1 Million Billion Billion Billion Billion Billion Billion: Number of Undiscovered Drugs

A new voyage into "chemical space" -- occupied not by stars and planets but substances that could become useful in everyday life -- has concluded that scientists have synthesized barely one tenth of 1 percent of the potential medicines that could be made. The report, in the journal ACS Chemical Neuroscience, estimates that the actual number of these so-called "small molecules" could be 1 novemdecillion (that's 1 with 60 zeroes), 1 million billion billion billion billion billion billion, which is more than some estimates of the number of stars in the universe.

A new voyage into "chemical space" -- occupied not by stars and planets but substances that could become useful in everyday life -- has concluded that scientists have synthesized barely one tenth of 1 percent of the potential medicines that could be made [Credit: Web]

Jean-Louis Reymond and Mahendra Awale explain that small molecules, which are able to cross cell walls and interact with biological molecules in the body, are prime targets for scientists who develop new medicines. Most existing medications are small molecules. The authors focused on the "chemical space" inhabited by all of the small molecules that could possibly exist according to the laws of physics and chemistry. 

Researchers have identified millions of these compounds -- the ACS' Chemical Abstracts Service database contains almost 67 million substances. Reymond and Awale estimate that the molecules synthesized and tested as potential drugs so far represent less than 0.1 percent of chemical space. To aid researchers looking for new ways to prevent and treat disease, they set out to find the best ways to search for new small molecules.

The authors discuss several ways of getting a handle on chemical space, including by the size, shape and makeup of molecules. They show how computers can help researchers efficiently narrow a search for a new drug candidate. Computer modeling of chemical interactions can help researchers find a handful of promising molecules to synthesize and test in the lab. "Small molecule drugs are essential to the success of modern medicine," the authors note, and suggest that their methods may be particularly useful for finding new pharmaceuticals that target the central nervous system.

Source: American Chemical Society [June 06, 2012]

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Scientists generate electricity from viruses

Imagine charging your phone as you walk, thanks to a paper-thin generator embedded in the sole of your shoe. This futuristic scenario is now a little closer to reality. Scientists from the U.S. Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab) have developed a way to generate power using harmless viruses that convert mechanical energy into electricity.

The scientists tested their approach by creating a generator that produces enough current to operate a small liquid-crystal display. It works by tapping a finger on a postage stamp-sized electrode coated with specially engineered viruses. The viruses convert the force of the tap into an electric charge.

Their generator is the first to produce electricity by harnessing the piezoelectric properties of a biological material. Piezoelectricity is the accumulation of a charge in a solid in response to mechanical stress.

The milestone could lead to tiny devices that harvest electrical energy from the vibrations of everyday tasks such as shutting a door or climbing stairs.

It also points to a simpler way to make microelectronic devices. That's because the viruses arrange themselves into an orderly film that enables the generator to work. Self-assembly is a much sought after goal in the finicky world of nanotechnology.

The scientists describe their work in a May 13 advance online publication of the journal Nature Nanotechnology.

"More research is needed, but our work is a promising first step toward the development of personal power generators, actuators for use in nano-devices, and other devices based on viral electronics," says Seung-Wuk Lee, a faculty scientist in Berkeley Lab's Physical Biosciences Division and a UC Berkeley associate professor of bioengineering.

He conducted the research with a team that includes Ramamoorthy Ramesh, a scientist in Berkeley Lab's Materials Sciences Division and a professor of materials sciences, engineering, and physics at UC Berkeley; and Byung Yang Lee of Berkeley Lab's Physical Biosciences Division.

The piezoelectric effect was discovered in 1880 and has since been found in crystals, ceramics, bone, proteins, and DNA. It's also been put to use. Electric cigarette lighters and scanning probe microscopes couldn't work without it, to name a few applications.

But the materials used to make piezoelectric devices are toxic and very difficult to work with, which limits the widespread use of the technology.

