chemistry – Page 4 – Akshat Rathi

The magical role of the doormen

October 10, 2012January 10, 2014 Akshat Rathi2 Comments

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.

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.

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:

Rasmussen et al, Nature, 2007
Buchen, Nature, 2011
Sansom, Chemistry World, 2010

Image from here.

A bigger bang

September 13, 2012December 22, 2013 Akshat RathiLeave a comment

A new hybrid explosive is safer to handle but still powerful

Modern warfare involves plenty of new technology, from pilotless drones to powerful computer networks and satellite sensors. But the explosives which are used in battle were invented a long time ago. The two most commonly deployed belong to a class of organic chemicals called nitramines. One, RDX, is also widely used in industrial applications like mining and demolishing buildings. Its use as an explosive began in the 1920s. HMX, a related compound and one of the most powerful explosives, dates back to the second world war. Both are sometimes used with trinitrotoluene, a different type of compound more commonly known as TNT. It is over 100 years old.

A good explosive needs to be extremely powerful but not too sensitive to avoid its being detonated accidentally, such as by dropping it. These can be conflicting properties. As Alex Contini of the Centre for Defence Chemistry at Cranfield University in Britain points out, explosives developed in recent years are either too sensitive or too expensive for large-scale use.

One such explosive is CL-20. This was developed by the American navy as a rocket propellant, a substance which involves the sudden release of energy by rapid oxidisation, in effect a controlled explosion. CL-20 is more powerful than RDX and HMX, but its higher sensitivity means that it also explodes more easily.

The most common way to desensitise an explosive is by mixing it with a non-explosive material, such as wax or paper. Although that works, it also reduces the amount of bang you get. What if the desensitising material is itself an explosive of lower sensitivity? The problem is that the resulting material is as sensitive as its most sensitive component.

Adam Matzger of the University of Michigan and his colleagues have discovered a way around that problem by using a process called co-crystallisation, which is commonly used by drugmakers to modify the physical properties of a pharmaceutical. They report in Crystal Growth & Design that by mixing CL-20 in such a way they have been able to lower its sensitivity but retain most of its explosive power.

At the heart of the process is the formation of crystals, an ability endowed to some materials by nature. Crystals are the result of molecules arranging themselves in a regular pattern extending in all three dimensions. Sometimes two crystalline materials that do not react with each other can be mixed to form a so-called co-crystal. To do that they are both dissolved in a common solvent, then left alone to crystallise together. Because the arrangement of molecules within the co-crystal is very different from the original crystal, it modifies the physical properties of the material—in this case CL-20’s sensitivity.

Dr Matzger made a co-crystal consisting of two parts of CL-20 and one part HMX. The hybrid explosive has nearly the same explosive power as CL-20 but the lower sensitivity of HMX. Because the process of crystallisation can be scaled up relatively easily, Dr Matzger, whose work was funded by America’s Defence Threat Reduction Agency, thinks this new explosive could make a bigger bang soon.

First published in The Economist. Also available in audio here.

References:

Matzger et al, Crystal Growth & Design, 2012
Matzger et al, Angew Chem Int Ed, 2009

List of references here. Free image from stock.xchng.

How does epigenetics shape life?

April 17, 2012January 10, 2014 Akshat RathiLeave a comment

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 the potential of revolutionising evolutionary and developmental biology, thus affecting practices from medicine to agriculture.