Tag Archives: genetic engineering

A Painful End

This should come as no surprise — advances to our understanding of biochemical and genetic processes seem to make the news with ever-increasing regularity. Researchers seem to have found the mechanism for switching physical pain on and off in mammals. They recently succeeded in blocking and restoring pain signals in mice. And, through the same discovery have been able to restore the sensation in a woman who has an extremely rare condition that makes her unable to feel any pain. It’s all in the Nav1.7 sodium ion channel and in its regulation of opioid peptides.

Fascinating, but where will this lead us? And, more to the point, will there ever be a pill to end the interminable pain of the US political process?

From ars technica:

Physical pain is a near universal problem, whether its sudden pangs or chronic aches. Yet, researchers’ efforts to quash it completely have fallen short—possibly due to a moonlighting channel in nerve cells. But that may be about to change.

The sodium ion channel, called Nav1.7, helps generate the electrical signals that surge through pain-related nerve cells. It’s known to play a key role in pain, but researchers’ past attempts to power-down its charged activities did little to soothe suffering. In a bit of a shocking twist, researchers figured out why; the channel has a second, un-channel-like function—regulating painkilling molecules called opioid peptides. That revelation, published in Nature Communications, provided researchers with the know-how to reverse painlessness in a woman with a rare condition, plus make mice completely pain free.

The link between Nav1.7 and opioid painkillers is “fascinating,” Claire Gaveriaux-Ruff, a pain researcher and professor at the University of Strasbourg, told Ars. And, she added, “this discovery brings hope to the many patients suffering from pain that are not yet adequately treated with the available pain medications.”

That source of hope has been a long time coming, John N. Wood, lead author of the study and a neuroscientist at University College London, told Ars. Researchers have been interested in Nav1.7 for years, he said. Excitement peaked in 2006 when scientists reported finding a family who lacked the channel and could feel no pain at all. After that, researchers excitedly scrambled to relieve pain with Nav1.7-blocking drugs. But the drugs inexplicably failed, Wood said. “So we thought, well maybe this channel isn’t just a channel, maybe it’s got some other activities as well.”

Using genetically engineered mice, Wood and colleagues found that completely shutting off Nav1.7 not only made mice pain-free, it cranked up their amount of opioid peptides in nerve cells. These molecules are natural painkillers that help the body moderate pain responses. In these Nav1.7-lacking mice, opioid levels were extremely high, blunting all twinges and throbs. When the researchers gave the mice a drug that blocks those opioids, the animals could feel pain normally. (The opioid-blocking drug, naloxone, treats overdoses of opioid drugs, such as morphine and codeine.)

Even more promising, Wood and colleagues saw the same result in a person. The test subject, a 39-year-old woman with a rare mutation that shuts off Nav1.7, had been pain-free all her life. But, when the researchers gave her a dose of the opioid-blocking naloxone, she felt pain for the first time—the sting of a tiny laser. She was happy to go back to her normal, painless state after the drug wore off, Wood reported. But, she hopes that the drug treatment can be used in children with the pain-free condition to keep them from unknowingly injuring themselves.

Read the entire article here.

Goodbye Poppy. Hello Narco-Yeast

S_cerevisiaeBioengineers have been successfully encoding and implanting custom genes into viruses, bacteria and yeast for a while now. These new genes usually cause these organisms to do something different, such as digest industrial waste, kill malignant hosts and manufacture useful chemicals.

So, it should come as no surprise to see the advent — only in the laboratory at the moment — of yeast capable of producing narcotics. There seems to be no end to our inventiveness.

Personally, I’m waiting for a bacteria that can synthesize Nutella and a fungus that can construct corporate Powerpoint presentations.

From the NYT:

In a widely expected advance that has opened a fierce debate about “home-brewed heroin,” scientists at Stanford have created strains of yeast that can produce narcotic drugs.

Until now, these drugs — known as opioids — have been derived only from the opium poppy. But the Stanford lab is one of several where researchers have been trying to find yeast-based alternatives. Their work is closely followed by pharmaceutical companies and by the Drug Enforcement Administration and Federal Bureau of Investigation.

