Shifted target in war against cancer raises hopes
Traditionally polled at the end of each year for the 10 most important scientific and thechnological breakthroughs, Science editors put the hope raising advances iachieved n the area of immunotherapy in the fight against cancer at No.1 position for 1913. With an interesting intro, the magazine let it be known that the choice came after much hesitation and debates because of past disappointments after similar announcements of breakthroughs which failed to live up to raised expectations. Besides the proliferating success stories, an emerging paradigm shift in cancer research was reportedly instrumental in persuading the editors to discard their doubts, namely, the targeting of the immune system instead of the tumor; in other words, the focus of the research shifting to the strengthening of the immune system to enable the body’s defenders to put up a better fight against tumor cells.
One of the instruments that led to the breakthrough came a quarter of a century ago when French researchers discovered a new protein receptor on the surface of T cells of the immune system, also called T lymphocytes. Later, American cancer immunologist James Allison found that the receptor, called cytotoxic T-lymphocyte antigen 4, or CTLA-4 for short, was putting the brakes on the T-cells, preventing an all-out immune reaction. After that, Allison and other cancer researchers concentrated on developing a cancer therapy based on “blocking the blocker”. As then mainstream pharmaceutical companies proved reticent because of past experience, it fell on to an obscure company to synthesize the antibody and produce the drug called Ipilimumab administered to melanoma patients. Impressed by positive results, industry giants began jumping in.
Meanwhile, another discovery by a Japanese biologist in early 1990s paved the way for the development of even more effective antibodies. What researcher discovered was a protein synthesized by T cells as they die. The researcher showed that the protein he called Programmed Death-1, or PD-1 for short, was another brake limiting the vigor of T cells. Intrigued by the discovery, oncologist Drew Pardoll of the Johns Hopkins University, arranged for the production of the antibody blocking the PD-1, (anti PD-1) by the same company which had originally produced the antibody blocking the CTLA-4. The spectacular results of trials witth patients in 2008 have reverberated across the medical world.
Another breakthrough in the realm of immunotherapy was the modification of patient’s T cells through genetic engineering. Pioneering the technique, Steven Rosenberg of the (US) National Cancer Institute first collected theT cells which had entered the tumor cells of patients, multiplied them in laboratory and then re-injected them. The technique, however, could only work if the doctors could access the tumour tissue. But when Rosenberg modified the T cells to seek out and home to tumor cells with a technique he dubbed chimeric antigen receptor therapy, or CAR therapy, striking results followed.
But researchers caution against premature conclusions that obstacle course has been negotiated. Despite the successes attained with CTLA-4 and anti PD-1, the mechanisms they utilise in the body are still not fully understood. The results themselves have not reached a reliable measure of stabilty. Another problem is the high cost of therapy which needs to be reduced for widespread apllication (the company producing ipilimumab charges 120.000 dollars for a course of treatment . Nevertheless, oncologists appear excited and hopeful after results which could not be imagined just a few years back.
Without assigning them to rungs, again in conformity with tradition, the science editors have identified the runners up as follows:
Genetic microsurgery for the masses
One of the most exciting breakthroughs of 2013 for the scientists, stimulating both the establishment of biotech companies and new research is a technique opening the door for the treatment of existing or potential ailments, by fixing a damaged gene or shutting off a faulty one.
Called CRISPR (which stands for clusters of regularly interspaced short palindromic repeats) the technology has acquired its name from repeating stretches of DNA, which the bacteria had evolved to defend themselves against a group of invasive viruses called bacteriophages.
The bacterium attaches a protein named Cas9 to a DNA sequence matching the virus’ genome and the complex cuts the viral DNA and disables it. RNA is a molecule easier to synthesize in a lab compared to a piece of a protein. Because it takes the place of the normal RNA which binds to the target DNA, CRISPR is more handy than the genome modification techniques developed over the past years. While some researchers are currently trying to modify the Cas9 structures to make it “nip” the DNA instead of cutting it, biochemists are working out their structures with a view to synthesiszing them. Some other labs, meanwhile are probing other Cas proteins to see wheter they work better than Cas9.
Clear images of brain with CLARITY
Brain, with its 100 billion odd nerve cells called neurons, a multitude of supporting cells and a host of specialized structures whose functions are still not fully deciphered, is our most complex organ. Former techniques developed to image the brain at work optically instead of indirectly with magnetic resonance imaging or positron emission tomography were not successful because they made neurons fragile.
