'Quadruple Helix' DNA Discovered In Human Cells

Image via: Gizmodo.com

In 1953, Cambridge researchers Watson and Crick published a paper describing the interweaving 'double helix' DNA structure - the chemical code for all life. Now, in the year of that scientific landmark's 60th Anniversary, Cambridge researchers have published a paper proving that four-stranded 'quadruple helix' DNA structures - known as G-quadruplexes - also exist within the human genome. They form in regions of DNA that are rich in the building block guanine, usually abbreviated to 'G'.

The findings mark the culmination of over 10 years investigation by scientists to show these complex structures in vivo - in living human cells - working from the hypothetical, through computational modelling to synthetic lab experiments and finally the identification in human cancer cells using fluorescent biomarkers. 

The research, published today in Nature Chemistry and funded by Cancer Research UK, goes on to show clear links between concentrations of four-stranded quadruplexes and the process of DNA replication, which is pivotal to cell division and production. 

By targeting quadruplexes with synthetic molecules that trap and contain these DNA structures - preventing cells from replicating their DNA and consequently blocking cell division - scientists believe it may be possible to halt the runaway cell proliferation at the root of cancer. 

"The research indicates that quadruplexes are more likely to occur in genes of cells that are rapidly dividing, such as cancer cells. For us, it strongly supports a new paradigm to be investigated - using these four-stranded structures as targets for personalised treatments in the future."

Physical studies over the last couple of decades had shown that quadruplex DNA can form in vitro - in the 'test tube', but the structure was considered to be a curiosity rather than a feature found in nature. The researchers now know for the first time that they actually form in the DNA of human cells. 

"This research further highlights the potential for exploiting these unusual DNA structures to beat cancer – the next part of this pipeline is to figure out how to target them in tumour cells," said Dr Julie Sharp, senior science information manager at Cancer Research UK. 

"We have found that by trapping the quadruplex DNA with synthetic molecules we can sequester and stabilise them, providing important insights into how we might grind cell division to a halt," said Balasubramanian. 

The study showed that if an inhibitor is used to block DNA replication, quadruplex levels go down - proving the idea that DNA is dynamic, with structures constantly being formed and unformed. 

The researchers also previously found that an overactive gene with higher levels of Quadruplex DNA is more vulnerable to external interference. 

"The possibility that particular cancer cells harbouring genes with these motifs can now be targeted, and appear to be more vulnerable to interference than normal cells, is a thrilling prospect. 

Via: "Phys"

The 4 Hardest Computing Problems On Earth

America's most powerful supercomputer runs calculations so quickly it makes your laptop look like an abacus. The machine, called Titan, is located at the Oak Ridge National Laboratory in Tennessee. It is also the fastest supercomputer the world. It can process more than 17 petaflops of data per second -- that's roughly 20,000 trillion simultaneous calculations. Though Titan has the strength of 500,000 laptops, computer scientists are hungry for more. Already, they are dreaming of a machine that could manage an exaflop of data, which would require about 50 times more processing power than Titan. So-called exascale computing could let researchers answer some of the toughest scientific problems. Here's a closer look.



Virtual Climate:

Building better climate models is becoming more important, as scientists work to predict the potential effects of a warming planet. Supercomputers are already integral to our understanding of atmospheric changes. "Whenever you see forecasters on TV, that weather movie took hours and hours to render on a supercomputer," says Sumit Gupta, a general manager at Nvidia's accelerated computing unit. (Nvidia's chips help power Titan.) But the best supercomputers today fall short of researchers' goals. If you think of the globe as an image, the best supercomputers can only render pixels the size of 14 square kilometers. An exascale computer could bring that down to one square kilometer. The effect? Scientists could see the impact of minutely detailed climate factors such as individual cloud formations and ocean eddies.



Digital Cells:

Much of the future of pharmaceuticals is in algorithms, not petri dishes. Researchers will develop drugs based on programs that predict how chemicals will interact with the body. Titan, for example, will advance these digital drug tests, says Jack Wells, the director of science at the Oak Ridge Leadership Computing Facility. It will let researchers solve equations that apply a technique called molecular dynamics. In this approach to solving problems in biology, chemistry, and materials sciences, scientists model the movement of individual atoms or molecules, factoring in the various forces exerted on them. Unfortunately, even with today's most powerful computers, scientists can only apply molecular dynamics to small clusters of atoms. A human cell, on the other hand, is composed of billions of atoms that all interact, and it is too complex for current computers to model. The hope is that future supercomputers could handle whole cells.



