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Category Archives: biochemistry

E. coli enters the energy game, could pump out petroleum

Growing chambers for algae, which could be engineered to continually pump biofuels out into their growth media.
Cal Poly

Bacteria are big news in the biofuel business—genetically engineered microorganisms can turn various combinations of biomass, sunlight, and even carbon dioxide into liquid fuels. The potential for replacing fossil fuels with these renewable energy sources is significant, but the efficient implementation of these technologies remains complicated.

Two studies published in the Proceedings of the National Academy of Sciences this week looked at how to make biofuel production more efficient.

A team of British scientists genetically engineered E. coli bacteria to produce a hydrocarbon molecule that mimics petroleum. Right now, conventional biofuels like ethanol have to be blended with sufficient traditional fuel so that our engines don’t detect their presence. These "mimic molecules," on the other hand, could go straight into our existing engines.

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Origin of life researchers figure out how to build bigger RNAs

A close up of the active site of a catalytic RNA.
UCB

We'll probably never know exactly how life on Earth got its start. The conditions in which it began have long since been lost, and there are simply too many precursor molecules and potential environments that could have gotten the process going. Nevertheless, researchers hope to put together a pathway that's at least plausible, starting from simple molecules that were present on the early Earth and building up to an enclosed system with basic inheritance (from there, evolution can take over).

A lot of progress has been made in understanding how a simple chemical, like hydrogen cyanide, can be built up through a series of reactions into a nucleotide, the basic building block of molecules like DNA and RNA. And we've learned quite a bit about how larger RNAs (more than 100 nucleotides long) can fold into complex structures that can catalyze reactions and undergo the chemical equivalent of Darwinian evolution. The challenge has been bridging the gap between the two, going from a handful of linked nucleotides to a large molecule that's potentially capable of catalyzing chemical reactions.

Now, the team that developed the earlier results is back with another publication. Their latest work shows how short molecules that are composed of just a handful of nucleotides can be linked together, eventually building longer, more complex chains. Once again, the chemistry is simple enough to occur on the early Earth, and the reaction might explain a curious bias in how DNA and RNA are built into long chains of nucleotides.

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Making HIV tests visible to the naked eye

One of the recurring themes in healthcare is that a lot of what works in the developed world doesn't work in the developing world. There may be limited access to basics like power or communications facilities, never mind the medical technologies that make a hospital one of the modern wonders of the world. Beyond simple access to expensive technologies and medicines, even something as basic as a diagnostic test might be too expensive or require skilled technicians to use.

Though cures might remain expensive—drug companies like their profits—every dime saved on diagnosis is a dime more for prevention and cure. That makes cheap, accurate, and simple diagnostic tests very, very desirable.

I was thinking about this when I came across an older paper that somehow didn't attract any attention when it came out. Last year, a group of researchers showed that they could detect HIV at extremely low concentrations. That by itself is nothing special: people are always improving diagnostic tests. What is special is that the test is very much like a pregnancy test, in that a simple visible color change indicates a positive result. Even better, it seems to work in real-life tests.

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Feeding our gut bacteria meat may enhance heart disease risks

Americans eat much more red meat than most other people, and Americans get a lot more cardiovascular disease than most other people. Red meat has lots of saturated fats and cholesterol, which causes cardiovascular disease, right? Not so fast. As with many commonly held assertions, especially in the field of nutrition, this one sounds good but does not quite have the data to support it.

Intestinal microbiota, or gut flora, are a trendy health topic right now; their importance has only been acknowledged in the past twenty years or so, but they have already been shown to impact such vital physiological processes as immune function and the development of cancer, diabetes, and obesity. Dietary choices—like the choice to eat red meat or not—are known to influence the relative ratios of the different bacterial species residing in our guts.

So researchers at the Cleveland Clinic decided to check out how different intestinal microbiota metabolize the components of meat. They found that bacteria present in the intestines of omnivores, but not present in the intestines of vegans or vegetarians, generate a molecule that promotes atherosclerosis when they are fed red meat.

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Head-on collisions of proteins create mutations

One of the central tenets of evolutionary theory is that mutations are random—you can't predict what the next one will be, or when it's going to happen. But it also turns out that mutations are probabilistic. Some of them are a bit more or less likely, depending on the chemistry of the DNA base and its location in the genome.

Now, researchers have identified a mechanism that makes certain types of mutation more probable. This mechanism is a head-on collision between proteins that involves the complex that copies DNA when a cell divides. Because of the mechanics of these collisions, there's a distinct bias towards mutations occurring on one of the two strands of DNA that make up a double helix. The researchers found that this bias is so fundamental that bacterial genes are arranged to take advantage of it, so that some key genes are kept safer from mutations, while others that are key to adaptation can mutate more often.

The problem with collisions arises from the structure of DNA itself. The sugars in the molecule's backbone have a distinctive top (the 5' carbon) and bottom (the 3' carbon). Even in a molecule that's millions of sugars long, every single one of those is oriented the same way. If you move down the strand in one direction, you'll always hit the 5' end first (if you go in the other direction, you'll always hit the 3' end).

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Learning hurts your brain

After publishing an especially challenging quantum mechanics article, it's not uncommon to hear some of our readers complain that their head hurts. Presumably, they mean that the article gave them a (metaphoric) headache. But it's actually possible that challenging your brain does a bit of physical damage to the nerve cells of the brain. Researchers are reporting that, following situations where the brain is active, you might find signs of DNA damage within the cells there. The damage is normally restored quickly, but they hypothesize that the inability to repair it quickly enough may underlie some neurological diseases.

