Daily Archives: May 7, 2017

3d render of a DNA spirals

One thing cells must do in order to become cancerous is to overthrow the normal checks on their growth. As a part of this process, the stringent controls on things like copying and repairing DNA start to break down. As a result, tumors often contain chromosomal rearrangements, which are places where genes are cut and pasted back together in ways that they shouldnt be.

In some cases, the breaks bring twogenes together in a way that causes what are called "driver mutations," forming a fusion protein thatpushes the cells further along the road to malignancy. For some types of cancer, nearly every tumor contains one of these chromosome breaks, making itsfusion genes ahallmark of that cancer. A group of researchers at the University of Pittsburgh School of Medicine just took advantage of this specificity by targeting thefusion genes to attackcancer cells and take them down.

The work relies on the CRISPR-Cas system, which is used by bacteria to recognize foreign DNA (like that of avirus) and chop it up. We've since learned how totarget any DNA sequence, making ita formidable means of gene editing. Here, the researchers used a CRISPR-Cas system to make a nicka single stranded cut in the double helixin the tumor DNA, right at the point where two genes are fused.

This break should trigger the cell'srepair pathway to fix that single stranded nick, sothe researchers hijacked this system by providing it with DNA to use in the repair. With the DNA supplied by the researchers, the repair system inserted an enzyme into the location of the gene fusion. The enzyme they chose takes a harmless drug precursor and metabolizes itinto its active form. So: they target the tumor cell because only it has this DNA rearrangement; then, when they apply the drug, only tumor cells are affected by it. Normal cells arent.

First, the researchers tested the approach by generating cells with the gene rearrangement they wanted; they took a fusion gene that recurs in prostate cancer and put it into a cell line that usually lacks it. Their approach worked: only cells that received all of the components (fusion gene, CRISPR-Cas, new enzyme, and drug) were killed. Cells without the fusion gene could not express the enzyme and thus were unaffected by the drug.

Next the researchers took the engineered cells and transplanted them into immunodeficient mice, where the cells grew into tumors. (This is a pretty standard way of generating tumors on which drugs can be tested.) If the mice were given all of the components of the CRISPR/drug system, the tumors shrank by 30percent. Control mice, whosetumors did not have the fusion gene, exhibited a metastasis rate of 50percenteven if they were given the CRISPR/drugcomponentsand died.

Then the researchers tried it in a human hepatocellular carcinoma cell line that had a different chromosomal rearrangement. This means they had to modify the CRISPR-Cas system to target this rearrangement. But they saw the same effect: up to 27percent of the cells expressed the enzyme (this rate is typical for gene editing using CRISPR-Cas), and up to 27percent of cells were killed by the drug.

Lastly, they put these cells in mice, and saw the same thing: mice that also got all of the other components had their tumors shrink, but mice that didnt died.

Current cancer therapeutics often rely on interrupting the signaling pathways that drive tumor growth and are thus almost begging the tumor to develop resistance. Since fusion-gene breakpoints may not be cancer drivers, using them to target tumor cells might not induce resistance in the same way. And even if using breakpoints does, some other bit of DNA damage in the tumorscan just be targeted, as long as one can be identified. Since the DNA damage isso highly specific, targeting itwith drugs doesnt generate the nasty side effects that result when drugs run afoul of normal cells instead of just cancer cells.

Since chromosomal breakpoints may differ among peopleand even among different tumors in the same personthis would be a highly individualized therapy. But if it is technically feasible, it might hold promise.

Nature Biotechnology, 2017. DOI: 10.1038/nbt.3843 (About DOIs).

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DNA damage in cancer cells targeted to kill them | Ars Technica - Ars Technica

Matsuyama Police suspect a woman in her 30s who recently committed suicide following police questioning about a murder in Imabari, Ehime Prefecture, may have been involved in an earlier killing in the city, investigative sources said Sunday.

A DNA sample, taken from the woman when she was questioned by police over the death on Wednesday of 92-year-old Yukie Okamoto, matched DNA collected from an object in the home of 81-year-old Satsuki Ochi, who was found dead with stab wounds on April 26, the sources said.

Knives, believed to be the murder weapons, were left in the victims homes, which were located only 400 meters apart.

Okamotos son, Hisayuki, 70, who was severely wounded, told investigators he had been stabbed by an unknown woman.

The woman in her 30s, who lived near to where Okamoto lived, underwent questioning on a voluntary basis last Thursday.

She was found dead Friday morning, just before investigators planned to take her in for further questioning. The woman left a suicide note in which she denied involvement in Okamotos death, one of her family members said.

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DNA evidence suggests woman who killed self was involved in second Ehime murder - The Japan Times

Researchers who have completed the first genetic analysis on the bones from the crew of the doomed Franklin expedition in Canada's Arctic say they're hoping to meet living descendants to match them with the remains of their ancestors.

Anne Keenlyside, an anthropologist at Trent University and co-author of a study on the remains, performed DNA analysis of tooth and bone samples recovered from eight sites where sailors died after they deserted the HMS Erebus and HMS Terror in April 1848.

Keenlyside said the analysis doesn't shed much light on what befell the expedition, which became icebound while looking for the Northwest Passage. But researchers have put a call out to genealogists in Canada and the United Kingdom for anyone who can trace a family tree to the Franklin sailors.

Matching the DNA with the living would indicate who died where, the study says.

"If we can find those living descendants if they're directly descended from those crew members and if they're willing to submit a DNA sample in the form of a ... cheek swab, then we can analyze their DNA, compare it to the DNA extracted from these skeletal remains and see if there is a match," Keenlyside told The Canadian Press.

Doug Stenton, lead author of the study released online in the Journal of Archeological Science: Reports, said knowing who the men were would shed light on their rank. That information would add to a bank of knowledge that could one day unlock the mystery of the failed mission.

"I think it's going to be a combination of things that ultimately lead to an understanding of what happened," said Stenton, who is with Nunavut's Culture and Heritage Department. "It's important we take advantage of as many sources as we can."

The Franklin expedition left England and headed north, never to return, in 1845. Its two ships were found within the last three years by underwater archeologists.

How things went so badly wrong has remained a mystery and a legend.

DNA analysis was difficult because many of the remains were exposed to the harsh northern elements for more than 150 years, Keenleyside said. DNA also degrades over time.

A cairn that was found in 1859 indicated that 105 men left the icebound ships in April 1848 and came ashore on the northwest coast of King William Island. It's believed their plan was to walk along the Back River to a Hudson Bay Co. post.

Franklin died almost a year earlier in June 1847.

The DNA study concluded that 21 people, or 20 per cent of the sailors who left the ships, died at five of the sites within a small area of Erebus Bay, which is only about 70 kilometres from where the crew came ashore. Since a few crew members made it 230 kilometres further to Montreal Island, the study's authors suggest there must have been significant health differences between the men when they left the ships.

"Why did so many men die so early on? Something must have gone severely wrong," Stenton said.

Some theories about why the mission failed include lead poisoning and spoiled tinned preserves.

This summer, Parks Canada's underwater archaeology team is to return to Nunavut to conduct some preliminary dives on HMS Terror and continue the archeological work on HMS Erebus.

Stenton said more clues are likely to be uncovered as dive teams explore the shipwrecks.

The researchers say they've already made preliminary contact with some descendants of the crews. And they say more clues are out there.

"Of the 129 crew members, we've only recovered the remains of maybe 30 of those individuals," Keenleyside said.

"What happened to the rest of them? It leaves you wondering whether additional human remains will be found of these crew members."

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Franklin researchers hope to link DNA from sailors' bones with descendants - Brandon Sun