Advocates of the rapidly advancing field of bioengineering say it promises to make the creation of important chemicals — in this case painkillers and cough suppressants — cheaper and more predictable than using poppies.

In one major advance more than a decade ago scientists in Berkeley added multiple genes to yeast until it produced a precursor to artemisinin, the most effective modern malaria drug, which previously had to be grown in sweet wormwood shrubs. Much of the world’s artemisinin is now produced in bioengineered yeast.

But some experts fear the technology will be more useful to drug traffickers than to pharmaceutical companies. Legitimate drug makers already have steady supplies of cheap raw materials from legal poppy fields in Turkey, India, Australia, France and elsewhere.

For now, both scientists and law-enforcement officials agree, it will be years before heroin can be grown in yeast. The new Stanford strain, described Thursday in the journal Science, would need to be 100,000 times as efficient in order to match the yield of poppies.

It would take 4,400 gallons of yeast to produce the amount of hydrocodone in a single Vicodin tablet, said Christina D. Smolke, the leader of the Stanford bioengineering team.

For now, she said, anyone looking for opioids “could buy poppy seeds from the grocery store and get higher concentrations.”But the technology is advancing so rapidly that it may match the efficiency of poppy farming within two to three years, Dr. Smolke added.

Read the story here.

Image: Saccharomyces cerevisiae cells in DIC microscopy. Public Domain.

Crispr – Designer DNA

The world welcomed basic genetic engineering in the mid-1970s, when biotech pioneers Herbert Boyer and Stanley Cohen transferred DNA from one organism to another (bacteria). In so doing they created the first genetically modified organism (GMO). A mere forty years later we now have extremely powerful and accessible (cheap) biochemical tools for tinkering with the molecules of heredity. One of these tools, known as Crispr-Cas9, makes it easy and fast to move any genes around, within and across any species.

The technique promises immense progress in the fight against inherited illness, cancer treatment and viral infection. It also opens the door to untold manipulation of DNA in lower organisms and plants to develop an infection resistant and faster growing food supply, and to reimagine a whole host of biochemical and industrial processes (such as ethanol production).

Yet as is the case with many technological advances that hold great promise, tremendous peril lies ahead from this next revolution. Our bioengineering prowess has yet to be matched with a sound and pervasive ethical framework. Can humans reach a consensus on how to shape, focus and limit the application of such techniques? And, equally importantly, can we enforce these bioethical constraints before it’s too late to “uninvent” designer babies and bioweapons?

From Wired:

Spiny grass and scraggly pines creep amid the arts-and-crafts buildings of the Asilomar Conference Grounds, 100 acres of dune where California’s Monterey Peninsula hammerheads into the Pacific. It’s a rugged landscape, designed to inspire people to contemplate their evolving place on Earth. So it was natural that 140 scientists gathered here in 1975 for an unprecedented conference.

They were worried about what people called “recombinant DNA,” the manipulation of the source code of life. It had been just 22 years since James Watson, Francis Crick, and Rosalind Franklin described what DNA was—deoxyribonucleic acid, four different structures called bases stuck to a backbone of sugar and phosphate, in sequences thousands of bases long. DNA is what genes are made of, and genes are the basis of heredity.

Preeminent genetic researchers like David Baltimore, then at MIT, went to Asilomar to grapple with the implications of being able to decrypt and reorder genes. It was a God-like power—to plug genes from one living thing into another. Used wisely, it had the potential to save millions of lives. But the scientists also knew their creations might slip out of their control. They wanted to consider what ought to be off-limits.

By 1975, other fields of science—like physics—were subject to broad restrictions. Hardly anyone was allowed to work on atomic bombs, say. But biology was different. Biologists still let the winding road of research guide their steps. On occasion, regulatory bodies had acted retrospectively—after Nuremberg, Tuskegee, and the human radiation experiments, external enforcement entities had told biologists they weren’t allowed to do that bad thing again. Asilomar, though, was about establishing prospective guidelines, a remarkably open and forward-thinking move.

