Scientists Solve DNA Puzzle of Cord Stem Cell Infection

Researchers studying diseases with an unknown cause may have a new method to try, as scientists reverse engineered a new bacterium responsible for a syndrome discovered fewer than two years ago.

The quest began in 2011, after doctors reported a syndrome they called cord colitis in a small group of patients treated with umbilical cord stem cells for blood cancer and other hematologic diseases. Researchers at Dana-Faber Cancer Institute in Boston hypothesized that the new ailment, which responded to antibiotics, stemmed from a previously unknown infectious agent.

Bacteria are typically identified after investigators obtain a living sample and grow it in laboratory dishes. In the case of cord colitis, all the researchers had was preserved biopsy specimens from colons of treated patients that weren’t alive and couldn’t grow. After sequencing the DNA from the specimens and eliminating those identified as human, they began assembling pieces of the genetic jigsaw puzzle that was left.

“If these patients had an infection, there should be human cells and bacterial cells,” said Ami Bhatt, the lead researcher and a clinical fellow in hematology and oncology at Dana-Faber. “What I expected to find was some weird variety of E. coli” or a similar bacteria found in the gut, she said in a telephone interview. “We didn’t find much of those at all.”

Meticulously fitting the DNA pieces together, aided by overlapping sequences that provided some continuity, the researchers assembled a draft genome that seemed to resemble a bacteria typically found in agriculture. They named it bradyrhizobium enterica.

First Feat

“This is to my knowledge is the first example of discovering a new bacteria using sequencing of a human disease tissue specimen,” Bhatt said. “It is a proof of concept: That from a human disease tissue specimen, you can go in with the hypothesis that the disease is caused by an infection and you can identify a yet undiscovered bacterium.”

The researchers compared DNA from the bacteria they assembled using tissue from two patients to biopsy specimens taken from three others with cord colitis. Testing showed similar genetic traits in all three. Another test run against samples taken from healthy people and those with colon cancer or graft-versus-host disease failed to find a match.

The assembly of the B. enterica genome by sequencing DNA taken from biopsy samples “is an amazing accomplishment,” wrote Eric Pamer, from Memorial Sloan-Kettering Cancer Center in New York, in an editorial that accompanied the report in the New England Journal of Medicine. It doesn’t, however, prove the bacteria caused the infection, he wrote.

Distinct Species

There are hundreds of distinct bacterial species in the healthy human gut, he wrote. The treatment stem-cell transplant patients first undergo to wipe out their immune system and allow the new cells to engraft can increase their susceptibility to microbial invasion, he said. Some microbes, meanwhile, don’t cause disease and are instead targets of the immune system.

The new bacteria may be a target of the patient’s immune system after it starts to recover from treatment, he said.

“For now, B. enterica stands indicted and presented as a possible perpetrator,” he wrote. “The final verdict, however, awaits additional evidence.”

Publication of the work thus far should help the researchers, Bhatt said. She is hoping doctors treating umbilical cord stem-cell transplant patients with cord colitis may led to samples that could be conventionally tested and grown. Researchers working in agricultural genetics may be able to run the new bacteria against their own databases, and help further identify the microbe.

“We have the genome sequence but we don’t yet have the organism,” she said. “There is a lot of work to be done to determine if this is the cause of the disease.”

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