Kevin: Very cool. It’s going to be a while before this is ready for any sort of practical application, but it is another great tool for the cyborg scientists of the future to use.
Engineers from the California Institute of Technology have created a “plug-and-play” synthetic RNA device–a sort of eminently customizable biological computer–that is capable of taking in and responding to more than one biological or environmental signal at a time.
In the future, such devices could have a multitude of potential medical applications, including being used as sensors to sniff out tumor cells or determine when to turn modified genes on or off during cancer therapy.
A synthetic RNA device is a biological device that uses engineered modular components made of RNA nucleotides to perform a specific function–for instance, to detect and respond to biochemical signals inside a cell or in its immediate environment.
Created by Caltech’s Christina Smolke, assistant professor of chemical engineering, and Maung Nyan Win, postdoctoral scholar in chemical engineering, the device is made up of modules comprising the RNA-based biological equivalents of engineering’s sensors, actuators, and information transmitters. These individual components can be combined in a variety of different ways to create a device that can both detect and respond to what could conceivably be an almost infinite number of environmental and cellular signals.
This modular device processes these inputs in a manner almost identical to the logic gates used in computing; it can perform AND, NOR, NAND, and OR computations, and can perform signal filtering and signal gain operations. Smolke and Win’s creation is the first RNA device that can handle more than one incoming piece of biological information. “There’s been a lot of work done in single-input devices,” notes Smolke. “But this is the first demonstration that a multi-input RNA device is possible.”
Their work was published in the October 17 issue of the journal Science.
The modular–or plug-and-play–nature of the device’s design also means that it can be easily modified to suit almost any need. “Scientists won’t have to redesign their system every time they want the RNA device to take on a new function,” Smolke explains. “This modular framework allows you to quickly put a device together, then just as easily swap out the components for other ones and get a completely different kind of computation. We could generate huge libraries of well-defined sensors and assemble many different tailored devices from such component libraries.”
Although the work in the Science paper was done in yeast cells, Smolke says they have already shown that they can translate to mammalian cells as well. This makes it possible to consider using these devices in a wide variety of medical applications.
For instance, ongoing work in Smolke’s laboratory is looking at the packaging of these RNA devices–configured with the appropriate sensor modules–in human T cells. The synthetic device would literally be placed within the cell to detect certain signals–say, one or more particular biochemical markers that are given off by tumor cells. If those biomarkers were present, the RNA device would signal the T cell to spring into action against the putative tumor cell.
Similarly, an RNA device could be bundled alongside a modified gene as part of a targeted gene therapy package. One of the problems gene therapy faces today is its lack of specificity–it’s hard to make sure a modified gene meant to fix a problem in the liver reaches or is inserted in only liver cells. But an RNA device, Smolke says, could be customized to detect the unique biomarkers of a liver cell–or, better yet, of a diseased liver cell–and only then give the modified gene the go-ahead to do its stuff.
Josh: This isn’t a field I’m that familiar with, but is it known how the baby’s immune system uses the antibodies provided by the mother’s milk? How does it stimulate the baby’s cells to produce the same anti-bodies? The mention of the clathrin coat not being completely shed is particularly interesting. Either their observations were flawed, other researchers never noticed that the coat was not completely shed, or this is a special case where the coat is just not completely shed.
The transportation of antibodies from a mother to her newborn child is vital for the development of that child’s nascent immune system. Those antibodies, donated by transfer across the placenta before birth or via breast milk after birth, help shape a baby’s response to foreign pathogens and may influence the later occurrence of autoimmune diseases. Images from biologists at the California Institute of Technology (Caltech) have revealed for the first time the complicated process by which these antibodies are shuttled from mother’s milk, through her baby’s gut, and into the bloodstream, and offer new insight into the mammalian immune system.
Newborns pick up the antibodies with the aid of a protein called the neonatal Fc receptor (FcRn), located in the plasma membrane of intestinal cells. FcRn snatches a maternal antibody molecule as it passes through a newborn’s gut; the receptor and antibody are enclosed within a sac, called a vesicle, which pinches off from the membrane. The vesicle is then transported to the other side of the cell, and its contents–the helpful antibody–are deposited into the baby’s bloodstream.