Future Fuel:

The equations behind burning fuel are extremely difficult to understand on the micro-scale. Scientists studying combustion must rely on guesswork. With Titan, scientists can model the chemical reactions for combustion of relatively simple fuels like alcohol and butanol. But because gasoline and biodiesels are complex fuels -- the molecules inside are longer and thus trickier to model -- more and more powerful supercomputers will be required to parse them.



Inside Supernova:

More powerful supercomputers could shine a light on some of the most foreign phenomena in the universe. For example, scientists in the future may be able to model the awesome forces that interact when a star explodes. Those events, called supernovae, often spew enough energy and light to outshine an entire galaxy. Supernovae involve not just astrophysics, but chemical and nuclear reactions. Running programs that includes all the sciences at play would require an exaflop of data. With that much power, the next generation of supercomputers could bring the mysteries of deep space closer to home.

Via: "CNN"

Children’s Cells Living In Mothers’ Brains

The Connection Between Mother and Child Is Ever Deeper Than Thought

Robert Martone reports,

The profound psychological and physical bonds shared by the mother and her child begin during gestation when the mother is everything for the developing fetus, supplying warmth and sustenance, while her heartbeat provides a soothing constant rhythm.

The physical connection between mother and fetus is provided by the placenta, an organ, built of cells from both the mother and fetus, which serves as a conduit for the exchange of nutrients, gasses, and wastes. Cells may migrate through the placenta between the mother and the fetus, taking up residence in many organs of the body including the lung, thyroid muscle, liver, heart, kidney and skin. These may have a broad range of impacts, from tissue repair and cancer prevention to sparking immune disorders.

... stunning results from a new study show that cells from other individuals are also found in the brain. In this study, male cells were found in the brains of women and had been living there, in some cases, for several decades. What impact they may have had is now only a guess, but this study revealed that these cells were less common in the brains of women who had Alzheimer’s disease, suggesting they may be related to the health of the brain.

... although we certainly consider our actions and decisions as originating in the activity of our own individual brains, cells from other individuals are living and functioning in that complex structure. However, the mixing of cells from genetically distinct individuals is not at all uncommon. This condition is called chimerism after the fire-breathing Chimera from Greek mythology, a creature that was part serpent part lion and part goat. Naturally occurring chimeras are far less ominous though, and include such creatures as the slime mold and corals.

 Microchimerism is the persistent presence of a few genetically distinct cells in an organism. This was first noticed in humans many years ago when cells containing the male “Y” chromosome were found circulating in the blood of women after pregnancy. Since these cells are genetically male, they could not have been the women’s own, but most likely came from their babies during gestation.

In this new study, scientists observed that microchimeric cells are not only found circulating in the blood, they are also embedded in the brain. They examined the brains of deceased women for the presence of cells containing the male “Y” chromosome. They found such cells in more than 60 percent of the brains and in multiple brain regions. Since Alzheimer’s disease is more common in women who have had multiple pregnancies, they suspected that the number of fetal cells would be greater in women with AD compared to those who had no evidence for neurological disease. The results were precisely the opposite: there were fewer fetal-derived cells in women with Alzheimer’s. The reasons are unclear.

Microchimerism most commonly results from the exchange of cells across the placenta during pregnancy, however there is also evidence that cells may be transferred from mother to infant through nursing. 

In addition to exchange between mother and fetus, there may be exchange of cells between twins in utero, and there is also the possibility that cells from an older sibling residing in the mother may find their way back across the placenta to a younger sibling during the latter’s gestation. Women may have microchimeric cells both from their mother as well as from their own pregnancies, and there is even evidence for competition between cells from grandmother and infant within the mother.

What it is that fetal microchimeric cells do in the mother’s body is unclear, although there are some intriguing possibilities. For example, fetal microchimeric cells are similar to stem cells in that they are able to become a variety of different tissues and may aid in tissue repair. 

One research group investigating this possibility followed the activity of fetal microchimeric cells in a mother rat after the maternal heart was injured: they discovered that the fetal cells migrated to the maternal heart and differentiated into heart cells helping to repair the damage. In animal studies, microchimeric cells were found in maternal brains where they became nerve cells, suggesting they might be functionally integrated in the brain. It is possible that the same may true of such cells in the human brain.

