The Government Aims to Use CRISPR to Make Soldiers Radiation-Proof

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The Government Aims to Use CRISPR to Make Soldiers Radiation-Proof
By: Emily Mulliln - OneZero - 9-27-19
RE: https://onezero.medium.com/the-gover...f-3e18b00c9553

"A Defense Department project plans to temporarily alter human genes, and shield people from deadly radiation exposure."

In the early morning hours of April 26, 1986, the Chernobyl Nuclear Power Plant in Ukraine exploded, releasing a cloud of toxic fumes and radioactive particles. The fire burned for 10 days, as hundreds of plant staff, firefighters, and emergency responders desperately worked, often without proper safety equipment, to quench the blaze.

Of those, 134 people were eventually diagnosed with acute radiation syndrome, the illness that occurs when a person is exposed to a high dose of radiation across the entire body in a short period of time. Though Chernobyl’s total death toll is still disputed, it has been conclusively documented that 28 first responders died in the three months after the accident from radiation exposure.

In the decades since the Chernobyl disaster, treatment for acute radiation syndrome has remained much the same — supportive care designed to help the body withstand the toxicity of radiation — despite billions of dollars of public investment into medical countermeasures. But an ambitious U.S. government project could change that. The Defense Advanced Research Projects Agency (DARPA), which develops cutting-edge technology for the military, is funding a team of researchers to develop a temporary, reversible radiation countermeasure that uses the gene-editing tool CRISPR. Akin to a vaccine, scientists are trying to produce a genetic medicine that is able to ramp up the body’s natural defenses before and after a person is exposed to radiation.

Researchers will use a modified form of CRISPR that can turn genes on and off without changing the DNA code itself.

CRISPR is a technique that enables scientists to cut, edit, or replace DNA, as if making revisions in a word processing document. But DARPA wanted an intervention that could protect against radiation without making permanent changes to a healthy person’s genome. “We can’t take the risk of permanently modifying the DNA,” DARPA program manager Renee Wegrzyn tells OneZero.

Researchers will instead use a modified form of CRISPR that can turn genes on and off without changing the DNA code itself. These fluctuations are known as gene expression. If DNA is the cell’s instruction manual, gene expression is the way those instructions are interpreted and carried out. At the most basic level, our genes carry instructions to make proteins, and gene expression is the process of those instructions being converted into proteins. Gene expression changes with a cell’s environment, which in turn affects when and how many proteins are made. Some of these proteins are beneficial, while others are harmful. By using CRISPR to tell genes to “stop” or “go,” scientists think they can boost the helpful proteins to protect against radiation while keeping the bad ones at bay.

“This is like giving people a molecular coat of armor,” says Fyodor Urnov, a gene editing pioneer and a professor of molecular and cell biology at the University of California, Berkeley, who is leading the DARPA project along with Jonathan Weissman, a professor of cellular and molecular pharmacology at the University of California, San Francisco. Urnov was a sophomore at Moscow State University during the Chernobyl disaster, and like most Soviet citizens at the time, he was deeply affected by it.

DARPA wants Urnov and Weissman’s team to make a pill or injection that soldiers, first responders, and civilians could take before going into an area with dangerously high radiation levels. Ideally, a similar treatment could also be given after exposure, such as in a nuclear disaster or dirty bomb scenario. In the future, a radiation protection therapy could also be useful for astronauts on long-term missions in space, where they’ll be exposed to cosmic rays and high-speed particles that damage DNA.

But while a handful of biotech companies have recently started clinical trials to use CRISPR in the eye or on cells outside the body, making changes directly inside the body — as Urnov and Weissman aim to do — is trickier because the CRISPR machinery has to reach the right cells, and enough of them, to have an effect. The researchers have received an initial $9.5 million in funding and have four years under the DARPA contract to produce an experimental drug that will be ready to test in human clinical trials.

When the body is exposed to high levels of radiation, cells can acquire mutations and start to malfunction or die off. Among the most susceptible are blood cells and those that line the stomach and esophagus. The loss of these cells makes it difficult for the body to fight infections or heal wounds, and causes symptoms associated with radiation poisoning like nausea and diarrhea.

Potassium iodide tablets have been available for decades, but they only protect the thyroid from radiation. In recent years, drugs that stimulate white blood cell recovery have also come onto the market, but there are no medications available for the gut, and none that address the genetic damage caused by radiation. Instead, doctors treat patients with radiation poisoning through supportive care, which might include blood transfusions, bone marrow transplants, and antibiotics.

Scientists know that the body can naturally repair some genetic damage, so DARPA reasons those mechanisms could be ramped up to make the body more resilient. The first step in the four-year timeline, which the researchers are starting now, is to identify a set of genes that, when turned on or off, can protect against the symptoms of acute radiation syndrome.

“We get exposed to radiation, in very low doses, all the time,” says Harris Wang, an assistant professor of systems biology at Columbia University, who is one of the DARPA-funded researchers. “The body has natural mechanisms that it uses to potentially repair some of the damages associated with these exposures. But those are present in very low levels.”

