Scientists Are Retooling Bacteria to Cure Disease

matter

By manipulating DNA, researchers are trying to create microbes that, once ingested, work to treat a rare genetic condition — a milestone in synthetic biology.

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A newborn is tested for PKU, a rare inherited blood disorder, at a hospital in California.CreditCreditSpencer Grant/Science Source
Carl Zimmer

In a study carried out over the summer, a group of volunteers drank a white, peppermint-ish concoction laced with billions of bacteria. The microbes had been engineered to break down a naturally occurring toxin in the blood.

The vast majority of us can do this without any help. But for those who cannot, these microbes may someday become a living medicine.

The trial marks an important milestone in a promising scientific field known as synthetic biology. Two decades ago, researchers started to tinker with living things the way engineers tinker with electronics.

They took advantage of the fact that genes typically don’t work in isolation. Instead, many genes work together, activating and deactivating one another. Synthetic biologists manipulated these communications, creating cells that respond to new signals or respond in new ways.

Until now, the biggest impact has been industrial. Companies are using engineered bacteria as miniature factories, assembling complex molecules like antibiotics or compounds used to make clothing.

In recent years, though, a number of research teams have turned their attention inward. They want to use synthetic biology to fashion microbes that enter our bodies and treat us from the inside.

The bacterial concoction that volunteers drank this summer — tested by the company Synlogic — may become the first synthetic biology-based medical treatment to gain approval by the Food and Drug Administration.

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The bacteria are designed to treat a rare inherited disease called phenylketonuria, or PKU. People with the condition must avoid dietary protein in foods such as meat and cheese, because their bodies cannot break down a byproduct, an amino acid called phenylalanine.

As phenylalanine builds up in the blood, it can damage neurons in the brain, leading to delayed development, intellectual disability and psychiatric disorders. The traditional treatment for PKU is a strict low-protein diet, accompanied by shakes loaded with nutritional supplements.

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A transmission electron microscopy image of Synlogic’s newly engineered bacteria.CreditW.M.Keck Biological Imaging Facility, The Whitehead Institute

The Synlogic team wanted the microbes to break down phenylalanine only in the right place and at the right time in the human body. So they engineered the bacteria to keep their phenylalanine genes shut down if they sensed high levels of oxygen around them.

Only when they arrived in a place with little oxygen — the gut — did they turn on their engineered genes.

To test the bacteria, the researchers created mice with the mutation that causes PKU. When the mice received a dose of the bacteria, the phenylalanine in their blood dropped by 38 percent, compared with mice without the microbes.

The researchers also tried out the bacteria on healthy monkeys. When monkeys without the microbes ate a high-protein diet, they experienced a spike of phenylalanine in their blood. The monkeys with engineered bacteria in their guts experienced only a gentle bump.

For their human trial, Synlogic recruited healthy people to swallow the bacteria. Some took a single dose, while others drank increasingly large ones over the course of a week. After ingesting the bacteria, the volunteers drank a shake or ate solid food high in protein.

On Tuesday, Synlogic announced that the trial had demonstrated people could safely tolerate the bacteria. In addition, the more bacteria they ingested, the more bits of phenylalanine wound up in their urine — a sign the bacteria were doing their job.

The next step will be to see if the microbes can lower phenylalanine levels in people with PKU.

“I’m amazed at how fast we got to where we are,” said Dr. Collins, who was not involved in Synlogic’s PKU research.

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