugs could help delay the development of resistance to drugs. To ensure that the new drugs that have been developed do not develop resistance, according to WHO guidelines, the artemisinin class of drugs must always be used in combination with other drugs. Arterolane falls in that class.

Funded by a Swiss non-profit, Medicines for Malaria Venture (MMV), arterolane (codenamed OZ277) was revealed in 2004 in a paper published in Nature. It was developed as part of a collaborative drug discovery project that consisted of researchers in the US, the UK, Switzerland and Australia. The aim of the project was to discover a new chemical entity (NCE) that could overcome the limitations of artemisinin, a widely-used antimalarial drug.

Among the many limitations of artemisinin is its price. It is produced from a plant-based source, making it an expensive solution to a poor man’s disease. Arterolane, on the other hand, can be synthesised from commercial chemicals and more cheaply (As a side, arterolane also has one of the funkiest chemical structures among drug molecules). With this molecule, MMV had achieved its goals of finding an NCE with desired qualities, but without further development through clinical trials, it would not have become a marketable drug. That is when Ranbaxy entered the scene. MMV tied up with Ranbaxy in 2003 and supported the development of the drug up until 2007.

According to LiveMint, MMV decided to stop funding the project after it reviewed preliminary data and other portfolio priorities. According to results that were presented at a conference in 2006, MMV found that results of Ranbaxy’s trials were not very satisfactory compared to other drug candidates available in the agency’s many collaborative projects. By this time, Ranbaxy had spent about $16 million. Despite losing MMV’s support, it planned to continue the development of the drug.

The IP-related issues surrounding arterolane remain unclear. In a conversation with Jonathan Vennerstrom, who led the study that was published in Nature, I was told that MMV owns the patent for arterolane (see here and here). By 2007, given that MMV had lost interest in arterolane might mean that it licensed the molecule to Ranbaxy at a low price.

Looking at the lack of confidence that MMV showed in the drug, in 2007, Ranbaxy was taking a risk by continuing research because there was no guarantee that the final clinical trials would be successful. It deserves credit to have been brave enough to plough in a further $15 million (of which $1 million came from the Department of Science Technology) to bring Synriam to the market. Whether they did that to avoid losses or because they truly believed that Synriam was going to be successful, I am not sure.

The drug is claimed to be more effective than any other drug currently available. The recommended dosage is one pill a day for three days, which is less than other for other drugs. Ranbaxy has also ensured that the price remains low at Rs. 130 for the three-day treatment. It is interesting to note that this is much cheaper than Cipla’s Mefliam Plus, which is priced at Rs. 300. Ranbaxy gets more points also because Mefliam Plus is a combination of artesunate and mefloquine, both of which are known molecules that have been used in different fixed-dose combinations previously.

Although Synriam does not qualify as ‘India’s first new drug’ (because none of its active ingredients were wholly developed in India), Ranbaxy deserves credit for being the first Indian pharmaceutical company to launch an NCE before it was launched anywhere else in the world.

This was published as a guest post on SpicyIP's blog. SpicyIP aims to be a leading repository of resources pertaining to Indian intellectual property (IP) law and policy.

Has India's new anti-malarial drug really been 'indigenously' developed?

I woke up to the news that Ranbaxy India has launched it's first indigenously developed drug: Synriam. A drug for malaria treatment, it is a combination consisting of arterolane maleate 150 mg and piperaquine phosphate 750 mg. I was pleased to hear that India's drug discovery initiatives had matured enough to produce new drugs and that the drug companies were acting very responsibly by working on a poor man's disease. Naturally, I dug into the story a little more.

Ranbaxy's press release (which is where most news sources have got their information from) claims:
  1. Synriam has been approved by Drug Controller General of India (DCGI) for marketing in India and conforms to the recommendations of the World Health Organization (WHO) for using combination therapy in malaria.
  2. Synriam has a high cure rate of 95%.
  3. Phase III clinical trials were conducted in India, Bangladesh and Thailand.
  4. Dose regimen is better than anything out there. Three pills over three days.

Arterolane's chemical structure
Credit: Wikipedia
So far so good. Out of curiosity I looked up the chemical structure of arterolane and was surprised to see that it features both an ozonide and an adamantane group in it. In all my synthetic organic chemistry work, I hadn't seen a drug like that. After all, organic ozonides (3 oxygen atoms in a 5-atom ring) are more explosive than organic peroxides (R-O-O-R)!