Lee and colleagues wondered if a virus studied in labs worldwide offered a better way. The M13 bacteriophage only attacks bacteria and is benign to people. Being a virus, it replicates itself by the millions within hours, so there's always a steady supply. It's easy to genetically engineer. And large numbers of the rod-shaped viruses naturally orient themselves into well-ordered films, much the way that chopsticks align themselves in a box.

These are the traits that scientists look for in a nano building block. But the Berkeley Lab researchers first had to determine if the M13 virus is piezoelectric. Lee turned to Ramesh, an expert in studying the electrical properties of thin films at the nanoscale. They applied an electrical field to a film of M13 viruses and watched what happened using a special microscope. Helical proteins that coat the viruses twisted and turned in response—a sure sign of the piezoelectric effect at work.

Next, the scientists increased the virus's piezoelectric strength. They used genetic engineering to add four negatively charged amino acid residues to one end of the helical proteins that coat the virus. These residues increase the charge difference between the proteins' positive and negative ends, which boosts the voltage of the virus.

The scientists further enhanced the system by stacking films composed of single layers of the virus on top of each other. They found that a stack about 20 layers thick exhibited the strongest piezoelectric effect.

The only thing remaining to do was a demonstration test, so the scientists fabricated a virus-based piezoelectric energy generator. They created the conditions for genetically engineered viruses to spontaneously organize into a multilayered film that measures about one square centimeter. This film was then sandwiched between two gold-plated electrodes, which were connected by wires to a liquid-crystal display.

When pressure is applied to the generator, it produces up to six nanoamperes of current and 400 millivolts of potential. That's enough current to flash the number "1" on the display, and about a quarter the voltage of a triple A battery.

"We're now working on ways to improve on this proof-of-principle demonstration," says Lee. "Because the tools of biotechnology enable large-scale production of genetically modified viruses, piezoelectric materials based on viruses could offer a simple route to novel microelectronics in the future."

Source: DOE/Lawrence Berkeley National Laboratory [May 13, 2012]

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Researchers discover bats may be a common source of many viral diseases

International researchers under the aegis of the University of Bonn have discovered the probable cause of not just one, but several infectious agents at the same time. Paramyxoviruses originate from ubiquitous bats, from where the pathogens have spread to humans and other mammals. This could make eradicating many dangerous diseases significantly more difficult than had been thought. The results of this study have just been published in the current issue of Nature Communications. 

[Image (c) Florian Gloza-Rausch/Uni Bonn/Noctalis Bad Segeberg]

Where do viruses dangerous to humans come from, and how have they evolved? Scientists working with Prof. Dr. Christian Drosten, Head of the Institute for Virology at the Universitätsklinikum Bonn, have made significant progress in answering this question. "We already knew from prior studies that bats and rodents play a role as carriers of paramyxoviruses," said Prof. Drosten. The many varied members of this large virus family cause, e.g., measles, mumps, pneumonias and colds. The highly dangerous Hendra and Nipah viruses cause types of encephalitis that result in death for one out of two patients. Paramyxoviruses also play a role in veterinary medicine, causing e.g., canine distemper or rinderpest. 

Researchers double the number of known paramyxovirus species 

With support from numerous scientific institutes in Germany and around the world, they tested a total of 9,278 animals from Europe, South America and Asia, including 86 bat and 33 rodent species. "These animals live in very large social communities with millions of individuals in some cases," reported the Bonn virologist. "Their close contact promotes mutual infection and provides for great variety in circulating viruses." Using molecular biology methods, the scientists identified which virus species are rampant in bats and rodents. According to their own estimates, they discovered more than 60 new paramyxovirus species. "That is about as many as the number that was already known," said Drosten. 

