Diagnosing Disease with DNA

A new DNA-screening technique that saved a young boy's life by linking his brain swelling to a bacterial infection that conventional medical tests had missed could lead to speedier diagnoses of critical conditions and more effective treatments of hard-to-identify maladies, doctors say. "We can test for any kind of disease-causing agent — viruses, bacteria, fungi and parasites — without having to know the suspects beforehand," said Charles Chiu, a pathologist at the University of California, San Francisco (UCSF).

Paging Dr. House For weeks, 15-year-old Joshua Osborn had been feeling unwell. Osborn, who is from Cottage Grove, Wisconsin, was admitted to the University of Wisconsin Hospital in April 2013 for fever and debilitating headaches, but was discharged when his symptoms improved. A few weeks later, he was hospitalized again, but was released when a spinal tap and a biopsy came back negative for infectious diseases.
Later that summer, his waxing and waning symptoms took a turn for the worse, and he was back in the hospital with brain-swelling encephalitis. At one point, the swelling was so bad that he experienced uncontrollable seizures, which forced physicians to place him in a coma. Doctors couldn't figure out what was wrong with him.

The situation was complicated by the fact that Josh had been born with severe combined immunodeficiency disease (SCID), a rare affliction that leaves people extremely vulnerable to infectious diseases. "Understanding the causes of disease symptoms in patients with altered, weakened immune systems poses special challenges," said James Gern, a pediatrician and an immunologist at the University of Wisconsin School of Medicine and Public Health who has coordinated Josh's medical care for most of the boy's life.
"The immune system itself may generate symptoms by attacking the body's own tissues," Gern explained. "Furthermore, the range of possible sources of infection can be much greater in these immune-compromised patients."

UCSF pathologist Charles Chiu (left) and UCSF molecular biologist Joseph DeRisi used state-of-the-art genetic sequencing machines capable of reading millions of DNA bases, or "letters," simultaneously, and custom software that they had developed to match the sequenced DNA with the DNA of organisms contained in national genome databases.

With few options left, Gern enlisted the help of a colleague of his from UCSF, Joseph DeRisi, who had a reputation for unearthing disease agents.

A New Test

DeRisi and his team wanted to perform a new DNA-sequencing technique on Josh's blood and cerebrospinal fluid samples. The idea was not to learn more about the patient's own DNA but rather to screen for the presence of anything in the blood and spinal fluid that wasn't human.
After the boy's parents, Clark and Julia Osborn, agreed to the procedure, the team jumped into action. They used state-of-the-art genetic sequencing machines capable of reading millions of DNA bases, or "letters," simultaneously, and custom software that they had developed, called SURPI (Sequence-based Ultra-Rapid Pathogen Identification), to match the sequenced DNA with the DNA of organisms contained in national genome databases. This kind of analysis would have taken days or weeks a few years ago, but DeRisi's team was able to complete it in less than two hours.

Within 48 hours of receiving Josh's blood and spinal fluid, the UCSF scientists had identified the culprit behind his crippling headaches: Leptospira santarosai, a bacterium native to Puerto Rico — where he and his family had visited a church camp a year before his symptoms appeared.
"We felt certain of the diagnosis," said Michael Wilson, a UCSF neurologist who was part of the team. "Encephalitis is a known complication of leptospirosis. Hundreds of pieces of DNA from Josh's spinal fluid matched, but none from the negative control samples contained any Leptospira DNA, so there was no indication of contamination during the lab procedures."
The medical team at the University of Wisconsin Hospital moved quickly to treat Josh with penicillin and the boy soon emerged from his coma and was able to return home.

A "Great Story"

Tom Slezak, who leads the pathogen informatics team at the Lawrence Livermore National Laboratory, called Josh's case "an absolutely great story". Slezak, who was not involved in the study, described the effort to identify the cause of the boy's encephalitis "a tremendous tour de force."
Slezak said that it could take years of further research before the new diagnostic test is approved for routine use, but that it would be immensely useful once it was approved.
Study coauthor Chiu agreed. He said that the DNA-probing technique his team used to save Josh's life, called "unbiased next-generation sequencing," could prove especially valuable in diagnosing not only certain types of encephalitis, but also certain types of respiratory and blood-borne illnesses, tick-borne diseases and even outbreaks of infections due to emerging agents such as the Middle Eastern Respiratory Syndrome (MERS) coronavirus.
"It could be one test to rule them all," DeRisi told the New York Times.

Discussion Questions

Besides the diseases mentioned in the story, what other health problems might be more readily diagnosed with the sort of DNA technology described here? What kinds of health problems might it not help with? What other benefits do you think may come from fast and cheap DNA sequencing?