Direct diagnosis: Typical methods to detect the microbe that causes tuberculosis (shown here in yellow), can take weeks. New sequencing-based methods could shorten that to 24 hours.
CDC/Ray Butler, Janice Carr
A startup is developing sequencing-based tests that could detect infections within 24 hours.
Current methods of diagnosing an infectious disease can take days to weeks. Now a Cambridge, MA-based startup called Pathogenica is developing a way to do it within a day--by reading the DNA sequence of pathogens.
Pathogenica is developing diagnostic tests designed to detect harmful microorganisms by zeroing in on the genes responsible for their harmful effects or their resistance to certain drugs. The company will initially focus on detecting the bacteria that cause urinary tract infections, and aims to have a product approved by the U.S. Food and Drug Administration by the end of 2012, with a target of $10 per test.
The cost of DNA sequencing has dropped exponentially in the last few years, thanks to new technologies. These new methods have been used to sequence human genomes, and they've also been used as part of public health efforts to detect the emergence of novel pathogens, such as the H1N1 virus. But for the most part, these technologies have not yet made their way into routine medical care. Pathogenica aims to change that by combining cheaper sequencing with new approaches to isolate specific pieces of the genome, such as the genes involved in an organism's ability to infect its host and cause harm.
"[Sequencing] allows the diagnostician the possibility of casting a very wide net and even to detect unsuspected dual or triple infections," says Ruben Donis, chief of the molecular genetics branch at the Centers for Disease Control and Prevention.
Today, physicians diagnose an infection by collecting a sample from a patient, growing the pathogens, and then identifying them by their appearance or the conditions under which they grow. But this approach is time-consuming and only works for a fraction of microbes. "The majority require days to get a result, which is frequently too late," says Ian Lipkin, an infectious-disease specialist at Columbia University. Lipkin is a member of Pathogenica's advisory board. Faster detection would help physicians distinguish between different infections that have similar symptoms but require different treatments, such as viral and bacterial meningitis.
A growing number of pathogens can be detected using so-called molecular tests, developed over the last decade, which identify microbes by isolating and amplifying specific chunks of DNA. Molecular testing is much faster than culture methods, and has improved medical care by letting doctors correctly diagnose a disease and begin treatment before a patient even leaves the doctor's office, says Lipkin. "But directly sequencing DNA is much more precise," he says. Sequencing also lets scientists search for multiple microbes simultaneously.
Sequencing the genes responsible for drug-resistance will let physicians immediately determine which antibiotics a microbe is immune to, helping them choose the most effective drugs from the start. "The standard of the field is to identify the species, rather than the [genetic variations] that cause them to be pathogenic or drug-resistant," says George Church, a geneticist at Harvard Medical School who sits on the company's science advisory board.
Tools that could quickly and cheaply monitor pathogens would also be useful in confirming the role of infectious microbes in other diseases, such as autoimmune disease, encephalitis, and some cancers, says Lipkin. Cervical cancer and some types of oral cancers, for example, are now known to be linked to the human papillomavirus.
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338 Comments
Interesting approach
Our molecular biology lab has to search for a variety of DNA matches for certain of our PCR tests. I.e there are often several strains of the bacteria and viruses we run them for. Plus new strains mutate and new strains are discovered so we get updated templates to identify species for the tests.
Resistance specific genes may vary similarly over time for the same gene and new genes that cause resistance to a specific drug by another method will also show up. These won't show up as positive by a specific sequence test even tho they confer resistance against a certain drug. But bacteria swap genetic info that could be detected by this kind of method between species even via direct exchange and by phages, kind of like teenagers exchange trinkets (and 20 somethings exchange chlamydia). This kind of exchange to confer resistance between species would be very useful to detect and it would be the most common way a new species acquires resistance. A whole new mechanism for resistance most likely would take much longer and larger populations.
So updating the tests will be an ongoing process of identifying new genes and variations - mutations in the sequences, but also noticing new mechanisms and IDing them.
24 hours? DNA tests are currently already as quick as like 20 minutes. It takes longer to draw the sample, prep, transport, put in the computer and send into the lab. I had a specimen taken at a drawsite to see if a Hep B vaccine had taken. Just a few hours later I get into work and go online to the lab site to check and the results are already in showing surface antigen (used in the vaccine) positive and core (indicating infection) negative. It had gone thru all these steps plus the test in a very short time.
Sounds like we'll probably be using the same machines we currently use with a different database to match, it's still DNA amplification. But this approach has advantages. Instead of running a specific organism DNA, e.g. CT/NG we could not only look for resistance dna but any dna, figure out what it is from and tell Dr what is present, much like our cultures which take much longer to grow as the article mentions but then have an organism that can be identified various ways.
We sometimes run culture for specific organisms and sometimes the Dr tells us to ID whatever is there instead of test for specific bug. But the power of matching DNA is illustrated by a complicated branching flow chart page in the microbio text: you try the organism on various types of agar to isolate what type or exact organism it is. There are even machines to do this culture flowchart with self contained cartridges, to identify what it will grow on, but still takes time being culture, and some things can't be grown on agar, others are finicky or grow very slowly (weeks or longer). The PCR flowchart next to this complicated flowchart simply has a single box: PCR identifies most organisms, very simple procedure wise. The computer will still do complex matching but this is hidden from the end user of the machine largely.
Eventually, these might be moved closer to the consumer for quicker results. Our mol bio area tho is sensitive since just an incredibly small sample (a few strands) of DNA can be amplified, which amplifies contaminants also. Low complexity tests are often moved to mid complexity labs and so on upwards because of inconvenient things like controls and someone to figure out if the sample is degraded or some other reason to invalidate the test.
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