It turned out that Derek Lowe of the famous In the Pipeline blog had written about arterolane in 2009. At the time it was in Phase III trial, which I assumed were the trials that Ranbaxy was conducting. But it turned out that arterolane was developed by a collaboration between researchers in the US, the UK, Switzerland and Australia who were funded by the World Health Organization and Medicines for Malaria Venture (a Swiss non-profit). They published this work in Nature in 2004 and further SAR (Structure Activity Relationship) studies in J Med Chem in 2010.

So Ranbaxy did not develop the drug from scratch? But the press release quotes Arun Sawhney, CEO and Managing Director of Ranbaxy which misleads people to think so: "It is indeed gratifying to see that Ranbaxy’s scientists have been able to gift our great nation its first new drug, to treat malaria, a disease endemic to our part of the world. This is a historic day for science and technology in India as well as for the pharmaceutical industry in the country. Today, India joins the elite and exclusive club of nations of the world that have demonstrated the capability of developing a new drug".

So Ranbaxy mixes a known active compound (piperaquine) with a new compound that someone else found to be active (arterolane) and claims that they developed a new drug? In an interview in LiveMint, Sawhney says, "Ranbaxy spent around $30 million on Synriam and the contribution from DST [India's Department of Science & Technology] was Rs.5 crore. The drug went through several phases of development since the project began in 2003. We did not look at this as a commercial development. Instead, this is a CSR [Corporate Social Responsibility] venture for us." That's a give away because developing a new drug from scratch has to cost more than $30 million + Rs.50 million. Why wasn't this put in the press release?

The initial high that I got from the news that Ranbaxy launches first 'made in India' drug just got murdered. India is yet to see a drug that it has 'indigenously' developed. I am sure that Synriam will do a lot of good for India and the many developing nations that suffer from a malaria epidemic, but it will be because of a 'made in India' drug not one that has been 'developed in India'. It's a shame that Ranbaxy did not acknowledge that the development of arterolane was funded by WHO and that their scientist have worked on developing a combination of two compounds both of which weren't developed in their lab. They should make it clear that they are claiming the combination to be a 'new drug', not the molecules that make up the combination.

Like an Apple product says, "Made in China. Designed in California.", Synriam should say, "Made in India. Developed by WHO + MMV + Ranbaxy."

UPDATE: Vidya Krishnan, LiveMint reporter who covered this story, answered my question about patentability. She said that Ranbaxy has a joint patent with the Government of India for the 'unique' combination that they have developed, not for arterolane itself.

UPDATE 2: I spoke to the lead author of the Nature and J Med Chem paper Jonathan Vennerstrom who confirmed that MMV holds the patent for arterolane and has licensed it to Ranbaxy since 2003. Thus, the clinical trials mentioned in both the papers were Ranbaxy's work even though arterolane was developed by other researchers.

Oral cancer in India: A public health menace

Oral cancer is the most prevalent of all cancers in India, which sees 5.6 million cancer deaths every year. A cheap and widely available chewing tobacco product, gutka, has some 5 million children addicted to it. The government of one state in India has woken up to its ill-effects, and, in a drastic step, it has banned sale of all chewing tobacco products.

I have an article published on the Economist's Asia blog, Banyan, discussing this.

References for the article:
  1. Most cancer patients in India die without medical attention: study, Down to Earth, March 29, 2012
  2. Madhya Pradesh bans gutkha and other chewing tobacco products, Down to Earth, April 3, 2012
  3. SC bans plastic gutka sachets from March 1, Times of India, December 8, 2010
  4. Global Adult Tobacco Survey: India, World Health Organization, October 19, 2010
  5. Gutka still sold in plastic sachets, The Hindu, March 13, 2011
  6. 2011 Census Data: Madhya Pradesh, Government of India

How does epigenetics shape life?

Identical twins, despite being biologically identical at birth, grow up to become unique individuals. Sure they may have a lot more things in common than two randomly picked individuals, yet there are many characteristics which belong only to one or the other. If the twins have the exact same DNA, then what is that makes them different?