At the end of the meeting, Baltimore and four other molecular biologists stayed up all night writing a consensus statement. They laid out ways to isolate potentially dangerous experiments and determined that cloning or otherwise messing with dangerous pathogens should be off-limits. A few attendees fretted about the idea of modifications of the human “germ line”—changes that would be passed on from one generation to the next—but most thought that was so far off as to be unrealistic. Engineering microbes was hard enough. The rules the Asilomar scientists hoped biology would follow didn’t look much further ahead than ideas and proposals already on their desks.

Earlier this year, Baltimore joined 17 other researchers for another California conference, this one at the Carneros Inn in Napa Valley. “It was a feeling of déjà vu,” Baltimore says. There he was again, gathered with some of the smartest scientists on earth to talk about the implications of genome engineering.

The stakes, however, have changed. Everyone at the Napa meeting had access to a gene-editing technique called Crispr-Cas9. The first term is an acronym for “clustered regularly interspaced short palindromic repeats,” a description of the genetic basis of the method; Cas9 is the name of a protein that makes it work. Technical details aside, Crispr-Cas9 makes it easy, cheap, and fast to move genes around—any genes, in any living thing, from bacteria to people. “These are monumental moments in the history of biomedical research,” Baltimore says. “They don’t happen every day.”

Using the three-year-old technique, researchers have already reversed mutations that cause blindness, stopped cancer cells from multiplying, and made cells impervious to the virus that causes AIDS. Agronomists have rendered wheat invulnerable to killer fungi like powdery mildew, hinting at engineered staple crops that can feed a population of 9 billion on an ever-warmer planet. Bioengineers have used Crispr to alter the DNA of yeast so that it consumes plant matter and excretes ethanol, promising an end to reliance on petrochemicals. Startups devoted to Crispr have launched. International pharmaceutical and agricultural companies have spun up Crispr R&D. Two of the most powerful universities in the US are engaged in a vicious war over the basic patent. Depending on what kind of person you are, Crispr makes you see a gleaming world of the future, a Nobel medallion, or dollar signs.

The technique is revolutionary, and like all revolutions, it’s perilous. Crispr goes well beyond anything the Asilomar conference discussed. It could at last allow genetics researchers to conjure everything anyone has ever worried they would—designer babies, invasive mutants, species-specific bioweapons, and a dozen other apocalyptic sci-fi tropes. It brings with it all-new rules for the practice of research in the life sciences. But no one knows what the rules are—or who will be the first to break them.

In a way, humans were genetic engineers long before anyone knew what a gene was. They could give living things new traits—sweeter kernels of corn, flatter bulldog faces—through selective breeding. But it took time, and it didn’t always pan out. By the 1930s refining nature got faster. Scientists bombarded seeds and insect eggs with x-rays, causing mutations to scatter through genomes like shrapnel. If one of hundreds of irradiated plants or insects grew up with the traits scientists desired, they bred it and tossed the rest. That’s where red grapefruits came from, and most barley for modern beer.

Genome modification has become less of a crapshoot. In 2002, molecular biologists learned to delete or replace specific genes using enzymes called zinc-finger nucleases; the next-generation technique used enzymes named TALENs.

Yet the procedures were expensive and complicated. They only worked on organisms whose molecular innards had been thoroughly dissected—like mice or fruit flies. Genome engineers went on the hunt for something better.

As it happened, the people who found it weren’t genome engineers at all. They were basic researchers, trying to unravel the origin of life by sequencing the genomes of ancient bacteria and microbes called Archaea (as in archaic), descendants of the first life on Earth. Deep amid the bases, the As, Ts, Gs, and Cs that made up those DNA sequences, microbiologists noticed recurring segments that were the same back to front and front to back—palindromes. The researchers didn’t know what these segments did, but they knew they were weird. In a branding exercise only scientists could love, they named these clusters of repeating palindromes Crispr.

Then, in 2005, a microbiologist named Rodolphe Barrangou, working at a Danish food company called Danisco, spotted some of those same palindromic repeats in Streptococcus thermophilus, the bacteria that the company uses to make yogurt and cheese. Barrangou and his colleagues discovered that the unidentified stretches of DNA between Crispr’s palindromes matched sequences from viruses that had infected their S. thermophilus colonies. Like most living things, bacteria get attacked by viruses—in this case they’re called bacteriophages, or phages for short. Barrangou’s team went on to show that the segments served an important role in the bacteria’s defense against the phages, a sort of immunological memory. If a phage infected a microbe whose Crispr carried its fingerprint, the bacteria could recognize the phage and fight back. Barrangou and his colleagues realized they could save their company some money by selecting S. thermophilus species with Crispr sequences that resisted common dairy viruses.