A new technique named CLARITY developed in 2013, has now removed that obstacle to make brain tissues transparent as glass to researchers, and potentially, to neuroscientists and surgeons. Involving the replacement of lipid molecules which form the cell membranes and scatter the light, with the molecules of a clear gel, the technique does not interfere with the normal functioning of other brain cells and specialised structures. It also allows the neuroscientists to explore brain tissues with special markers designed for different cell types, neurotransmitters or proteins, and then to withdraw them and investigate other tissues, using different markers. According to researchers, CLARITY will speed up work for establishing the exact number of neurons in a brain sector a hundredfold. The technique, however, is still in its infancy. Right now, making a mere 4 mm wide region of a mouse brain transparent takes nine days.
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After more than a decade of failed attempts, scientists succeeeded in cloning human embryos and using them as a source for extremely versatile embryonic stem cells or ESCs. Having an identical make up with the cloned cells, ESCs are powerful tools for research and medicine. The technique used in human cloning is the same with the one used 17 years ago in the cloning of sheep Dolly. After the nucleus is removed from an egg cell, the remaining material is fused with a cell from the person to be cloned and an applied electrical shock starts the cell division. The end product is an embryo bearing a perfect genetic match to the person whose cell was taken. The technique, used successfully for the cloning of an ever increasing number of animal species, had persistently failed for humans, merely yielding some low-quality embryos unable to produce ESCs. Things had started to change in 2007 when American geneticists at the Oregon Primate Research Center were able to clone monkeys and obtain ESCs from them. Building on the experience gained from these experiments, Oregon researchers finally announced they had cloned human embryos from which ESCs could be extracted.
Importance of the success, however, looks eclipsed by another breakthrough coming in the years since the first attempts at human cloning. In 2007, genetic engineers were able to produce stem cells, called induced pluripotent stem cells (iPSC) readily convertible to any cell, just by re-programming certain somatic cells (any cell in the body except germ cells [egg and sperm]) without any need for human eggs or embryos. Whether cloning technique centered on nuclear transfer from the egg will gain widespread use, will depend on the outcome of the comparison between eSCs and the iPSCs. Meanwhile, scientists at the Oregon Health and Science University where the human cloning was done, assure that “clone babies” a theme constantly on the agenda of the opponents of the method and science fiction fans were out of question, at least for now. They point to the fact that despite tried hundreds of times, none of the cloned monkey embroys could start pregnancy in females.
Mini-organs in lab dishes
Pluripotent stem cell s have the ability to mature into the diverse set of body cells. Left to themselves, however, they differentiate to cells with specific purposes in the body, from the heart cells to neurons; from, dental cells to hair cells in a random fashion. Until now, efforts to intervene to the process and coax the stem cells into the desired cells were foundering in difficulties.
Hence, for science editors, the success of a group of scientists in goading the induced pluripotent stem cells (iPSCs) to form clusters and then guiding them to construct tissues and specialised areas reminiscent of certain organelles of the brain in tiny structures growing in lab dishes was spectacular enough to be flagged as one of the top breakthroughs.
An international team of scientists led by Madeline Lancaster first guided the iPSCs to turn into neural membranes in petri dishes at the Molecular Biology Institute of the Austrian Academy of Sciences in Vienna. To overcome the reticence of the membranes to cluster, the researchers inserted them into miniscule spheres made of a gelatinous substance called madrigel, thus enabling them to form 3-D structures. Spinning these in a bioreactor for 8-to-10 days for the nutrients to be absorbed, the scientists reported that they had grown to blobs wwith sizes up to 4 mm containing interacting regions with features specific to brain tissues such as cortex, prefrontal lobe, middle and posterior brain areas and hipocampus as well as retinal tissues.
Energetic particles traced to cosmic accelerators
The earth is under constant bombardment of particles from the sky. Called cosmic rays, these are chiefly comprised of protons and some atomic nuclei. But among them are some packing tremendous energies which have befuddled researchers for decades as to their origins.Cosmic ray researchers think that these particles are rotated by powerful magnetic fields within the shock waves created by supernova explosions in the interstellar medium, like the ones that circulate in particle accelarators like the LHC, gaining energies hundreds of times above the levels attainable by terrestrial colliders. The proof, however, were proving elusive, because the positively charged particles hurled into space after accumulating phenomenal energies were thwarted by huge magnetic fields on their paths, which prevent them from following straight traectories that reveal their points of origin.
At last, the sought proof came in 1913, courtesy of the Fermi Gamma Ray Space Telescope in Earth orbit. As the protons circulate without colliding in the extremely thin interstellar medium, gaining velocity and energy, few collisions which still occure produce short-lived particles called “pi-zero”. These, in turn, quickly decay into a pair of high-energy photons, which produce a discernible spike in the energy spectrum of photons from a supernova remnant whn plotted in a special way. Five years of Fermi data yielded in the end the signature of proton acceleration in two supernova remnants. While missing the fanfare accorded to their earthly sibling after the discovery of the Higgs boson, the particle accelerators in the sky thus demonstrated the punch they pack.
