Building a molecular lego to fight malaria and TB
We need newer methods and drugs to kill these pathogens mycobacterium tuberculosis and plasmodium falciparum.
Tuberculosis and malaria are the most prevalent diseases that kill mankind today. Currently available methods and drugs are unable to stem the tide. This is why governments, the Gates Foundation, Wellcome Trust and others are investing large sums to find ways to stop or reduce their prevalence and to help develop new methods and molecules as drugs.
The battle between these pathogens and people is a colossal one. We need newer methods and drugs to kill these pathogens mycobacterium tuberculosis (Mtb) and plasmodium falciparum (and p. vivax). And the battle is literally mind over mutations. The human mind has continuously attempted to devise novel molecules as drugs such as the fluoroquinolones, rifampicin, and artemisinin. On the other side, even though large numbers are killed by these drugs, an occasional outlier bug which does not succumb to the drug, thanks to a random “error” in its genetic sequence (mutation), survives and reproduces more of itself. Pretty soon, this drug-resistant mutant propagates to become the main strain, and the thoughtfully crafted drug is no longer effective.
It is also a battle of time scale. While we take years to create effective drugs and distribute them for everyday use, microbes take just hours and days to reproduce and propagate to billions in months. While the TB strains of just a few years ago could not survive rifampicin (which blocks the bug’s RNA making machinery, thus stopping its growth), today’s strains have evolved to find alternate paths to carry on. Similarly, with malaria, while artemisinin (the wonder drug of yesteryears) acts on the blood ingested by the parasite, “burns” it through oxidative stress and thus kills the pathogen, today’splasmodium strains have evolved with a mechanism to detoxify this oxidative stress and become artemisinin-resistant. We are thus facing hosts of multi-drug-resistant pathogens infecting us.
It is against this background that some new ideas have come about which could hopefully side-step this resistance issue. Note that the earlier drugs act on the pathogen after it enters the target cells in the body — be it blood, liver or elsewhere — and use the host machinery to grow and multiply. What if we stop the entry itself? Would that would stop the pathogen on its track and thus stop the infection?
Some minds have been thinking such a thought and carried out research towards this idea. The most recent one, published two weeks ago (on Pongal Day, 14-1-2015) in the journal Nature Communications is by Drs. Anand Ranganathan, Pawan Malhotra and their colleagues at the International Centre for Genetic Engineering and Biotechnology, and All India Institute of Medical Sciences, both in New Delhi, India (6:6049/DOI:10.1038/ncomms7049/www.nature.com/naurecommunications).
The group has capitalised on the idea that some molecules on the surface of cells, termed intercellular adhesion molecules (ICAMs, which are part of the immunoglobulin super-family) act as sentries, regulating the entry and adhesion of other cells, native or foreign. The molecule ICAM-1 is seen on various cell types, notably macrophages (a type of white blood cells that ingests foreign material). ICAM-4, on the other hand, is restricted to the surface of red blood cells. One can thus see that while ICAM-1 would regulate the entry and invasion by Mtb into macrophages, ICAM-4 would regulate malaria parasites likewise.
If only we could discover or invent a decoy molecule that sits at this gate, blocking the entry of Mtb, we could overcome infection by this deadly pathogen. Likewise, if we can block the entry and invasion byplasmodium into red blood cells, using a decoy molecule that binds to ICAM-4, we would have a drug against malaria. Note too that these decoys do not work after the event (like the drugs above do), but deny the unwelcome visitor the ‘visa’ to enter and do damage.
Molecular Lego pieces
To this end, the Delhi group decided to work on a novel idea that Dr Anand Ranganathan had come up with a decade ago, which he calls the “codon shuffling method” of making small protein molecules (seeJ. Biol. Chem. 280: 23605, 2005). This involves the use of a series of properly chosen “DNA Bricks”, each 6 bases long (two codons-long, for the cognosenti), linking them together to various lengths to produce a ‘library’ of peptide/protein molecules of various sizes and predictable shapes. This is an easy and crafty way, using these DNA bricks, to make a whole host of mini-proteins as potential drugs.
They next tested to see which members of the above library interact with ICAM-1 and with ICAM-4. Happily enough, a large peptide named M5 was found to bind strongly to both ICAM-1 and ICAM-4. They next challenged Mtb with macrophages in the presence of M5. While Mtb infects control samples efficiently, the rate dropped by 80 per cent in the M5-added samples. Likewise, when added to red blood cells, infection by the malaria parasite dropped by 80 per cent.