As more researchers sequenced more bacteria, they found Crisprs again and again—half of all bacteria had them. Most Archaea did too. And even stranger, some of Crispr’s sequences didn’t encode the eventual manufacture of a protein, as is typical of a gene, but instead led to RNA—single-stranded genetic material. (DNA, of course, is double-stranded.)

That pointed to a new hypothesis. Most present-day animals and plants defend themselves against viruses with structures made out of RNA. So a few researchers started to wonder if Crispr was a primordial immune system. Among the people working on that idea was Jill Banfield, a geomicrobiologist at UC Berkeley, who had found Crispr sequences in microbes she collected from acidic, 110-degree water from the defunct Iron Mountain Mine in Shasta County, California. But to figure out if she was right, she needed help.

Luckily, one of the country’s best-known RNA experts, a biochemist named Jennifer Doudna, worked on the other side of campus in an office with a view of the Bay and San Francisco’s skyline. It certainly wasn’t what Doudna had imagined for herself as a girl growing up on the Big Island of Hawaii. She simply liked math and chemistry—an affinity that took her to Harvard and then to a postdoc at the University of Colorado. That’s where she made her initial important discoveries, revealing the three-dimensional structure of complex RNA molecules that could, like enzymes, catalyze chemical reactions.

The mine bacteria piqued Doudna’s curiosity, but when Doudna pried Crispr apart, she didn’t see anything to suggest the bacterial immune system was related to the one plants and animals use. Still, she thought the system might be adapted for diagnostic tests.

Banfield wasn’t the only person to ask Doudna for help with a Crispr project. In 2011, Doudna was at an American Society for Microbiology meeting in San Juan, Puerto Rico, when an intense, dark-haired French scientist asked her if she wouldn’t mind stepping outside the conference hall for a chat. This was Emmanuelle Charpentier, a microbiologist at Ume?a University in Sweden.

As they wandered through the alleyways of old San Juan, Charpentier explained that one of Crispr’s associated proteins, named Csn1, appeared to be extraordinary. It seemed to search for specific DNA sequences in viruses and cut them apart like a microscopic multitool. Charpentier asked Doudna to help her figure out how it worked. “Somehow the way she said it, I literally—I can almost feel it now—I had this chill down my back,” Doudna says. “When she said ‘the mysterious Csn1’ I just had this feeling, there is going to be something good here.”

Read the whole story here.

Of Mice and Men

Biomolecular and genetic engineering continue apace. This time researchers have inserted artificially constructed human genes into the cells of living mice.

From the Independent:

Scientists have created genetically-engineered mice with artificial human chromosomes in every cell of their bodies, as part of a series of studies showing that it may be possible to treat genetic diseases with a radically new form of gene therapy.

In one of the unpublished studies, researchers made a human artificial chromosome in the laboratory from chemical building blocks rather than chipping away at an existing human chromosome, indicating the increasingly powerful technology behind the new field of synthetic biology.

The development comes as the Government announces today that it will invest tens of millions of pounds in synthetic biology research in Britain, including an international project to construct all the 16 individual chromosomes of the yeast fungus in order to produce the first synthetic organism with a complex genome.

A synthetic yeast with man-made chromosomes could eventually be used as a platform for making new kinds of biological materials, such as antibiotics or vaccines, while human artificial chromosomes could be used to introduce healthy copies of genes into the diseased organs or tissues of people with genetic illnesses, scientists said.

Researchers involved in the synthetic yeast project emphasised at a briefing in London earlier this week that there are no plans to build human chromosomes and create synthetic human cells in the same way as the artificial yeast project. A project to build human artificial chromosomes is unlikely to win ethical approval in the UK, they said.

However, researchers in the US and Japan are already well advanced in making “mini” human chromosomes called HACs (human artificial chromosomes), by either paring down an existing human chromosome or making them “de novo” in the lab from smaller chemical building blocks.