Super material for solar energy
Solar energy is getting increasing recourse as the depletion of fossil fuel resources and mounting concerns about a climate change force the industrialised world to allocate larger budgets to ways of harnessing alternate energy sources. Although available in unlimited supply with no harmful waste products, the limited efficiency of materials used in converting the sunlight to electricity has been the stumbling block in the quest for widespread use of solar panels. Until now, two types of materials were going into the production of photovoltaic vsolar cells: “organic solar cells” produced by depositing sunlight absorbing chemicals onto thin and elastic substrates, and the silicon-based solar cells assembled in thin layers over semi-conducting bases. Now, a new method, discovered in 2013 appears to have the potential to spark a revolution in the field and accelerate the widespread use of solar power. The method is the use of perovskite, a material possessing a crystalline quality high enough even for laser applications, in the production of solar cells.
Conversion efficiency, 3.8 percent for organic solar cells, quadruples to to 15 percent in perovskite cells. The efficiency of the perovskite based cells still lags behind the 20 or even 25 percent efficiency levels the silicon based photovoltaics have reached; but the attractiveness of the perovskite use lies in its simplicity and cheapness. Producing the semiconducting material used in silicon based photovoltaics in required purity calls for high temperatures and expensive nanotechnology. In contrast, the production of perovskites is both simple and fast, since it is done merely by dissolving certain substances in a solution which is then sprayed on a surface. Another attractive feature of perovskites is their absorption of high-energy green and blue wavelengths in the sunlight. Silicon based solar cells, on the other hand, absorb longer (and less energetic) red and infrared wavelengths. Thus, when mounted on silicon-based photovoltaics piggyback fashion, perovskites expand the absorption spectrum of the cells and boost their efficiency to a whopping 30 percent. But before the stampede for solar energy, the researchers have to devise insulation methods that would prevent the deterioration of perovskite in contact with air or water and prevent the lead content in the existing samples to spread to the environment.
Sleep sweeps the brain
Identification of the chief function of sleep was another achievement of 2013 the Science editors found worth citing among the winners. Although such functions of the brain as reinforcing the immune system and consolidating the memories were known to researchers for a long time, scientists were suspecting a deeper relation between sleep and this complex organ. The search finally bore fruit in 2013 with the chief funcion of sleep emerging to be cleansing the brain from its garbage with a vast network of drainage canals.
The canals, filled with cerebrospinal fluid, expand by 60 percent during sleep and increased flow carries out the metabolismic waste products, such as Beta-amiloid whose accumulation causes such debilitating conditions as Alzheimer’s. Until this discovery, the scientists were thinking the only way of purging the brain from metabolistic wastes was breaking them within the cell into reusable materials.
Microbial tenants shape our health
There is no consensus among the scientists as to thenumber of cells in our bodies with estimates ranging from 10 to 100 trillion. And the number of genes spread across the DNA coiled around pairs of chromosomes contained in every cell, instructing the production of proteins we depend for our lives, giving us our features and determining our susceptibility to diseases and conditions are thought to number 20,000 to 25,000.
But our bodies also host guests no less crowded than our own cells. Researchers reckon there are some 100 trillion microbes carrying about three million different genes. A number of discoveries in 2013 established that these microbes were as effective as our genes in our ailments and tendencies.
Vaccines against deadly diseases with structural biology
Structural biology is a field of science which investigates the molecules of living organisms nearly with atomic level resolution. With their creative work in the field, researchers made important strides towards producing antibodies targeting weak spots of viruses to develop vaccines against deadly diseaes. One of these Respiratory Syncytial Virus (RSV) causing millions of children to contract pneumonia and other respiratory diseases, asthma and serious allergies with 160.000 fatalities worldwide each year.
Scientists discovered a protein called F on the surface of the virus which it uses to fuse with the cell in the process of infection, and developed an antibody which targets and disables this structure. A salient feature of protein F is a spring mechanism resembling a jack-in-the-box. The virus keeps the spring under lid until it binds to the cell, and then releases it so that protein punctures the cell membrane for it to infect.
The virus is most vulnerable in the stage where the F protein remains cocked and visible. After establishing the existence of protein F and deciphering its mechanism, reasoned that the best way of teaching the body’s immune system the weak spot of the virus would be developing a vaccine which incorporates the cocked stage of the protein. Trial of the vaccine on animals, yielded positive results almost instantenously.
Researchers were hopeful that the vaccine could be used on humans within 18 months. A similar strategy began to be investigated against human immunodeficiency virus (HIV) responsible for AIDS. Hopes are also high for employing the same method for defeating other pathogens like hepatitis C, dengue fever and West Nile virus with proven ability to deceive the immune system.