Actually, the codon-shuffling approach is more general and extendable to fight other pathogens too. And this approach is quite akin to Lego, the toy game with interlocking plastic bricks, which can be put together to make models of objects like buildings. While Lego is a game of pleasure, this molecular Lego opens the door for drug discovery.
Ebola vaccine safe, generates immune response, shows trial
The first trial results of Ebola vaccine at Oxford University suggest the vaccine has an acceptable safety profile and is able to generate an immune response.
“The Ebola vaccine was well tolerated. Its safety profile is pretty much as we had hoped,” said professor Adrian Hill of the Jenner Institute at Oxford University who led the trial.
The results suggest that the vaccine is suitable for further testing in West Africa during the current outbreak.
The Ebola vaccine is being co-developed by the US National Institutes of Health (NIH) and pharmaceutical firm GlaxoSmithKline (GSK) against the Zaire strain of Ebola, which is the one circulating in West Africa.
The first doses for use in large scale trials in West Africa have been delivered to Liberia by GSK.
The vaccine uses a single Ebola virus gene in a chimpanzee adenovirus to generate an immune response.
As it does not contain infectious Ebola virus material, it cannot cause a person who is vaccinated to become infected with Ebola.
During the trial, 60 healthy volunteers were vaccinated at the Jenner Institute.
The results showed safety data and immune responses for the volunteers for 28 days after immunisation.
Two people experienced a moderate fever within 24 hours of receiving the vaccine but this passed within a day.
“People typically experienced mild symptoms that lasted for one or maybe two days, such as pain or reddening at the injection site, and occasionally people felt feverish,” professor Hill explained.
The primary goal of the trial was to assess safety. However, the scientists also assessed immune responses to Ebola seen in the volunteers before and after vaccination.
Importantly, the vaccine generated immune responses against Ebola in the volunteers.
Levels of antibodies increased over a period of 28 days after vaccination and there was no significant difference in the levels seen at different doses.
Levels of T cells — cellular immunity is the other arm of the body’s immune system — peaked at 14 days.
“Larger trials in West Africa are needed to tell whether immune responses are large enough to protect against Ebola infection and disease,” the team added.
The Oxford University trial is one of several safety trials of the GSK/NIH vaccine candidate — in the USA, Britain, Mali and Switzerland — that have been fast-tracked in response to the Ebola outbreak in West Africa.
The Oxford University scientists have also begun testing the safety of a candidate booster vaccine against Ebola, to find out whether it could further increase the immune responses.
According to the World Health Organisation (WHO), the Ebola outbreak in West Africa has killed over 8,000 people so far.
The initial findings were published in the New England Journal of Medicine (NEJM).
Affordable swine flu vaccine that never made it
The death of over 30 persons in two months and a spate of swine flu cases have forced the public in Hyderabad to go for vaccine shots by spending anywhere between Rs. 450 and Rs. 1,000 per shot. Those who can afford are able to access the vaccine, but the vast majority who can’t are anxious about the safety of their near and dear ones.
Ironically, do you know that the swine flu vaccine could have been made available for just Rs. 100 in Hyderabad? Could the lives of over 30 people lost been saved if governments, both Centre and State, promoted indigenous flu vaccine?
CMD, Bharat Biotech, Dr. Krishna Ella says the deaths could have been prevented. “Authorities effectively killed the Indian swine flu vaccine after promoting it initially. They backed out leaving millions of unsold swine flu vaccines in 2010-11. We could have offered a better version of H1N1 vaccine for just Rs. 100 and lives could have been saved,” he rues.
At present, H1N1 vaccines being given in Hyderabad are imported. Ironically, the cell culture vaccine of Bharat Biotech was manufactured at Genome Valley in Hyderabad in 2010-11. “The GOI had given three Indian pharma companies nearly Rs. 10 crore to manufacture affordable vaccine when swine flu was at its peak and people were dying. Later, they pulled the plug and we even returned the money,” he said.
Along with Bharat Bio-tech, Serum Institute, Pune and Panacea Biotech, New Delhi were to produce indigenous swine flu vaccine. However, after the peak of 2009 and 2010, the cases of swine flu cases started to dip and the need for a vaccine was not felt, doctors privy to the issue said. In 2010-11, millions of doses of indigenous H1N1 vaccines were destroyed because there were no takers. They were produced in the hope that government agencies would stock them for health care workers and public would get vaccinated for prevention.
“Look what’s happening now. Swine flu cases are going up, there is loss of life and winter will be long in North India. We could have saved lives. Decision makers should have vision,” he added.
Indian companies could have made shots available for Rs. 100 had the government encouraged them
Experts give tips to keep swine flu at bay
While there was no need for people to get panicky about swine flu, there was every need for them to be cautious, experts said.