Natalay Kouprina of the US National Cancer Institute in Bethesda, Maryland, is part of the team that has successfully produced genetically engineered mice with an extra human artificial chromosome in their cells. It is the first time such an advanced form of a synthetic human chromosome made “from scratch” has been shown to work in an animal model, Dr Kouprina said.

“The purpose of developing the human artificial chromosome project is to create a shuttle vector for gene delivery into human cells to study gene function in human cells,” she told The Independent. “Potentially it has applications for gene therapy, for correction of gene deficiency in humans. It is known that there are lots of hereditary diseases due to the mutation of certain genes.”

Read the entire article here.

Image courtesy of Science Daily.

Grow Your Own… Heart

A timely article for Valentine’s Day. Researchers continue to make astonishing progress in areas of cell biology and human genomics. So, it should come as no surprise that growing a customized, replacement heart in a lab from reprogrammed cells will one day be on the horizon.

[div class=attrib]From the Guardian:[end-div]

Every two minutes someone in the UK has a heart attack. Every six minutes, someone dies from heart failure. During an attack, the heart remodels itself and dilates around the site of the injury to try to compensate, but these repairs are rarely effective. If the attack does not kill you, heart failure later frequently will.

“No matter what other clinical interventions are available, heart transplantation is the only genuine cure for this,” says Paul Riley, professor of regenerative medicine at Oxford University. “The problem is there is a dearth of heart donors.”

Transplants have their own problems – successful operations require patients to remain on toxic, immune-suppressing drugs for life and their subsequent life expectancies are not usually longer than 20 years.

The solution, emerging from the laboratories of several groups of scientists around the world, is to work out how to rebuild damaged hearts. Their weapons of choice are reprogrammed stem cells.

These researchers have rejected the more traditional path of cell therapy that you may have read about over the past decade of hope around stem cells – the idea that stem cells could be used to create batches of functioning tissue (heart or brain or whatever else) for transplant into the damaged part of the body. Instead, these scientists are trying to understand what the chemical and genetic switches are that turn something into a heart cell or muscle cell. Using that information, they hope to programme cells at will, and help the body make repairs.

It is an exciting time for a technology that no one thought possible a few years ago. In 2007, Shinya Yamanaka showed it was possible to turn adult skin cells into embryonic-like stem cells, called induced pluripotent stem cells (iPSCs), using just a few chemical factors. His technique radically advanced stem cell biology, sweeping aside years of blockages due to the ethical objections about using stem cells from embryos. He won the Nobel prize in physiology or medicine for his work in October. Researchers have taken this a step further – directly turning one mature cell type to another without going through a stem cell phase.

And politicians are taking notice. At the Royal Society in November, in his first major speech on the Treasury’s ambitions for science and technology, the chancellor, George Osborne, identified regenerative medicine as one of eight areas of technology in which he wanted the UK to become a world leader. Earlier last year, the Lords science and technology committee launched an inquiry into the potential of regenerative medicine in the UK – not only the science but what regulatory obstacles there might be to turning the knowledge into medical applications.

At Oxford, Riley has spent almost a year setting up a £2.5m lab, funded as part of the British Heart Foundation’s Mending Broken Hearts appeal, to work out how to get heart muscle to repair itself. The idea is to expand the scope of the work that got Riley into the headlines last year after a high-profile paper published in the journal Nature in which he showed a means of repairing cells damaged during a heart attack in mice. That work involved in effect turning the clock back in a layer of cells on the outside of the heart, called the epicardium, making adult cells think they were embryos again and thereby restarting their ability to repair.

During the development of the embryo, the epicardium turns into the many types of cells seen in the heart and surrounding blood vessels. After the baby is born this layer of cells loses its ability to transform. By infusing the epicardium with the protein thymosin ?4 (T?4), Riley’s team found the once-dormant layer of cells was able to produce new, functioning heart cells. Overall, the treatment led to a 25% improvement in the mouse heart’s ability to pump blood after a month compared with mice that had not received the treatment.

[div class=attrib]Read the entire article after the jump.[end-div]

[div class=attrib]Image courtesy of Google Search.[end-div]

Vaccinia – Prototype Viral Cancer Killer

The illustrious Vaccinia virus may well have an Act Two in its future.