The common answer to this question is it’s the environment that they live in which shapes them differently. Researchers have found that such environmental factors cause chemical modifications to the genome without affecting the nucleotide sequence, leading to the unique characteristics that we observe. This field of research is called epigenetics, and beyond the DNA, it’s what shapes our lives.

Rat mothers nurture their pups by licking and grooming. Researchers in Canada studying epigenetic changes found that rats whose mothers licked them more than normal expressed hundreds of genes differently from those who were licked less than normal. These differences were consistent and predictable, and led to a number of behavioural changes among the rats, including one where highly licked rats’ response to stress was a lot better than the less‐licked rats’.

Epigenetic changes don’t just occur through environmental factors but are also a different form of inheritance, one that doesn’t have to suffer from the randomness of natural selection. The licking of the rat encodes specific information onto her pup’s DNA without modifying to the sequence of base pairs. Mom’s behaviour programs the pup’s DNA in a way that will make it more likely to succeed. Such information is stored in the DNA in many ways, one of which is through DNA methylation. Through this process methyl groups are attached on to the DNA, and their attachment at specific positions leads to genes being turned on or off. This makes epigenetic changes reversible. For example, you can take a low‐nutured rat, inject its brain with a drug that removes methyl groups, and make it act like a high‐nurtured rat.

DNA methylation also plays a key role in cell division and cancer cells are known to divide faster than normal cells. Researchers in the US have developed drugs to interfere with DNA methylation as a treatment for cancer. They use molecules that mimic cytosine, one of the four bases of DNA. In cell replication, the fake cytosine swaps places with real cytosine in the growing stand of DNA, which then in turn traps DNA methyltransferase. When used in low enough doses, the drug allows the formation of the cell but with less methylated DNA. These drugs are currently being used to treat myelodysplastic syndrome, a prelukemia condition.

As Brona McVittie says, like the conductor of an orchestra controls the performance of musicians, epigenetic factors govern how the cell plays the notes in DNA. A better understanding of these factors has  he potential of revolutionising evolutionary and developmental biology, thus affecting practices from medicine to agriculture.

Further reading:

  1. Learn Genetics, The University of Utah
  2. Introduction to epigenetics from Science magazine
  3. More ways to fight cancer through epigenetics, The Economist
Image credit: SciShark

In search for life through the twists of light

Finding Earth-like planets is common place now. What about detecting life on them?

Two centuries ago a French engineer noticed something special about light from the sun. As it reflected from the window and passed through a crystal of calcium carbonate, depending on the angle at which the crystal was placed, the image it created grew stronger or weaker. Étienne-Louis Malus had discovered a phenomenon called polarisation of light. The simplest example of this can be seen in the above images whereremoval of certain polarised light increases the contrast with clouds.

Sunlight is unpolarised which means that the electromagnetic waves that make up sunlight are not restricted in their spatial orientation. But when this light interacts with biological molecules like sugars, amino acids or chlorophyll it changes its spatial orientation, and, more importantly, we are able to detect the change and measure it.

This week researchers using the Very Large Telescope in Chile used this characteristic of light to show the presence of water, clouds, and vegetation in Earthshine – the sunlight that’s been reflected off of Earth to the dark portion of the Moon’s face and then back to our planet – through a method dubbed spectropolarimetry. Michael Sterzik, an astronomer at the European Southern Observatory in Santiago, Chile, said that the state of polarisation contains a lot of information that hasn’t been used very often.

Comparing their measurements of Earthshine with models of how various land and sea surfaces reflect polarised light, the researchers could discern which part of our planet was covered with oceans and which with land mass. They also identified the biosignature of chlorophyll which showed up when land masses on Earth were illuminated.

The upshot is that it might be possible to use this technique to spot the presence of water and other biological molecules on the many Earth-like planets that have been discovered recently. The techniques currently available can only detect the presence of water and other simpler molecules which is not enough to ascertain the existence of life. The occurrence of biological molecules on the other hand increases the probability of finding life by many factors.

But as these planets are usually many light years away, the light received from them is very faint. Researchers will have to wait for the next generation of telescopes, such as the European Extremely Large Telescope planned for 2022, to gather the required data. But possibly, within a decade, the twists of light will help us seal the fate of life beyond our planet.

