Wednesday, July 18, 2018

Boost in Alzheimer's Drug Success!

Introduction

Alzheimer's is a type of dementia that causes problems with memory, thinking and behavior. Symptoms usually develop slowly and get worse over time, becoming severe enough to interfere with daily tasks.
Figure 1: Older people are susceptible to Alzheimer's (fig. source: Google)
Alzheimer's is not a normal part of aging. The greatest known risk factor is increasing age, and the majority of people with Alzheimer's are 65 and older. But Alzheimer's is not just a disease of old age. Approximately 200,000 Americans under the age of 65 have younger-onset Alzheimer’s disease (also known as early-onset Alzheimer’s). Alzheimer's worsens over time. Alzheimer's is a progressive disease, where dementia symptoms gradually worsen over a number of years. In its early stages, memory loss is mild, but with late-stage Alzheimer's, individuals lose the ability to carry on a conversation and respond to their environment. Alzheimer's is the sixth leading cause of death in the United States. 

Cause of Alzheimer’s Disease

The brain has 100 billion nerve cells (neurons). Each nerve cell connects with many others to form communication networks. Groups of nerve cells have special jobs. Some are involved in thinking, learning, and remembering. Others help us see, hear and smell. To do their work, brain cells operate like tiny factories. They receive supplies, generate energy, construct equipment and get rid of waste. Cells also process and store information and communicate with other cells. Keeping everything running requires coordination as well as large amounts of fuel and oxygen.
Figure 2: Different brain morphology
Scientists believe Alzheimer's disease prevents parts of a cell's factory from running well. They are not sure where the trouble starts. But just like a real factory, backups, and breakdowns in one system cause problems in other areas. As damage spreads, cells lose their ability to do their jobs and, eventually die, causing irreversible changes in the brain.
Two abnormal structures called plaques and tangles are prime suspects in damaging and killing nerve cells. Plaques are deposits of a protein fragment called beta-amyloid (BAY-tuh AM-uh-loyd) that build up in the spaces between nerve cells. Tangles are twisted fibers of another protein called tau that builds up inside cells. Amyloid plaques are characteristic features of Alzheimer's disease (Figure 3). When amyloid plaques accumulate outside neurons, they lead to a degeneration of the affected neurons.

Quest of solution

Researchers in University laboratories and pharmaceutical companies have been trying hard for a long time to develop the medicine to treat this disease. But, sadly, there's been one glaring absence of breakthroughs in recent decades: a drug to treat Alzheimer’s Disease! The search for a drug to treat dementia has been one of modern medicine's greatest frustrations: a 99.6 percent failure rate.
Figure 3: Amyloid Plaque
On July 5, 2018, Biogen (a pharmaceutical company based in Boston, MA, USA) in collaboration with Eisai (a Japan-based company) reported “statistically significant” evidence that the drug, BAN2401, an antibody targeting the beta-amyloid protein, can slow progression of the deadly disease. This was a great news! Eventually, Biogen enjoyed a big jump in its stock price after releasing positive news. July 5 is our wedding anniversary day. We were relaxing and a news popped on my phone and Sijan and me were overwhelmed with this news as our lab was working on this very disease.
The beta amyloid protein has long been hypothesized as the primary cause of Alzheimer’s, and as a result, the target of a majority of drug trials. Removing amyloid oligomers does lessen oxidative stress which may lead to a slower progression of Alzheimer's disease early on. It's the first time a drug has shown the ability to clear the amyloid plaque and more importantly that the clearance of plaque was associated with a slowdown of the cognitive decline.

References: 
1. Alzheimer's Association
2. Biogen (www.biogen.com) 
3. CNBC News 

Sunday, June 17, 2018

Molecular Mechanics that Drives Animals to Sleep

For a long time, a simplistic idea to know the mechanism that drives us to sleep with the amount of sleep we banked the night before had been unknown. Recently, researchers working in Japan, China, and the USA centred at Japan's University of Tsukuba find that a group of phosphoproteins accumulates when animals are awake and dissipates during sleep. This research work was carried out in mice. They described how sleep and wake have global effects on brain, from measuring the electrical voltage changes of the brain to explore brain waves during sleep, down to the effects on the single neuron, to how sleep changes communication between brain cells, and the global expression of genes in the brain.

The study was published in Nature describes how phosphorylation of just 80 proteins in the brain induce the need to sleep. What’s more, they show that these proteins are typically associated with synapses, the junctions between brain cells where cellular communication takes place. Naming these proteins, ‘sleep-need-index phosphoproteins’ (SNIPPs), they describe how the level of phosphorylation of these SNIPPs forms a molecular signature for the drive to sleep. 

They go on to describe how a mutant protein called SLEEPY preferentially associates with SNIPPs. It was found that the inhibition of the activity of SLEEPY and its normal variant in mice reduced phosphorylation of SNIPPS and reduced the drive to sleep. The researchers claim that this reduction in sleep drive was so powerful it also worked in sleep-deprived mice.

Their elaborated research work suggests that phosphorylating and dephosphorylating SNIPPs presents a major regulatory mechanism by which sleep homeostasis is achieved. Increasing phosphorylation of SNIPPs increases the drive to sleep, and SNIPP dephosphorylation decreases sleep drive. 

Study of the mechanisms that regulate circadian rhythms and sleep homeostasis at the level of protein phosphorylation is important. Findings from studies like this will not only inform our understanding of sleep/wake cycles but also shed light on the how brain physiology is affected throughout the 24-hour period, and could greatly influence human health. 

At last, this important finding exhibits that modulating SNIPP phosphorylation will be a viable therapeutic angle for treating insomnia or jetlag or mediating the health effects of shift work.