“If we can make those two types of cells resistant to radiation, that would improve a person’s ability to survive exposure to radiation.”

One is a gene that makes G-CSF, a protein that stimulates the bone marrow to produce white blood cells. G-CSF is available as a drug today, under the brand names Neupogen, Granix, and Zarxio. DARPA’s Wegrzyn says that instead of giving patients the drug, a CRISPR therapy could boost the expression of that gene so the body naturally makes more of the protein.

To find potentially protective genes, scientists will use a method developed by Weissman to screen the entire genome. They’ll then test promising genes in human organoids, tiny blobs of lab-grown tissue that mimic organ function. After that, they’ll move on to animal testing. Wang says they will likely need to target several different genes, rather than just one or two, to provide enough protection.

The researchers are focusing on two main cell types: hematopoietic stem cells, which generate blood cells, and the epithelial cells that line the gut. These cells are constantly dividing, which makes them particularly vulnerable to radiation because they don’t have enough time to repair the genetic damage before they divide again, and thus pass on mutations to descendant cells. “If we can make those two types of cells resistant to radiation, that would improve a person’s ability to survive exposure to radiation,” Weissman says.

A ccording to the U.S. Nuclear Regulatory Commission, the average person is exposed to three millisieverts of background radiation over the course of a year. To put that in comparison, survivors of the atomic bombings of Hiroshima and Nagasaki were exposed to about 200 millisieverts of radiation on average. When he was in space for a year, American astronaut Scott Kelly got about 146 millisieverts — almost as much. Going to Mars is far more dangerous. A 100-day mission to the Red Planet could expose an astronaut to more than 1,000 millisieverts of radiation — many times more than medical guidelines for annual exposure. Without some kind of enhanced defense against radiation exposure in space, it’s difficult to see how long-term space travel would ever be possible for human beings.

Christopher Mason, an associate professor of physiology and biophysics at Weill Cornell Medicine, isn’t involved in the DARPA effort, but he’s a proponent of using genetic medicine to keep astronauts safe in space. Mason has studied the effects of being in space on the human body, and led a team of scientists chosen by NASA to compare genetic, physiologic, and behavioral changes in identical twins Scott and Mark Kelly during Scott’s year in space and Mark’s time on the ground.

The twin study revealed that genes involved in the immune system and in DNA repair are particularly responsive to spaceflight. What’s not known is whether those genes can simply be ramped up before astronauts go into space, and if so, when you’d need to make those adjustments. “It might have to be immediately before radiation exposure or a month before,” Mason says. “The timing of when the optimal interval would be to activate these pathways is almost entirely unknown.”

One gene that Mason and others have been interested in is p53, a regulator gene that helps protect against cancer. Mutations in this gene can cause cancer cells to grow and spread in the body. Elephants, which rarely get cancer, have many copies of the p53 gene, whereas humans and other mammals only have one. Why not ramp up p53 before astronauts go to space? His lab is experimenting with adding extra p53 to human cells to study its effects.

In the future, astronauts could even be engineered with genes from other species. One such gene Mason has studied, Dsup, is a protective protein found in tardigrades that suppresses DNA breaks caused by radiation. The near-microscopic tardigrades, which look like a cross between a bear and a caterpillar, can be found just about everywhere on Earth. And the aquatic invertebrates are so hardy they’re able to survive in outer space. (Recently, scientists discovered tardigrades living on the moon.) Mason and his team have succeeded at putting this tardigrade gene in human cells in a dish. Now they’re exposing the cells to radiation in the lab to see how they hold up.

Mason is aware that there are many ethical considerations before deciding whether we should genetically modify astronauts, even if it’s only meant to be temporary. He argues that we’re ethically obligated to protect astronauts because they undertake huge risks by going into space. But he also wants to make sure scientists get it right. “We need to make sure we’re doing something that doesn’t look like Jurassic Park or a Michael Crichton movie,” Mason says.

The DARPA-funded researchers face a tall order. No one has ever tried to make a medicine like this before. Urnov admits that even with the latest genetic technology, it might be impossible to shield humans from what would be a lethal dose of radiation.

“I don’t think we’ll have a drug in four years,” says Isabel Jackson, a radiobiologist at the University of Maryland who’s an expert in medical countermeasures. The regulatory pathway is a long one. The first drug approved by the U.S. Food and Drug Administration specifically for acute radiation sickness, Neupogen, wasn’t until 2015. The drug, which spurs the production of blood cells, was approved in 1991 for cancer patients. However, DARPA says it’s working with the FDA, which could potentially fast-track a medical countermeasure based on public health need.

Andrew Karam, a health physicist who previously served in the U.S. Navy’s nuclear power program, says the researchers are stepping into unknown territory. He’s not sure the project will be successful but says it’s a necessary first step to understand the important biological pathways involved in radiation sickness. “They don’t know how big the territory is or what there is to find,” Karam says.

About this writer: Emily Mullin is a Staff writer at OneZero, covering the intersection of biology and technology. emullin@medium.com