First published on Science Oxford Online. Sterzik, M., Bagnulo, S., & Palle, E. (2012). Biosignatures as revealed by spectropolarimetry of Earthshine Nature, 483 (7387), 64-66 DOI: 10.1038/nature10778

Macromolecules from miniature templates

From my article in Chemistry World:

UK researchers have designed a new highly effective method to construct large molecules of a defined size using simple templates.Recent approaches to the construction of nanomaterials have made use of advanced methods such as living polymerisation and self-assembly, but these techniques often produce a mixture of products. Taking inspiration from nature, which uses sophisticated templates such as the ribosome to make precise complex molecules, Harry Anderson's group at the University of Oxford has developed a new strategy to synthesise macromolecules with precise lengths using basic more.

Using fruit flies' sweet tooth

From my article in Chemistry World:

Australian researchers have used fruit flies' sweet tooth to help in attempts to develop new sugar alternatives.The Drosophila melanogaster species of fruit fly has marked similarity to humans in its choice of sweeteners, a fact exploited by a team led by Anne Rae at the Commonwealth Scientific and Industrial Research Organisation in Queensland to aid the search for new sweeteners as demand for healthier sugar alternatives more.

We need all the support we can get

I rarely 'reblog' but these are powerful words from Seth's blog. They deserve your attention.
Society changes when we change what we're embarrassed about. In just fifty years, we've made it shameful to be publicly racist. In just ten years, someone who professes to not know how to use the internet is seen as a fool.

The question, then, is how long before we will be ashamed at being uninformed, at spouting pseudoscience, at believing thin propaganda? How long before it's unacceptable to take something at face value? How long before you can do your job without understanding the state of the art?

Does access to information change the expectation that if you can know, you will know?
We can argue that this will never happen, that it's human nature to be easily led in the wrong direction and to be willfully ignorant. The thing is, there are lots of things that used to be human nature, but due to culture and technology, no longer are.

Today, on the Curious Wavefunction you will find a lengthy blog post about the state of Indian science. It was written after a set of articles that appeared in last week's Science titled India Rising. In the few pages of Science there were more arguments to convince the reader about the potential of Indian Science that there were in a whole book written by Angela Saini (Geek Nation: How Indian Science is Taking Over the World). Even then, there was a lot that was left out. Ashutosh attempts fill in those gaps and points out the faults in the roots of the system that make it difficult to do great science in India.

I also have to agree to Ashutosh's prediction that the kind of transformation that Indian Science needs will take a long time, maybe 20 years or more. Seth's blog post gives me hope though. We have achieved extraordinary things in the past as a group. If we are really serious about doing something to change the state of Indian science, I know that we have the capacity to it soon. What we lack right now is the wide-spread desire to do so.

Science, funding, impact - some more questions

To allow the scientists to do good science, governments and the industry need to fund it. Not long ago I pondered why all the governments of big nations spend less than 1% of their GDP on science to which I got no satisfactory answer. Now an article in the Economist has brought interesting facts to light and raised some more interesting questions.

  • The global R&D spend in 2007 was $1.15 trillion. 45% more compared to 2002. Despite all that spending, innovation has stalled. So much so that Tyler Cowen calls this period 'The Great Stagnation'. What is wrong here?
  • In 2007, the US spent 2.7% of its GDP on R&D (GERD), produced 28% of world's publications and 41.6% of world's patents. In comparison, at the same time, the EU spent 1.8% of its GDP on R&D, produced 37% of world's publications and 26.4% of world's patents. Does that make the EU more academically oriented and the US more commercially oriented? Why? What are the factors that contribute to such big differences?
  • China has 1.5 million scientists which is equal to the sum of scientists in Europe and North America. In comparison, India, which has a population only second to China, has one-tenth the number of scientists as China. An anomaly? Is it something to do with the culture of the countries?
Credit: The Economist
Scientists have different motivations to do good science. Making an impact on the world is one of their greatest motivations. Although 'impact' can be a hard thing to define and measure, there are some methods that a scientist can rely on. Even though they aren't flawless, they are the best ways to measure we have today - number of publications, citations and patents and methods that use these base numbers to give a better idea of impact, for example, the h-index

But when figures like the one's quoted by the Economist try to measure the impact of scientists based on spending or question the cultures of different countries in the way they treat scientists, I am left to wonder how to make sense of it.

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