Pamela Bjorkman, Max Delbrück Professor of Biology at Caltech and an investigator with the Howard Hughes Medical Institute, and her colleagues were able to watch this process in action using gold-labeled antibodies (which made FcRn visible when it picked up an antibody) and a technique called electron tomography. Electron tomography is an offshoot of electron microscopy, a now-common laboratory technique in which a beam of electrons is used to create images of microscopic objects. In electron tomography, multiple images are snapped while a sample is tilted at various angles relative to the electron beam. Those images can then be combined to produce a three-dimensional picture, just as cross-sectional X-ray images are collated in a computerized tomography (CT) scan.
“You can get an idea of movement in a series of static images by taking them at different time points,” says Bjorkman, whose laboratory studies how the immune system recognizes its targets, work that is offering insight into the processes by which viruses like HIV and human cytomegalovirus invade cells and cause disease.
The electron tomography images revealed that the FcRn/antibody complexes were collected within cells inside large vesicles, called “multivesicular bodies,” that contain other small vesicles. The vesicles previously were believed to be responsible only for the disposal of cellular refuse and were not thought to be involved in the transport of vital proteins.
The images offered more surprises. Many vesicles, including multivesicular bodies and other more tubular vesicles, looped around each other into an unexpected “tangled mess,” often forming long tubes that then broke off into the small vesicles that carry antibodies through the cell. When those vesicles arrived at the blood-vessel side of the cell, they fused with the cell membrane and delivered the antibody cargo. The vesicles also appeared to include a coat made from a molecule called clathrin, which helps form the outer shell of the vesicles. Researchers previously believed that a vesicle’s clathrin cage was completely shed before the vesicle fused with the cell membrane. The new results suggest that only a small section of that coating is sloughed off, which may allow the vesicle to more quickly drop its load and move on for another.
“We are now studying the same receptor in different types of cells in order to see if our findings can be generalized, and are complementing these studies with fluorescent imaging in live cells,” Bjorkman says. “The process of receptor-mediated transport is fundamental to many biological processes, including detection of developmental decisions made in response to the binding of hormones and other proteins, uptake of drugs, signaling in the immune and nervous systems, and more. So understanding how molecules are taken up by and transported within cells is critical for many areas of basic and applied biomedical research,” she adds.
Josh: I wrote about this same enzyme earlier in the year, but this is a new paper on it. The earlier study reported the NMR structure of the enzyme, but this study focused on the X-ray crystal structure. The authors note “In the X-ray structure, these APOBEC3G active-site loops [that are directly involved in substrate binding] form a continuous ‘substrate groove’ around the active centre. The orientation of this putative substrate groove differs markedly (by 90 degrees) from the groove predicted by the NMR structure”.
Humans have a built-in weapon against HIV, but until recently no one knew how to unlock its potential.
A study published online by the journal Nature reveals the atomic structure of this weapon – an enzyme known as APOBEC-3G – and suggests new directions for drug development.
APOBEC-3G is present in every human cell. It is capable of stopping HIV at the first step of replication, when the retrovirus transcribes its RNA into viral DNA.
The study’s authors, led by Xiaojiang Chen of the University of Southern California, were able to show the atomic structure of the active portion of APOBEC-3G.
The discovery suggests how and where the enzyme binds to the viral DNA, mutating and destroying it.
“We understand how this enzyme can interact with DNA,” said Chen, a professor of molecular and computational biology at USC. “This understanding provides a platform for designing anti-HIV drugs.”
If APOBEC-3G works so well, why do people get AIDS? Because the HIV virus has evolved to encode the protein Vif, known as a “virulence factor,” that blocks APOBEC-3G.
With APOBEC-3G out of the way, the RNA of the HIV virus can be successfully transcribed to viral DNA, an essential step for infection and for producing many more HIV viruses.
Chen said his group’s research offers important clues on where Vif binds to APOBEC-3G. The knowledge could be used to design drugs that would prevent Vif from binding and allow APOBEC-3G to do its job, Chen said.