Bats are the original paramyxovirus hosts 

Using computational biology methods, the scientists calculated a common evolutionary tree for the new and the known viruses. They then deduced, using mathematical methods, in which host animals the viruses have most likely taken up residence during their evolutionary history. "Our analysis shows that almost all of the forebears of today's paramyxoviruses have existed in bats," explained Prof. Drosten. "Just as with influenza, where we are keeping an eye on birds as a source of new pandemic viruses, we will now have to study the bat viruses to see if they are a danger to humans." So, the current data might play a useful role in early detection and prevention of epidemics – a major new goal in virus research. 

Mumps viruses have jumped to humans 

The findings also included that the Hendra and Nipah viruses that cause encephalitis in Asia and Australia really came from Africa. "This results in an urgent need to conduct medical studies in Africa," said the Bonn virologist, adding that many disease cases on this continent remain unexplained and might possibly have been caused by such new viruses. In one case, the scientists have already found proof that bat viruses transfer directly to humans. "Our data show that the human mumps virus comes directly from bats – and can be found there to this day," reported Prof. Drosten. 

Dangerous viruses cannot be eradicated anytime soon 

These results indicate that it may not be as easy to eradicate dangerous viruses as had been assumed. For eliminating an infectious agent permanently from the population by means of vaccination requires that there are no animal hosts from which a new infection might come. "In bats, we assume that there is a vast reservoir of such agents," said Drosten. "If the vaccination campaigns are stopped once a virus has been eradicated, this might present a potential risk - maybe we will have to rethink." This is why Drosten advocates taking into account ecological data when planning vaccination campaigns. Eradicating bats or other wild animals would be neither possible nor sensible. "Bats and other small wild mammals are of immeasurable value for our planet's ecosystems," Drosten summarized his and his colleagues' unanimous opinion. 

Source: University of Bonn [April 24, 2012]

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Researchers create synthetic DNA/RNA that can evolve

Researchers have created artificial genetic material known as Xenonucleic acids, or XNAs, that can store information and evolve over generations in a comparable way to DNA. 

The research, reported Friday in the journal Science, has implications for the fields of molecular medicine and biotechnology, and sheds new light on how molecules first replicated and assembled into life billions of years ago. 

Living systems owe their existence to the information-carrying molecules DNA and RNA.  These fundamental chemical forms have two features essential for life: they display heredity, meaning they can encode and pass on genetic information, and they can adapt over time. 

Whether these traits could be performed by molecules other than DNA and RNA has been a long-debated issue. 

For the current study, an international team of researchers developed chemical procedures to convert DNA and RNA into six genetic polymers known as XNAs.  The process switches the deoxyribose and ribose (the “d” and “r” in DNA and RNA) for other molecules. 

The researchers demonstrated for the first time that all six XNAs could form a double helix with DNA, and were more stable than natural genetic material.  Moreover, one of these XNAs, a molecule known as anhydrohexitol nucleic acid, or HNA, was capable of undergoing directed evolution and folding into biologically useful forms. 

Philipp Holliger of MRC Laboratory of Molecular Biology in Cambridge, the study’s senior author, said the work demonstrated that heredity and evolution were possible using alternatives to natural genetic material. 

“There is nothing Goldilocks about DNA and RNA,” he told Science. 

“There is no overwhelming functional imperative for genetic systems or biology to be based on these two nucleic acids.” 

Both RNA and DNA embed data in their sequences of four nucleotides.  This information is vital for conferring hereditary traits and for supplying the coded recipe essential for building proteins from the 20 naturally occurring amino acids.  However, precisely how and when this system began remains one of the most perplexing and hotly contested areas of biology. 

According to one hypothesis, the simpler RNA molecule preceded DNA as the original informational conduit. The RNA world hypothesis proposes that the earliest examples of life were based on RNA and simple proteins.  Because of RNA’s great versatility—it is not only capable of carrying genetic information but also of catalyzing chemical reactions like an enzyme—it is believed by many to have supported pre-cellular life. 

Nevertheless, the spontaneous arrival of RNA through a sequence of purely random mixing events of primitive chemicals was, at the very least, an unlikely occurrence. 

