Almost half of world’s adults aged 85 and over have Alzheimer’s Disease.
The amyloid-B precursor protein (APP) plays a key role in the development of the amyloid plaques that are the hallmark of Alzheimer’s disease. Now, researchers claim to have identified thousands of genetic variants of the APP gene that codes for the protein in the brains of patients with the most common form of Alzheimer’s disease, known as late-onset or sporadic AD (SAD).
The study reveals for the first time how this genetic variation occurs – by a mechanism involving the enzyme reverse transcriptase, the same type of enzyme used by HIV to infect cells.
APP forms plaques in the brain, as shown above in a light micrograph.
Our findings provide a scientific rationale for immediate clinical evaluations of HIV antiretroviral therapies in people with AD,’ says Jerold Chun, senior VP of Neuroscience Drug Discovery at Sanford Burnham Prebys Medical Discovery Unit (SBP), an idea that the researchers say is supported by the relative absence of proven AD in ageing HIV patients on antiretroviral medication.
The APP gene variants were created by reverse transcription, the researchers note, when RNA acts as a template to form complementary DNA sequences that are then reinserted back into the original genome.
Discovery of possible Alzheimer’s treatment. Video: Sanford Burnham Prebys Medical Discovery Institute
This process of gene recombination – which occurs each time cells divide to make new ones – has not previously been reported in nerve cells (neurons) in the brain but could also help to explain the complexity and diverse functions of our brain cells.
Microscopic membranous vesicles floating outside of cells were first discovered 50 years ago; 30 years later, a subset of these was coined exosomes. At the time, these membrane bubbles were believed to be nothing more than a cellular waste disposal mechanism. But within the past decade, extracellular vesicles – and exosomes in particular – have piqued scientists’ interests, resulting in a research boom.
In 2006, there were just 115 publications referencing exosomes; by 2015, this number had mushroomed to 1010. Today, a PubMed search brings up more than 7500 publications. Consulting firm Grand View Research estimates that the global exosome market could reach $2.28bn by 2030.
Advancements in exosome research could lead to breakthroughs in prostate cancer treatment.
The interest in exosomes has been driven by the new finding that exosomes are more than just a waste disposal system – they are also a means of communication between cells and have the ability to carry cargos such as proteins and mRNA, suggesting there could be potential medical applications.
‘Currently, research into exosomes and other extracellular vesicles is very strong,’ says Jason Webber, Prostate Cancer UK research fellow in the Division of Cancer and Genetics at Cardiff University. ‘I think this field of research will continue to grow and I believe we’ll also see greater clinical application of exosomes and a drive towards research exploring the therapeutic potential of exosomes.’
Exosomes in Cancer Research. Video: Thermo Fisher Scientific
Exosomes are best described as extracellular vescles – essentially membrane sacs – formed by the inward budding of the membrane of intracellular compartments known as multivesicular bodies (MVBs) or multivesicular endosomes (MVEs). They are released from cells when MVBs fuse with the cell’s plasma membrane, releasing its contents outside the cell. These vesicles, made of a phospholipid bilayer and ranging between 40nm and 150nm in diameter, are found in all biological fluids including blood, urine, saliva, bile, semen and breast milk.
Around 700,000 people worldwide die every year from bacteria that have developed resistance to antibiotics. In the UK alone, that figure is at least 12,000 – more deaths than from breast cancer. And those numbers look set to rise even higher.
‘It’s not just the fact that resistance is increasing – that’s inevitable,’ says Nick Brown, Director of advocacy group, Antibiotic Action. ‘The issue is more the rate of increase in resistance, which appears to be accelerating.’
The Infectious Diseases Society of America recently reported resistance to drugs within six months of antibiotics coming onto the market, and in some cases, even before the drug goes on the market. Many bacterial strains are increasingly displaying resistance to combinations of commonly used and last-resort antibiotics.
Of 33 antibiotics in development targeting priority pathogens, just nine belong to five new antibiotic classes. Image: Public Domain Pictures
‘The end of the antibiotic era isn’t on the horizon just yet,’ Brown says. ‘But we can see it wouldn’t take much to get that way.’
Failure to tackle antibiotic-resistant superbugs could result in 10m deaths a year by 2050, according to the UK government-commissioned Review on Antimicrobial Resistance. The UN and G20 have both made political commitments to combat the problem. Nevertheless, time is running out.
‘This is an urgent and rapidly rising global health problem,’ says Ghada Zoubiane, science lead for the Wellcome Trusts’ drug-resistant infections team. ‘We need greater investment in developing new ways to treat and protect people from these deadly infections and we need better understanding of how resistance spreads.’
What causes antibiotic resistance? Video: TED-Ed
Despite calls for increased R&D, no new classes of antibiotics have been approved since the early 1980s, apart from the approval of linezolid in 2000, and the last new class to treat Gram-negative bacteria was discovered in 1962, Zoubiane says.
Big pharma withdrew en masse from the antibiotic space in the 1990s, due to the low returns on the high level of investment required in antibiotic R&D. Recognising the urgency of the problem, however, in January 2016 more than 90 pharma and biotech companies committed to enhancing antibiotic discovery.
The move has been accompanied by more research into understanding resistance mechanisms, as well as a shift to more outside-of-the-box thinking about alternative treatments.