These microchimeric cells may also influence the immune system. A fetal microchimeric cell from a pregnancy is recognized by the mother’s immune system partly as belonging to the mother, since the fetus is genetically half identical to the mother, but partly foreign, due to the father’s genetic contribution. This may “prime” the immune system to be alert for cells that are similar to the self, but with some genetic differences. Cancer cells which arise due to genetic mutations are just such cells, and there are studies which suggest that microchimeric cells may stimulate the immune system to stem the growth of tumors. Many more microchimeric cells are found in the blood of healthy women compared to those with breast cancer, for example, suggesting that microchimeric cells can somehow prevent tumor formation. In other circumstances, the immune system turns against the self, causing significant damage. Microchimerism is more common in patients suffering from Multiple Sclerosis than in their healthy siblings, suggesting chimeric cells may have a detrimental role in this disease, perhaps by setting off an autoimmune attack.

Via: "Scientific American"

Introducing 'Bi-Fi' - The Biological 'Internet'

The researchers, Monica Ortiz, a doctoral candidate in bioengineering, and Drew Endy, PhD, an assistant professor of bioengineering, have parasitized the parasite and harnessed M13's key attributes -- its non-lethality and its ability to package and broadcast arbitrary DNA strands -- to create what might be termed the biological Internet, or "Bi-Fi." Their findings were published online Sept. 7 in the Journal of Biological Engineering.

Using the virus, Ortiz and Endy have created a biological mechanism to send genetic messages from cell to cell. The system greatly increases the complexity and amount of data that can be communicated between cells and could lead to greater control of biological functions within cell communities. The advance could prove a boon to bioengineers looking to create complex, multicellular communities that work in concert to accomplish important biological functions.

Medium and Message

M13 is a packager of genetic messages. It reproduces within its host, taking strands of DNA -- strands that engineers can control -- wrapping them up one by one and sending them out encapsulated within proteins produced by M13 that can infect other cells. Once inside the new hosts, they release the packaged DNA message.

The M13-based system is essentially a communication channel. It acts like a wireless Internet connection that enables cells to send or receive messages, but it does not care what secrets the transmitted messages contain.

"Effectively, we've separated the message from the channel. We can now send any DNA message we want to specific cells within a complex microbial community," said Ortiz, the first author of the study.

It is well-known that cells naturally use various mechanisms, including chemicals, to communicate, but such messaging can be extremely limited in both complexity and bandwidth. Simple chemical signals are typically both message and messenger -- two functions that cannot be separated.

"If your network connection is based on sugar then your messages are limited to 'more sugar,' 'less sugar,' or 'no sugar'" explained Endy.

Cells engineered with M13 can be programmed to communicate in much more complex, powerful ways than ever before. The possible messages are limited only by what can be encoded in DNA and thus can include any sort of genetic instruction: start growing, stop growing, come closer, swim away, produce insulin and so forth.

Rates and Ranges

In harnessing DNA for cell-cell messaging the researchers have also greatly increased the amount of data they can transmit at any one time. In digital terms, they have increased the bit rate of their system. The largest DNA strand M13 is known to have packaged includes more than 40,000 base pairs. Base pairs, like 1s and 0s in digital encoding, are the basic building blocks of genetic data. Most genetic messages of interest in bioengineering range from several hundred to many thousand base pairs.

Ortiz was even able to broadcast her genetic messages between cells separated by a gelatinous medium at a distance of greater than 7 centimeters.

"That's very long-range communication, cellularly speaking," she said.

Down the road, the biological Internet could lead to biosynthetic factories in which huge masses of microbes collaborate to make more complicated fuels, pharmaceuticals and other useful chemicals. With improvements, the engineers say, their cell-cell communication platform might someday allow more complex three-dimensional programming of cellular systems, including the regeneration of tissue or organs.

"The ability to communicate 'arbitrary' messages is a fundamental leap -- from just a signal-and-response relationship to a true language of interaction," said Radhika Nagpal, professor of computer science at the Wyss Institute for Biologically Inspired Engineering at Harvard University, who was not involved in the research. "Orchestrating the cooperation of cells to form artificial tissues, or even artificial organisms is just one possibility. This opens a door to new biological systems and solving problems that have no direct analog in nature."

Ortiz added: "The biological Internet is in its very earliest stages. When the information Internet was first introduced in the 1970s, it would have been hard to imagine the myriad uses it sees today, so there's no telling all the places this new work might lead."

Via: "Science Daily"