“This is a big question,” said study leader John Chaput, a researcher at Arizona State University’s Biodesign Institute. 

“If the RNA world existed, how did it come into existence? Was it spontaneously produced, or was it the product of something that was even simpler than RNA?” 

This pre-RNA world hypothesis has been gaining ground, primarily through study of XNAs, which provide plausible alternatives to the current biological system and could have acted as chemical stepping-stones to the eventual emergence of life. 

Threose nucleic acid, or TNA, for example, is one candidate for this critical intermediary role. 

“TNA does some interesting things,” Chaput said, noting the molecule’s capacity to bind with RNA through antiparallel Watson-Crick base pairing. 

“This property provides a model for how XNAs could have transferred information from the pre-RNA world to the RNA world.” 

Nucleic acid molecules, including DNA and RNA, consist of 3 chemical components: a sugar group, a triphosphate backbone and combinations of the four nucleic acids.  By manipulating these structural elements, researchers can engineer XNA molecules with unique properties. 

However, in order for any of these molecules to have acted as a precursor to RNA in the pre-biotic epoch, they would need to have been able to transfer and recover their information from RNA. To do this, specialized enzymes, known as polymerases are required. 

And while nature has made DNA and RNA polymerases capable of reading, transcribing and reverse transcribing normal nucleic acid sequences, no naturally occurring polymerases exist for XNA molecules. 

So the researchers, led by Holliger, painstakingly evolved synthetic polymerases that could copy DNA into XNA, and other polymerases that could copy XNA back into DNA. 

Ultimately, polymerases were found that transcribe and reverse-transcribe six different genetic systems: HNA, CeNA, LNA, ANA, FANA and TNA. The experiments demonstrated that these unnatural DNA sequences could be rendered into various XNAs when the polymerases were fed the appropriate XNA substrates. 

Using these enzymes as tools for molecular evolution, the team evolved the first example of an HNA aptamer through iterative rounds of selection and amplification.  Starting from a large pool of DNA sequences, a synthetic polymerase was used to copy the DNA library into HNA. The pool of HNA molecules was then incubated with an arbitrary target. The small fraction of molecules that bound the target were then separated from the unbound pool, reverse transcribed back into DNA with a second synthetic enzyme, and amplified by PCR. After many repeated rounds, HNAs were generated that bound HIV trans-activating response RNA (TAR) and hen egg lysosome (HEL), which were used as binding targets. 

“This is a synthetic Darwinian process,” Chaput said. 

“The same thing happens inside our cells, but this is done in vitro.” 

The method for producing XNA polymerases draws on Holliger’s pervious, path-breaking work, and uses cell-like synthetic compartments of water/oil emulsion to conduct directed evolution of enzymes, particularly polymerases. 

By isolating self-replication reactions from each other, the process greatly improves the accuracy and efficiency of polymerase evolution and replication. 

“What nobody had really done before,” Chaput said, “is to take those technologies and apply them to unnatural nucleic acids. ” 

Chaput said the study advances the case for a pre-RNA world, while revealing a new class of XNA aptamers capable of fulfilling many useful roles. 

And while many questions surrounding the origins of life remain, he is optimistic that solutions are coming into view. 

“Further down the road, through research like this, I think we’ll have enough information to begin to put the pieces of the puzzle together.” 

In an article accompanying the study in the journal Science, Gerald Joyce of the Scripps Research Institute wrote that “the work heralds the era of synthetic genetics, with implications for exobiology (life elsewhere in the Universe), biotechnology, and understanding of life itself”. 

However, he stressed that the work does not yet represent a full synthetic genetics platform. For that, a self-replicating system that does not require the DNA intermediary must be developed. 

If that happens, “construction of genetic systems based on alternative chemical platforms may ultimately lead to the synthesis of novel forms of life”. 

Source: RedOrbit [April 20, 2012]

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