In 2016, over $500m was invested into research into antibiotic resistance. Image: PxHere
In February 2017, the World Health Organization (WHO) published its list of 12 antibiotic-resistant ‘priority pathogens’ that pose the greatest threat to human health. Most notable are the Gram-negative bacteria, which possess an additional outer cell membrane and are harder to treat with antibiotics than Gram-positive bacteria.
‘These bacteria have been assessed as the most critical priority for antibiotic R&D, as strains are emerging worldwide that cannot be treated with any of the antibiotics currently on the market,’ WHO says.
Despite the increased commitment to R&D, however, a WHO report in September 2017 lamented the ‘serious lack of new antibiotics under development’. Among the 33 new chemical entity antibiotics in development targeting priority pathogens, just nine belong to five new antibiotic classes.
There are 16 products, both antibiotics and biologics, with activity against one or more Gram-positive priority pathogens – although mostly targeting methicillin-resistant Staphylococcus aureus (MRSA) – including two new antibiotic classes.
Meanwhile, ‘the situation is worse for Gram-negative bacterial infections’, says WHO. Of ten products in Phase 1 trials, ‘almost all the agents are modifications of existing antibiotic classes […] active only against specific pathogens or a limited subset of resistant strains’.
The 2016 Lister Memorial Lecture: Dame Sally Davies on Global antiiotic resistance. Video: SCI
WHO warns that ‘more investment is needed in basic science, drug discovery and clinical development, especially for the critical priority Gram-negative carbapenem-resistant pathogens P. aeruginosa, A. baumannii, and Enterobacteriaceae.’
‘We need to find a strategy not to overcome resistance, but to be able to live with and manage it,’ Brown reflects. ‘I’m more optimistic than some. It’s important to remember that before antibiotics were discovered, the human race didn’t die out.’
Antimicrobial drug discovery
The US is in the midst of a healthcare epidemic. Tens of thousands of people are dying each year from opioid drugs, including overdoses from prescription painkillers such as OxiContin (oxycodone) and the illicit street drug heroin, and each year the numbers rise.
The opioid epidemic is currently killing almost twice as many people as shootings or motor vehicle accidents, with overdoses quadrupling since 1999. According to Gary Franklin, medical director of the Washington State Department of Labour and Industries and a professor of health at the University of Washington, the opioid epidemic is ‘the worst man-made epidemic in modern medical history in the US’.
Montgomery, Ohio, is at the centre of the epidemic, with the most opioid-related deaths per capita this year. Image: Wikimedia Commons
Incredibly, an influx of synthetic opioids is making the problem worse. Fentanyl, a licensed drug to treat severe pain, is increasingly turning up on the street as illicit fentanyl, often mixed with heroin. According to the NCHS, fentanyl and synthetic opioids are blamed for 20,145 of the 64,070 overdose deaths in 2016. Heroin contributed to 15,446 deaths, while prescription opioids caused 14,427.
Fentanyl (C22H28N20), a lipophilic phenylpiperidine opioid agonist, is generally formulated as a transdermal patch, lollipop and dissolving tablet. Like the opioids derived from opium poppies, such as morphine, fentanyl binds to opioid receptors in the brain and other organs of the body, specifically the mu-receptor.
Heroin and other opioids come from the opium poppy. Image: Max Pixel
Such binding mimics the effects of endogenous opiates (endorphins), creating an analgesic effect, as well as a sense of well-being when the chemical binds to receptors in the rewards region in the brain. Drowsiness and respiratory depression are other effects, which can lead to death from an overdose.
Rise of illicit fentanyl
The opioid epidemic can be traced back to the 1990s when pharmaceutical companies began producing a new range of opioid painkillers, including oxycodone, touting them as less prone to abuse. In addition, prescribing rules were relaxed, while advocates championed the right to freedom from pain. Soon, opioids were being prescribed at alarming rates and increasing numbers of patients were becoming hooked.
Why is there an opioid crisis? Video: SciShow
Franklin, who was the first person to report in 2006 on the growing death rate from prescribed opioids, says: ‘OxyContin is only a few atoms different to heroin – I call it pharmaceutical heroin.’
A crackdown on prescribing was inevitable. But then, with a shortage of prescription opioids, addicts turned to illicit – and cheaper – heroin. According to Franklin, 60% of heroin users became addicted via a prescribed opioid. ‘You don’t have to take these drugs for very long before it’s very hard to get off,’ he says: ‘Just days to weeks.’ Heroin use soared and with it increased tolerance, leading users to seek out more potent highs. By 2013, there were almost 2m Americans struggling with an opioid-use disorder.
Drugs to fight drugs
President Trump declared the opioid crisis a public health emergency in October. Image: Pixabay
Attention is finally being given to the epidemic. US president Donald Trump recently declared a public health emergency, although no new funds will be assigned to deal with the crisis.
There is particular interest around research into a vaccine against fentanyl. Developed by Kim Janda at The Scripps Research Institute, California, US, the vaccine, which has only been tested in rodents, can protect against six different fentanyl analogues, even at lethal doses. ‘What we see with the epidemic, is the need to find alternatives that can work in conjunction with what is used right now,’ he says.
This vaccine could treat heroin addiction. Video: Seeker
The vaccine works by taking advantage of the body’s immune system to block fentanyl from reaching the brain. Its magic ingredient is a molecule that mimics fentanyl’s core structure, meaning the vaccine trains the immune system to recognise the drug and produce antibodies in its presence. These antibodies bind to fentanyl when someone takes the drug, which stops it from reaching the brain and creating the ‘high’.