Chairman of a corporate hospital Y. Ramesh Babu said that those suffering from cough and cold should not cough or sneeze in the open.
Tissue paper
They should have a handkerchief, tissue paper was even better because it could be disposed of safely. He said that only 0.1 per cent of the persons infected by swine flu faced situations that were life threatening.
Pulmonologist with a corporate hospital M.S. Gopalakrishna said that persons infected by swine flu were contagious for seven days and H1N1 virus was active for two hours in the droplets that are sneezed or coughed out by a patient.
Three categories
He said those infected by swine flu could be classified into three categories. ‘A’ category patients with mild fever, cough, sour throat, body and headache, diarrhoea and vomiting should be treated symptomatically.
Home isolation
‘B’ category patients with high grade fever and severe sour throats along with all the other symptoms of ‘A’ category patients required home isolation and treatment with Oseltamivir (Tamiflu).
‘C’ category patients with all the above symptoms combined with breathlessness, chest pain, bluish discolouration of nails, etc. should be hospitalised. Specialist in Internal Medicine C. Padma who worked in the USA when swine flu became a pandemic (2009) said only patients who required hospitalisation need to be tested for swine flu.
A corporate hospital managing director and specialist in critical care Padma Movva said all suspected cases of swine flu were being treated with Oseltamivir, because facilities for detecting the specific flu was not available in Vijayawada.
Early treatment better
The earlier treatment was started with the specific anti-viral, better the results, she said.
Ancient star with five Earth size planets discovered
After analysing over four years of data from NASA’s Kepler spacecraft, a team of astronomers has discovered a star that is 11.2 billion years old and has at least five Earth-size planets.
“The findings show that Earth-size planets have formed throughout most of the universe’s 13.8-billion-year history, leaving open the possibility for the existence of ancient life in the galaxy,” said Tiago Campante, research fellow at the University of Birmingham who led the research project.
The paper describes Kepler-444, a star that is 25 percent smaller than our Sun and is 117 light years from Earth.
The star’s five known planets have sizes that fall between Mercury and Venus.
Those planets are so close to their star that they complete their orbits in fewer than 10 days.
At that distance, they are all much hotter than Mercury and are not habitable.
“Kepler-444 is very bright and can be easily seen with binoculars. This is one of the oldest systems in the galaxy,” added Steve Kawaler, an Iowa State University professor of physics and astronomy who is also the co-author of the paper.
Kepler-444 came from the first generation of stars.
“This system tells us that planets were forming around stars nearly seven billion years before our own solar system,” Kawaler noted.
Planetary systems around stars have been a common feature of our galaxy for a long, long time.
That discovery is going to help astronomers learn even more about the history of the Milky Way.
“From the first rocky exoplanets to the discovery of an Earth-size planet orbiting another star in its habitable zone, we are now getting first glimpses of the variety of Galactic environments conducive to the formation of these small worlds,” the astronomers wrote.
As a result, the path toward a more complete understanding of early planet formation in the Galaxy starts unfolding before us, they concluded in the paper that appeared in the Astrophysical Journal.
Of Darwin’s line, the professor has a poser on development
Are social movements anti-development? Or do they exemplify the real essence of the term?
Is equitable distribution of natural resources the real meaning of development? Or was it the exhaustion of such resources through rapid industrialisation? These were the questions posed by prominent anthropologist Felix Padel, who is a descendent of evolutionary biologist Charles Darwin.
Dr. Padel, who was delivering a lecture on What is Real Development – Balancing Ecology and Economy at Osmania University’s Department of Political Science said that many social movements in India and other countries were resisting the takeover of land and resources, orchestrated through foreign investment. Such movements were generally led by marginalised groups and women.
He sought to know if these movements were anti-development or did they represent the real essence of the term. Real development, he felt, was the proper sharing of resources to guarantee proper access to everyone for food, water, justice and health care.
Prof. G. Krishna Reddy, co-ordinatora the department’s Centre for Advanced Studies said Dr. Felix, who has published extensively on tribal issues, will be delivering a series of lectures.
New primitive human species discovered?
Researchers have identified the first known prehistoric human from Taiwan which may represent an entirely new species that lived as recently as 10,000 years ago. The newly discovered big-toothed human, “Penghu 1,” might have co-existed and even interbred with our species.
The discovery supports the growing body of evidence that Homo sapiens was not the only species from our genus living in Europe and Asia between 200,000 and 10,000 years ago.
