For years, scientists and doctors have treated common viral and bacterial infections with somewhat dull therapies. If you caught a stomach bug or sinus infection, you would likely be prescribed a broad-spectrum antibiotic that would eliminate many different types of bacteria. Antiviral drugs assist in treating viral illnesses in much similar way by hampering the pathogen’s ability to reproduce and disperse in the body.
But microorganisms are quick to develop, and many have developed defenses against the methods invented to kill them. A growing number of bacteria are now unaffected to one or more antibiotics. Each year approximately 700,000 people around the globe die from such infections, and by 2050 the number could increase to 10 million, according to United Nations figures. Viruses, too, speedily evolve new ways of concealing themselves from drugs, often by hiding inside host cells. Fewer than 100 antiviral drugs have successfully made it all the way to the clinic since the original was approved in 1963.
Anxious to find new medicines against pathogenic microorganisms, scientists are eyeing Crispr, the gene-editing tool. Crispr has typically been contemplated for macroscopic tasks: changing mosquitoes so they can’t spread malaria, altering tomatoes, so they are more flavorful, and treating certain genetic diseases in humans. Now researchers are using Crispr to turn a bacterium’s machinery against itself or against viruses that target human cells.
“Crispr is the next step in antimicrobial treatment,” said David Edgell, a biologist at the Western University in London, Ontario, and the chief author of a study published previously this month in Nature Communications.
Crispr is a specified region of DNA that makes what amount to genetic scissors — enzymes that allow the cell or a researcher to precisely edit other DNA or its sister molecule, RNA. Crispr is diminutive form for “clustered regularly interspaced short palindromic repeats.” Crispr was initially discovered in bacteria, where it helps keep footprint of past injury. When a virus attacks, the bacterium stocks small portions of the viral genome within its own DNA. It helps the bacterium identify viral infections when they occur again. Then, employing Crispr-associated enzymes, it can deactivate the virus and inhibit the infection from spreading.
In their latest study, Dr. Edgell and his colleagues successfully used a Crispr-associated enzyme called Cas9 to remove a species of Salmonella. By encoding the Cas9 to see the bacterium itself as the enemy, Dr. Edgell and his associates were able to force Salmonella to make deadly cuts to its own genome.
The team started with a conjugated plasmid — a small packet of genetic material that can duplicate itself and be distributed from one bacterium to the next. To the plasmid the scientists inserted the encoded instructions for Crispr enzymes that would aim Salmonella DNA. The plasmid was then put inside E. coli bacteria. Dr. Edgell discussed that most types of E. coli are usually part of healthy gut microbiome and would previously be present if a person consumed pathogenic Salmonella by, say, eating an unclean salad. The E. coli could then transmit the engineered plasmid to the Salmonella, where the Crispr system would start, destroying the harmful bacteria.
That is precisely what the researchers witnessed in a petri dish. The Crispr system eliminated nearly all Salmonella bacteria, while leaving E. coli whole.
“This represents a noteworthy advance in being able to aim bacteria in a highly particular way,” said Mitch McVey, a biologist at Tufts University who was not engaged in the study.
Crispr-based antibiotic pills aren’t up till now, anywhere near pharmacy shelves. But developing such treatments could allow scientists to exploit the power of the human body’s own resident microbes in avoiding disease.
“Scientists are starting to find out that microbiota can also be extremely beneficial for our health,” said Luciano Marraffini, a microbiologist at the Howard Hughes Medical Institute and Rockefeller University.
Traditional antibiotics do not differentiate between good and bad bacteria, eliminating everything indiscriminately and seldom creating problems for people with weakened immune systems.
“A major advantage of Crispr is that we can program it to kill only particular pathogenic bacteria and leave alone the remaining of our good microbes,” Dr. Marraffini said.
A few companies have started to follow Crispr-based antibiotics that can be delivered through viruses that have been engineered so that they cannot replicate or cause infections themselves, as well as other methods. Dr. Marraffini is a co-partner of one such start-up, Eligo Bioscience.
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The specificity of Crispr is equally appealing to researchers considering to target pathogenic viruses. Rather than having Crispr kill viruses that infect bacteria, as it does in nature, scientists are encoding it to chop up viruses that affect humans. In a paper, also published this month in Molecular Cell, scientists at the Broad Institute of M.I.T. and Harvard showed that another CRISPR enzyme, Cas13, could be programmed to identify and destroy three different single-stranded RNA viruses that infect human cells: lymphocytic choriomeningitis virus, influenza A virus and vesicular stomatitis virus.
Utilizing this Crispr system, researchers saw up to a 40-fold decline in viral RNA within 24 hours. The enzymes damaged the viral genomes considerably enough that few viruses could attack new cells. In the situation of the flu virus, Cas13 lessened its infectiousness by more than 300-fold.
“This is a great proof-of-concept,” said Rodolphe Barrangou, a microbiologist at North Carolina State University, who also co-founded a firm for Crispr-based antimicrobial products and was not engaged in the study. If researchers can make Crispr technology against three fairly mild human viruses, such as lymphocytic choriomeningitis virus, influenza and vesicular stomatitis virus, they can likely alter it to treat more deadly viral infections as well.
Compared to existing antiviral drugs, Crispr has the benefit of being easy to modify as needed. “If a virus develops and mutates, we can simply change the Crispr system to correspond whatever the virus is doing,” said Cameron Myhrvold, a postdoctoral researcher at Broad.
Nowadays researchers face the challenge of proving that Crispr antiviral and antibacterial drugs are effective in humans and in living animals, not only in the lab, and that they will be cheaper than traditional therapies, Dr. Barrangou said.
“We’re not prepared for clinical prime time yet,” he said. “But we’re moving in that direction.”