That would unlock humans’ innate ability to fight HIV.
“We were born with it, and it’s there waiting,” Chen said.
In addition to fighting HIV, APOBEC-3G can inhibit the Hepatitis B virus. Other members of the APOBEC family serve important roles in antibody maturation, fat metabolism and heart development.
Mapping the structure of APOBEC-3G at the atomic level is a goal that “has been sought after worldwide because of its significance,” Chen said.
Editor’s note: this is the 500th ThinkGene.com post, hurray!
It’s amazing how the cells look like conscious organisms chasing one another. Organisms on any level that are effectively predator and prey behave the same, be they single cells, insects, or animals.
Kevin: Our growing understanding that some cancers are viral in origin starts to make cancer seem a lot less mysterious. I’m optimistic about continued progress in this important area.
University of Pittsburgh scientists are uncovering more evidence that a virus they recently discovered is the cause of Merkel cell carcinoma, an aggressive and deadly form of skin cancer.
The findings, published in this week’s early online edition of the Proceedings of the National Academy of Sciences, put to rest the possibility that MCV infects tumors that already have formed. If that were the case, the virus would be a passenger rather than the driver of the disease.
Experiments in human tumors reveal that the cancer develops in two steps: during infection, the Merkel cell polyomavirus, or MCV, integrates into host cell DNA and produces viral proteins that promote cancer formation. Tumors occur when a mutation removes part of a viral protein needed for the virus to reproduce and infect other healthy cells, explained senior investigator, Patrick Moore, M.D., M.P.H, professor of microbiology and molecular genetics at the School of Medicine and director of the Molecular Virology Program at the University of Pittsburgh Cancer Institute. The virus then can spread only as the cancer cells themselves multiply.
Clearly, “MCV infects normal cells before they turn into cancer cells,” Dr. Moore noted. “The virus could not have infected a tumor afterwards because it can no longer replicate. It looks very much like MCV is the culprit that causes the disease.”
The researchers propose two possible reasons why these mutations develop: If viral replication continues, the immune system could recognize the intruder to eliminate diseased cells, or the viral replication itself will lead to the death of the cancer cells. Both of these possibilities provide promising leads to find better ways to kill Merkel cell cancer cells without harming healthy tissues.
Also, “this research shows evolution within tumors on a molecular level,” Dr. Moore pointed out. “You can see the specific molecular steps.” The team’s current work could account for known risk factors for Merkel cell carcinoma such as UV exposure and ionizing radiation, which damage DNA and can lead to the viral mutations.
Merkel cell cancers are rare, occurring in about 1,500 Americans annually. Half of patients who have advanced disease die within nine months of diagnosis, and two-thirds die within two years. The elderly and people with compromised immune systems are at greater risk of developing the cancer, which arises in skin nerve cells that respond to touch or pressure.
In a paper published in Science in January, Dr. Moore and his wife, Dr. Yuan Chang, who co-directs their lab, reported their identification of the virus and that it could be found in 80 percent of Merkel cell tumors. They cautioned that although up to 16 percent of the population carries MCV, very few will develop cancer.
There is no treatment for MCV infection right now, but identifying the agent and understanding how it triggers disease could lead to targeted interventions, Dr. Moore said.
Our friendly government lists some available genetic tests: these are the real deal, high penetrance tests for things you already have or conditions you will get.
Unlike Sergey Brin, I don’t particularly care about a mutation that gives me a slightly increased risk for a disease. That’s not significant, though if the placebo effect of a 23andMe test gets you to exercise more, congratulations.
However, if I knew I was bound to get Huntington’s Disease, I would really live my life differently with the moral superiority provided by knowing that my time on this earth was sadly limited by my genetics. I would just take things so much more seriously than all those suckers blissfully unaware of the cold, cruel nature of reality.
For now, it’s prohibitively expensive to get every single genetic test. With how much I would have to spend today to get 50 patented tests I would be better off waiting a year and getting my genome sequenced, then analyzing the data myself to (illegally?) check for every high penetrance mutation.
Think Gene at Technorati