References:
1.
Wang, Z. et al. Quantitative phosphoproteomic analysis of the molecular substrates of sleep need, Nature(June 2018 issue) 
2. Funato, H. et al. Forward-genetics analysis of sleep in randomly mutagenized mice. Nature 539, 378–383 (2016)


Thursday, January 18, 2018

Top Five Chemistry Inventions: Avenue for Modern World

Chemistry, well-known as the central science, a creative tributary of science involves the study of the composition, structure, and properties of matter. There are numerous inventions till this date in chemistry and this exercise will not end until the last day of the earth! Actually, Chemistry is the vital part of every living creatures. What they eat to what they wear is the boon of chemistry. Yet, it turns out that most people just don’t have a good idea of what chemists do, or how chemistry contributes to the modern world. Few people know that the discovery of ammonia was the single most important reason for the world’s population explosion from 1.6 billion in 1900 to 7 billion today! Or that polythene, the world’s most common plastic, was accidentally invented twice!
Here, I will reveal, in chronological order, the most significant discoveries made so far that changed the lifestyle of human beings.
                    1. The Haber-Bosch Process of Synthesis of Ammonia
Fritz Haber and Carl Bosch
Picture from Google
Nitrogen the most common gas in our atmosphere and plays a critical role in the biochemistry of every living thing. But plants and animals can’t extract it from the air as this gas doesn’t like reacting with very much. Consequently, a major limiting factor in agriculture has been the availability of nitrogen. In 1910, German chemists Fritz Haber and Carl Bosch changed all this when they combined atmospheric nitrogen and hydrogen into ammonia. This, in turn, can be used as crop fertilizer, eventually filtering up the food chain to us. Today about 80% of the nitrogen in our bodies comes from the Haber-Bosch process, making this single chemical reaction probably the most important factor in the population explosion of the past 100 years.

                   2. Discovery of Penicillin
Before the discovery of antibiotics, a prick from a thorn or a sore throat could have easily turned fatal. In 1928, Alexander Fleming observed how a mold growing on his Petri dishes suppressed the growth of nearby bacteria. But he failed to extract any usable penicillin. In 1939, Australian pharmacologist Howard Florey and his team of chemists figured out a way of purifying penicillin in usable quantities.

Alexander Fleming
Picture from Google
As World War II was raging at this time, scientific equipment was in short supply. There were thousands of wounded military persons and common people seeking a medicine to cure their wounds. Thank God! penicillin saved their life. By seeing the miracle of penicillin, the team cobbled together a totally functional penicillin production plant from bathtubs, milk churns and bookshelves. Not surprisingly the media were extremely excited about this new wonder drug, but Florey and his colleagues were rather shy of publicity. Instead, Fleming took the limelight.

Full-scale production of penicillin took off in 1944 when the chemical engineer Margaret Hutchinson Rousseau took Florey’s Heath Robinson-esque design and converted it into a full-scale production plant.

            3Discovery of Progesterone
In the 1930s, physicians had realized the potential use of hormone-based therapies to treat cancers, menstrual disorders and of course, for contraception. But research and treatments were held back by massively time-consuming and inefficient methods for synthesizing hormones.

Progesterone
Back then progesterone cost the equivalent (in today’s prices) of $1,000 per gram while now the same amount can be bought for just a few dollars. Russel Marker, a professor of organic chemistry at Pennsylvania State University, slashed the costs of producing progesterone by discovering a simple shortcut in the synthetic pathway. He went scavenging for plants with progesterone-like molecules and stumbled upon a Mexican yam. From this root vegetable, he isolated a compound that took one simple step to convert into progesterone for the first contraceptive pill.

               4. Discovery of Polyethylene - the common plastic
Polyethylene or polythene is the most common plastic. The annual global production is around 80 million tonnes. Its primary use is in packaging. Most common plastic objects, from water pipes to food packaging and hardhats, are forms of polythene. The 80 million tones of the stuff that is made each year is the result of two accidental discoveries.

Hans von Pechmann
Picture from Google
The first occurred in 1898 when German chemist Hans von Pechmann, while investigating something quite different, noticed a waxy substance at the bottom of his tubes. Along with his colleagues, he investigated and discovered that it was made up of very long molecular chains which they termed polymethylene. The method they used to make their plastic wasn’t particularly practical, so much like the penicillin story, no progress was made for some considerable time.

Then in 1933, an entirely different method for making the plastic was discovered by chemists at, the now defunct chemical company, ICI. They were working on high-pressure reactions and noticed the same waxy substance as von Pechmann. At first, they failed to reproduce the effect until they noticed that in the original reaction oxygen had leaked into the system. Two years later ICI had turned this serendipitous discovery into a practical method for producing the common plastic that’s almost certainly within easy reach of you now.

 

                5. The Discovery of Liquid Crystal - the screen you are reading on
Liquid crystal
Plans for a flat-screen color display date back to late 1960  when the British Ministry of Defense decided that it wanted flat-screens to replace bulky and expensive cathode ray tubes in its military vehicles. It settled on an idea based on liquid crystals. It was already known that liquid crystal displays (LCDs) were possible, the problem was that they only really worked at high temperatures. So not much good unless you are sitting in an oven.


Phone Screen uses liquid crystal
In 1970 the MoD commissioned George Gray at the University of Hull to work on a way to make LCDs function at more pleasant (and useful) temperatures. He did just that when he invented a molecule known as 5CB. By the late 1970s and early 1980s, 90% of the LCD devices in the world contained 5CB and you’ll still find it in the likes of cheap watches and calculator. Meanwhile, derivates of 5CB make the phones, computers, and TVs possible.











Reference:
1. The Conversation Edition, June 1, 2015
2. Google.com., January 18, 2018