This research clearly started out as an attempt to understand Alzheimer's disease. The authors were working with mice that were genetically modified to mimic some of the mutations associated with early-onset forms of the disease in humans. As part of their testing, the team (based at UCSF) looked for signs of DNA damage in the brains of these animals. They generally found that the indications of damage went up when the brains of mice were active—specifically, after they were given a new environment to explore.

That might seem interesting on its own, but the surprise came when they looked at their control mice, which weren't at elevated risk of brain disorders. These mice also showed signs of DNA damage (although at slightly lower levels than the Alzheimer's-prone mice).

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Wetware advances: Biological logic gate built by splitting viral gene

MIT

In recent years, researchers in the messy world of biology have been able to build systems that function like the clean, binary switches on computer chips—and we've covered a number of reports in this area. Unfortunately, most of these share a significant limitation: they rely on proteins from bacteria that act as switches to turn genes on and off under specific conditions. We know about only a limited number of these genetic switches, which may set a severe limit on the number of logical operations we can string together inside a cell.

A paper in this week's PNAS describes a system that may allow us to get around this limitation. The new method takes a protein from a virus that infects bacteria and cuts it in two, making a pair of genes (A and B) that each produce part of the mature protein. The two parts then act as a biological version of an AND logic gate, with output (in the form of protein activity) present only when both A and B interact. When either or both A and B are missing, the output is off.

In biological terms, the inputs usually involve a simple molecule that can be sensed by proteins inside a bacteria. This paper, for example, used two kinds of sugars (arabinose and lactose). When the sugars are present, they attach to proteins inside the cell, activating genes that are controlled by those proteins. To make an AND gate, you need to design a bit of biology that can respond to both of these signals—it should be active only when both a gene regulated by arabinose and a gene regulated by lactose are each active.

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MP3 files written as DNA with storage density of 2.2 petabytes per gram

The general approach to storing a binary file as DNA, described in detail below.
Goldman et al., Nature

It's easy to get excited about the idea of encoding information in single molecules, which seems to be the ultimate end of the miniaturization that has been driving the electronics industry. But it's also easy to forget that we've been beaten there, and by a few billion years. The chemical information present in biomolecules was critical to the origin of life, and probably dates back to whatever interesting chemical reactions preceded it.

It's only within the past few decades, however, that humans have learned to speak DNA. Even then, it took a while to develop the technology needed to synthesize and determine the sequence of large populations of molecules. But, we're there now, and people have started experimenting with putting binary data in biological form. Now, a new study has confirmed the flexibility of the approach by encoding everything from an MP3 to the decoding algorithm into fragments of DNA. The cost analysis done by the authors suggest that the technology may soon be suitable for decade-scale storage, provided current trends continue.

Trinary encoding

Computer data is in binary, while each location in a DNA molecule can hold any one of four bases (A, T, C, and G). Rather than using all that extra information capacity, however, the authors used it to avoid a technical problem. Stretches of a single type of base (say, TTTTT) are often not sequenced properly by current techniques—in fact, this was the biggest source of errors in the previous DNA data storage effort. So, for this new encoding, they used one of the bases to break up long runs of any of the other three.

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Why would a biotech company keep a secret herd of goats?

These happy looking goats would undoubtedly not run afoul of USDA regulations.
USDA

The typical image of a modern biological research lab involves high-tech machinery and table-sized microscopes; at most, there might be some dishes of cells or a few mice floating around. For people with those images in mind, yesterday's odd report on how federal inspectors were surprised to find 841 goats at a California biotech facility they didn't even know existed might come as a surprise. Why, you might wonder, would Santa Cruz Biotechnology need a secret herd of goats at all?

As it turns out, goats (along with rabbits and a handful of other animals) play a key role in modern bioscience—but on the supply side, not the research side. A paper found in a major science journal might well have depended on a goat in some way; it's just that the lab never saw the animal. Instead, the goat probably lived at a facility like the one that's under investigation, while the research lab received the goat's contribution via a UPS shipment.

The men who stare at goats

So what does a goat (or a bunny) offer a biologist? Antibodies. Antibodies are useful for several procedures conducted by biologists because they can stick so specifically to a single target. If you can raise antibodies against a specific protein, you can then use those antibodies to purify that protein out of the huge mix of proteins produced by a cell. If you can generate antibodies to a protein that's on the surface of a cell, you can use them to purify whole cells out of a mixed population.

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Bacterial “immune system” used to engineer human DNA in human cells

Artist's conception of the CRISPR system in action, with the guide RNA (red) leading a protein to a specific site in the genomic DNA (blue) where it makes a cut.
Stephen Dixon and Feng Zhang

Precisely engineering the genome of human cells remains largely in the realm of science fiction. It's possible, with the right virus, to get new or modified genes into cells. But the regular collection of the genes in the cell are still there—we can't typically eliminate a gene that has gone bad or replace a broken copy with a working one. Although some progress has been made in creating proteins that target specific spots in the genome, it's tough to make these proteins both specific enough to only target a single sequence yet flexible enough to work on lots of targets.

Now, it turns out we don't have to make proteins after all. Bacteria have a system that targets the DNA of viral invaders, acting a bit like an immune system. And two teams of researchers have shown it's possible to direct that system so it targets specific locations in a mammalian genome. Once targeted, the cell's normal DNA repair system can replace the sequence with an engineered one of the researchers' choosing.

The efficiency is under 10 percent, so don't start thinking we're going to edit every cell of the human body. But that rate still makes it practical for a variety of purposes—and potentially even therapies.

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