Category Archives: Transhuman News

These days, cancer is as much a target for researchers with number-crunching skills and their data-mining tools as it is for scientists in biomedical research labs. And one potentially powerful big-data approach to conquering cancerwhich involves discovering clever genetic tricks to make cancer cells kill themselveshas moved in a promising new direction this month.

Scottish, Israeli, and American researchers have reported a new discovery that analyzes existing cancer gene databases for clues to combinations of genes that together can kill tumor cells while leaving healthy cells untouched. The idea takes advantage of a phenomenon called synthetic lethality, which in oncology was first explored 17 years ago as a potentially fruitful new line of cancer treatment.

One of the new papers coauthors, Eytan Ruppin, director of the University of Marylands Center for Bioinformatics and Computational Biology, says cancer cells are like regular cells run amok. They, like regular cells, typically have some 10,000 genes. But in cancer cells, many more of these genes are inactivemeaning that for whatever reasons, those genes dont produce the proteins that a healthy version of the cell would be producing.

Since the 1920s, its been observed that all cells in fact have networks of secret self-destruct switches: When both of a key pair of genes become inactive, the entire cell begins the process of shutdown and cell death.

So, Ruppin says, the hurdle that needs to be overcome in order to make this possible broad-spectrum genetic cancer treatment work is discovering and cataloging as many of these secret synthetically lethal (SL) gene pair combinations as nature has provided. Then, when a patients cancer is biopsied, and its genome is taken, an oncologist can look to see which genes in the patients cancer cells are inactive.

For example, say that the oncologist discovers in an SL database that an inactive gene in a patients tumor (call it Gene A) happens to have a corresponding synthetically lethal partner gene (call it Gene B).

In this case, then, a drug that inactivates Gene B will trigger the cell death process in the tumor but not in the persons healthy cells. (Depending on what Gene B does, there might also be side effects from switching Gene B off. But so long as Gene A remains active throughout the rest of the persons body, those side-effects should not include cell death.)

Ruppin and his collaborators used a clever data mining technique to discover more than a thousand candidate SL gene combinations. They plumbed the U.S. National Cancer Institutes Cancer Genome Atlas, which itself contains thousands of genomes of different biopsied tumor samples.

They then ran searches for various inactive genes. So, for the sake of example, say they found some of the cancers in the database with Gene X inactivated. And some of the cancers in the database had Gene Y inactivated. If Genes X and Y dont form an SL pair, there should then be plenty of examples in the database of cancers where both X and Y were inactive. However, if Genes X and Y do form an SL pair, then there should be almost no examples of tumors in the database where those two genes are both inactive.

You would have expected them to be inactive together at a certain rate, given their individual inactive frequencies, Ruppin says. But when you look at the data, you find that they are never inactive together, Ruppin adds that this, is a very strong indication that they are synthetically lethal. Because whenever they were inactive together, they were actually eliminated from the population. Because these cells died.

Continued here:
Hacking the Cancer Genome

Imagine going to the hospital with one disease and coming home with something much worse, or not coming home at all.

With the emergence and spread of antibiotic-resistance pathogens, healthcare-associated infections have become a serious threat. On any given day about one in 25 hospital patients has at least one such infection and as many as one in nine die as a result, according to the Centers for Disease Control and Prevention.

Consider Klebsiella pneumoniae, not typically a ferocious pathogen, but now armed with resistance to virtually all antibiotics in current clinical use. It is the most common species of carbapenem-resistant Enterobacteriaceae (CRE) in the United States. As carbapenems are considered the antibiotic of last resort, CREs are a triple threat for their resistance to nearly all antibiotics, high mortality rates and ability to spread their resistance to other bacteria.

But there is hope. A team of Sandia National Laboratories microbiologists for the first time recently sequenced the entire genome of a Klebsiella pneumoniae strain, encoding New Delhi Metallo-beta-lactamase (NDM-1). They presented their findings in a paper published in PLOS One, "Resistance Determinants and Mobile Genetic Elements of an NDM-1 Encoding Klebsiella pneumoniae Strain."

The Sandia team of Corey Hudson, Zach Bent, Robert Meagher and Kelly Williams is beginning to understand the bacteria's multifaceted mechanisms for resistance. To do this, they developed several new bioinformatics tools for identifying mechanisms of genetic movement, tools that also might be effective at detecting bioengineering.

"Once we had the entire genome sequenced, it was a real eye opener to see the concentration of so many antibiotic resistant genes and so many different mechanisms for accumulating them," explained Williams, a bioinformaticist. "Just sequencing this genome unlocked a vault of information about how genes move between bacteria and how DNA moves within the chromosome."

Meagher first worked last year with Klebsiella pneumoniae ATCC BAA-2146 (Kpn2146), the first U.S. isolate found to encode NDM-1. Along with E.coli, it was used to test an automatic sequencing library preparation platform for the RapTOR Grand Challenge, a Sandia project that developed techniques to allow discovery of pathogens in clinical samples.

"I've been interested in multi-drug-resistant organisms for some time. The NDM-1 drug resistance trait is spreading rapidly worldwide, so there is a great need for diagnostic tools," said Meagher. "This particular strain of Klebsiella pneumoniae is fascinating and terrifying because it's resistant to practically everything. Some of that you can explain on the basis on NDM-1, but it's also resistant to other classes of antibiotics that NDM-1 has no bearing on."

Unlocking Klebsiella pneumoniae

Assembling an entire genome is like putting together a puzzle. Klebsiella pneumoniae turned out to have one large chromosome and four plasmids, small DNA molecules physically separate from and able to replicate independently of the bacterial cell's chromosomal DNA. Plasmids often carry antibiotic resistant genes and other defense mechanisms.

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Clues to superbug evolution: Microbiologists sequence entire genome of a Klebsiella pneumoniae strain