For Act One, over the last 150 years or so, it has been successfully used to vaccinate most of the world’s population against smallpox. This helped eradicate smallpox in the United States in the early 1970s.

Now, researchers are using it to target cancer.

First, take the Vaccinia virus — a relative of the smallpox virus. Second, re-engineer the virus to inhibit its growth in normal cells. Third, add a gene to the virus that stimulates the immune system. Fourth, set it to work on tumor cells and watch. While, such research has been going on for a couple of decades, this enhanced approach to attacking cancer cells with a viral immune system stimulant shows early promise.

[div class=attrib]From ars technica:[end-div]

For roughly 20 years, scientists have been working to engineer a virus that will attack cancer. The basic idea is sound, and every few years there have been some promising-looking results, with tumors shrinking dramatically in response to an infection. But the viruses never seem to go beyond small trials, and the companies making them always seem to focus on different things.

Over the weekend, Nature Medicine described some further promising results, this time with a somewhat different approach to ensuring that the virus leads to the death of cancer cells: if the virus doesn’t kill the cells directly, it revs up the immune system to attack them. It’s not clear this result will make it to a clinic, but it provides a good opportunity to review the general approach of treating cancer with viruses.

The basic idea is to leverage decades of work on some common viruses. This research has identified a variety of mutations keeping viruses from growing in normal cells. It means that if you inject the virus into a healthy individual, it won’t be able to infect any of their cells.

But cancer cells are different, as they carry a series of mutations of their own. In some cases, these mutations compensate for the problems in the virus. To give one example, the p53 protein normally induces aberrant cells to undergo an orderly death called apoptosis. It also helps shut down the growth of viruses in a cell, which is why some viruses encode a protein that inhibits p53. Cancer cells tend to damage or eliminate their copies of p53 so that it doesn’t cause them to undergo apoptosis.

So imagine a virus with its p53 inhibitor deleted. It can’t grow in normal cells since they have p53 around, but it can grow in cancer cells, which have eliminated their p53. The net result should be a cancer-killing virus. (A great idea, but this is one of the viruses that got dropped after preliminary trials.)

In the new trial, the virus in question takes a similar approach. The virus, vaccinia (a relative of smallpox used for vaccines), carries a gene that is essential for it to make copies of itself. Researchers have engineered a version without that gene, ensuring it can’t grow in normal cells (which have their equivalent of the gene shut down). Cancer cells need to reactivate the gene, meaning they present a hospitable environment for the mutant virus.

But the researchers added another trick by inserting a gene for a molecule that helps recruit immune cells (the awkwardly named granulocyte-macrophage colony-stimulating factor, or GM-CSF). The immune system plays an important role in controlling cancer, but it doesn’t always generate a full-scale response to cancer. By adding GM-CSF, the virus should help bring immune cells to the site of the cancer and activate them, creating a more aggressive immune response to any cells that survive viral infection.

The study here was simply checking the tolerance for two different doses of the virus. In general, the virus was tolerated well. Most subjects reported a short bout of flu-like symptoms, but only one subject out of 30 had a more severe response.

However, the tumors did respond. Based on placebo-controlled trials, the average survival time of patients like the ones in the trial would have been expected to be about two to four months. Instead, the low-dose group had a survival time of nearly seven months; for the higher dose group, that number went up to over a year. Two of those treated were still alive after more than two years. Imaging of tumors showed lots of dead cells, and tests of the immune system indicate the virus had generated a robust response.

[div class=attrib]Read the entire article after the leap.[end-div]

[div class=attrib]Image: An electron micrograph of a Vaccinia virus. Courtesy of Wikipedia.[end-div]

Living Organism as Software

For the first time scientists have built a computer software model of an entire organism from its molecular building blocks. This allows the model to predict previously unobserved cellular biological processes and behaviors. While the organism in question is a simple bacterium, this represents another huge advance in computational biology.

[div class=attrib]From the New York Times:[end-div]

Scientists at Stanford University and the J. Craig Venter Institute have developed the first software simulation of an entire organism, a humble single-cell bacterium that lives in the human genital and respiratory tracts.