“The available evidence at least does not exclude the possibility that they survived until the appearance of Homo sapiens in the region, and it is tempting to speculate about their possible contact,” co-author Yousuke Kaifu told ‘Discovery News’.
Dr. Kaifu is an associate professor in the Department of Biological Sciences at The University of Tokyo. Dr. Kaifu, lead author Chun-Hsiang Chang, and their team studied the remains of the new human — a jawbone with big teeth still in it, dredged up off the coast of Taiwan in Penghu channel.
Chang and his team said Penghu 1 could represent a new human species or a regional group of Homo erectus, also known as “Upright Man.” He and his colleagues believe that, due to its size, the jawbone came from an adult individual and possibly a senior, because its teeth are worn severely.
Jawbone’s size
The jawbone’s size further reveals that Penghu 1 was not a dwarf, unlike tiny Homo floresiensis, which lived on the island of Flores, Indonesia, where other animals were also smaller than usual.
Penghu 1, instead, lived on what was then mainland Asia in an ecosystem that included many other animals.
While Penghu 1’s precise identity remains a mystery for now, researchers are sure that this big-toothed human was not a member of our species.
Fossil finds push back snake origins
The oldest found in Oxford is of a 25-cm reptile that lived 167 million years ago
Snakes have been slithering on Earth far longer than anyone ever realised.
Scientists on Tuesday described the four oldest-known snake fossils, the most ancient of which was a roughly 25-cm reptile called Eophis underwoodiunearthed in a quarry near Oxford, England, that lived about 167 million years ago.
The remarkable fossils from Britain, Portugal and the United States rewrite the history of snake evolution, pushing back snake origins by tens of millions of years.
Until now, the oldest snake fossil dated from about 102 million years ago, said University of Alberta paleontologist Michael Caldwell, who led the study published in the journal Nature Communications.
Scientists say snakes evolved from lizards, and a number of previously discovered fossils of primitive snakes featured small back legs.
Those described on Tuesday did not include entire skeletons, but the researchers say all four may have had some form of reduced forelimbs and hind limbs.
That does not mean they walked. “It seems probable that they were slithering, so to speak, though the limbs might still have been used for grasping,” Mr. Caldwell said.
“Snakes have generated fear and fascination since ancient times,” said paleontologist Sebastiàn Apesteguþa of Argentina’s National Scientific and Technical Research Council (CONICET) and Universidad Maimonides, another of the researchers.
“However, we know very little about their very origins,” said Mr. Apesteguþa.
The four snakes lived during the age of dinosaurs. Eophis, the oldest, was a swamp dweller that probably ate small minnows, insects and tadpoles.
The largest, named Portugalophis lignites and discovered in a coal mine in central Portugal, measured about 1.2 metres and was 155 million years old.
It may have eaten small mammals, young dinosaurs, lizards, birds and frogs.
Diablophis gilmorei, a snake from about 155 million years ago, was found in western Colorado. It was a bit larger than Eophis and probably ate similar prey.
Parviraptor estesi, found in sea cliffs near Swanage, England, was about 60 cm long and 144 million years old.
Caldwell said the four snakes’ skull anatomy was similar to modern snakes and other fossil snakes. Caldwell said the characteristic snake skull design likely emerged before these reptiles acquired their elongated and legless body plan.
The best shot yet of icy dwarf planet Ceres
If you haven’t heard of Ceres, a planet that sits somewhere between Mars and Jupiter, you can be forgiven. It was originally classified as a true planet in the 1800s, then demoted to an asteroid and finally in 2006 promoted again as a “dwarf planet” — a status it now shares with Pluto.
But the icy Ceres, right through the changing nomenclature, has held a unique fascination for scientists: not least because it is thought to contain vast reserves of water. And so, when the sharpest image yet of the dwarf planet emerges, it is cause to celebrate. NASA’s Dawn spacecraft has sent back a picture of Ceres taken from a distance of 237,000 km. The image — although fairly blurry — is 30 per cent higher in resolution than those taken by NASA’s Hubble Space Telescope 10 years ago from 241 million kilometres away.
As the spacecraft moves closer to Ceres, the images sent back will get better. Dawn will enter into Ceres’ orbit on March 6 to capture detailed images and measure variations in reflected light to get insights into the planet's surface composition.
Last year, astronomers who studied data from ESA’sHerschel Space Observatory reported plumes of vapour emerging from Ceres’ surface, suggesting that it contained regions rich in water ice. Dawn will be the first spacecraft to visit any dwarf planet. At 950 km diameter Ceres is the smallest known dwarf planet, but the largest object in the asteroid belt between Mars and Jupiter.