The scientists and other experts said the work was a giant step toward developing computerized laboratories that could carry out complete experiments without the need for traditional instruments.

For medical researchers and drug designers, cellular models will be able to supplant experiments during the early stages of screening for new compounds. And for molecular biologists, models that are of sufficient accuracy will yield new understanding of basic biological principles.

The simulation of the complete life cycle of the pathogen, Mycoplasma genitalium, was presented on Friday in the journal Cell. The scientists called it a “first draft” but added that the effort was the first time an entire organism had been modeled in such detail — in this case, all of its 525 genes.

“Where I think our work is different is that we explicitly include all of the genes and every known gene function,” the team’s leader, Markus W. Covert, an assistant professor of bioengineering at Stanford, wrote in an e-mail. “There’s no one else out there who has been able to include more than a handful of functions or more than, say, one-third of the genes.”

The simulation, which runs on a cluster of 128 computers, models the complete life span of the cell at the molecular level, charting the interactions of 28 categories of molecules — including DNA, RNA, proteins and small molecules known as metabolites that are generated by cell processes.

“The model presented by the authors is the first truly integrated effort to simulate the workings of a free-living microbe, and it should be commended for its audacity alone,” wrote the Columbia scientists Peter L. Freddolino and Saeed Tavazoie in a commentary that accompanied the article. “This is a tremendous task, involving the interpretation and integration of a massive amount of data.”

They called the simulation an important advance in the new field of computational biology, which has recently yielded such achievements as the creation of a synthetic life form — an entire bacterial genome created by a team led by the genome pioneer J. Craig Venter. The scientists used it to take over an existing cell.

For their computer simulation, the researchers had the advantage of extensive scientific literature on the bacterium. They were able to use data taken from more than 900 scientific papers to validate the accuracy of their software model.

Still, they said that the model of the simplest biological system was pushing the limits of their computers.

“Right now, running a simulation for a single cell to divide only one time takes around 10 hours and generates half a gigabyte of data,” Dr. Covert wrote. “I find this fact completely fascinating, because I don’t know that anyone has ever asked how much data a living thing truly holds. We often think of the DNA as the storage medium, but clearly there is more to it than that.”

In designing their model, the scientists chose an approach that parallels the design of modern software systems, known as object-oriented programming. Software designers organize their programs in modules, which communicate with one another by passing data and instructions back and forth.

Similarly, the simulated bacterium is a series of modules that mimic the different functions of the cell.

“The major modeling insight we had a few years ago was to break up the functionality of the cell into subgroups which we could model individually, each with its own mathematics, and then to integrate these sub-models together into a whole,” Dr. Covert said. “It turned out to be a very exciting idea.”

[div class=attrib]Read the entire article after the jump.[end-div]

[div class=attrib]Image: A Whole-Cell Computational Model Predicts Phenotype from Genotype. Courtesy of Cell / Elsevier Inc.[end-div]

Evolution machine: Genetic engineering on fast forward

[div class=attrib]From the New Scientist:[end-div]

Automated genetic tinkering is just the start – this machine could be used to rewrite the language of life and create new species of humans

IT IS a strange combination of clumsiness and beauty. Sitting on a cheap-looking worktop is a motley ensemble of flasks, trays and tubes squeezed onto a home-made frame. Arrays of empty pipette tips wait expectantly. Bunches of black and grey wires adorn its corners. On the top, robotic arms slide purposefully back and forth along metal tracks, dropping liquids from one compartment to another in an intricately choreographed dance. Inside, bacteria are shunted through slim plastic tubes, and alternately coddled, chilled and electrocuted. The whole assembly is about a metre and a half across, and controlled by an ordinary computer.

Say hello to the evolution machine. It can achieve in days what takes genetic engineers years. So far it is just a prototype, but if its proponents are to be believed, future versions could revolutionise biology, allowing us to evolve new organisms or rewrite whole genomes with ease. It might even transform humanity itself.

These days everything from your food and clothes to the medicines you take may well come from genetically modified plants or bacteria. The first generation of engineered organisms has been a huge hit with farmers and manufacturers – if not consumers. And this is just the start. So far organisms have only been changed in relatively crude and simple ways, often involving just one or two genes. To achieve their grander ambitions, such as creating algae capable of churning out fuel for cars, genetic engineers are now trying to make far more sweeping changes.

[div class=attrib]More from theSource here.[end-div]

J. Craig Venter

[div class=attrib]From Discover:[end-div]

J. Craig Venter keeps riding the cusp of each new wave in biology. When researchers started analyzing genes, he launched the Institute for Genomic Research (TIGR), decoding the genome of a bacterium for the first time in 1992. When the government announced its plan to map the human genome, he claimed he would do it first—and then he delivered results in 2001, years ahead of schedule. Armed with a deep understanding of how DNA works, Venter is now moving on to an even more extraordinary project. Starting with the stunning genetic diversity that exists in the wild, he is aiming to build custom-designed organisms that could produce clean energy, help feed the planet, and treat cancer. Venter has already transferred the genome of one species into the cell body of another. This past year he reached a major milestone, using the machinery of yeast to manufacture a genome from scratch. When he combines the steps—perhaps next year—he will have crafted a truly synthetic organism. Senior editor Pamela Weintraub discussed the implications of these efforts with Venter in DISCOVER’s editorial offices.

Here you are talking about constructing life, but you started out in deconstruction: charting the human genome, piece by piece.
Actually, I started out smaller, studying the adrenaline receptor. I was looking at one protein and its single gene for a decade. Then, in the late 1980s, I was drawn to the idea of the whole genome, and I stopped everything and switched my lab over. I had the first automatic DNA sequencer. It was the ultimate in reductionist biology—getting down to the genetic code, interpreting what it meant, including all 6 billion letters of my own genome. Only by understanding things at that level can we turn around and go the other way.

In your latest work you are trying to create “synthetic life.” What is that?
It’s a catchy phrase that people have begun using to replace “molecular biology.” The term has been overused, so we have defined a separate field that we call synthetic genomics—the digitization of biology using only DNA and RNA. You start by sequencing genomes and putting their digital code into a computer. Then you use the computer to take that information and design new life-forms.

How do you build a life-form? Throw in some mito­chondria here and some ribosomes there, surround ?it all with a membrane—?and voilà?
We started down that road, but now we are coming from the other end. We’re starting with the accomplishments of three and a half billion years of evolution by using what we call the software of life: DNA. Our software builds its own hardware. By writing new software, we can come up with totally new species. It would be as if once you put new software in your computer, somehow a whole new machine would materialize. We’re software engineers rather than construction workers.

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Evolution by Intelligent Design

[div class=attrib]From Discover:[end-div]

“There are no shortcuts in evolution,” famed Supreme Court justice Louis Brandeis once said. He might have reconsidered those words if he could have foreseen the coming revolution in biotechnology, including the ability to alter genes and manipulate stem cells. These breakthroughs could bring on an age of directed reproduction and evolution in which humans will bypass the incremental process of natural selection and set off on a high-speed genetic course of their own. Here are some of the latest and greatest advances.

Embryos From the Palm of Your Hand
In as little as five years, scientists may be able to create sperm and egg cells from any cell in the body, enabling infertile couples, gay couples, or sterile people to reproduce. The technique could also enable one person to provide both sperm and egg for an offspring—an act of “ultimate incest,” according to a report from the Hinxton Group, an international consortium of scientists and bioethicists whose members include such heavyweights as Ruth Faden, director of the Johns Hopkins Berman Institute of Bioethics, and Peter J. Donovan, a professor of biochemistry at the University of California at Irvine.

The Hinxton Group’s prediction comes in the wake of recent news that scientists at the University of Wisconsin and Kyoto University in Japan have transformed adult human skin cells into pluripotent stem cells, the powerhouse cells that can self-replicate (perhaps indefinitely) and develop into almost any kind of cell in the body. In evolutionary terms, the ability to change one type of cell into others—including a sperm or egg cell, or even an embryo—means that humans can now wrest control of reproduction away from nature, notes Robert Lanza, a scientist at Advanced Cell Technology in Massachusetts. “With this breakthrough we now have a working technology whereby anyone can pass on their genes to a child by using just a few skin cells,” he says.

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