Crispr Can Edit Directly Genes Inside Human Bodies

A decade ago, biologists Jennifer Doudna and Emmanuelle Charpentier published a landmark paper describing a natural immune system found in bacteria and its potential as a tool for editing the genes of living organisms. A year later, in 2013, Feng Zhang and his colleagues at the Broad Institute of MIT and Harvard reported that they’d harnessed that systemknown as Crispr, to edit human and animal cells in the lab. The work by both teams led to an explosion of interest in using Crispr to treat genetic diseases, as well as a 2020 Nobel Prize for Doudna and Charpentier.

Many diseases arise from gene mutations, so if Crispr could just snip out or replace an abnormal gene, it could in theory correct the disease. But one of the challenges of turning test tube Crispr discoveries into cures for patients has been figuring ouhow to get the gene-editing components to the place in the body that needs treatment.

One biotech company, Crispr Therapeutics, has gotten around that issue by editing patients’ cells outside the body. Scientists there have used the tool to treat dozens of people with sickle cell anemia and beta thalassemia—two common blood disorders. In those trials, investigators extract patients’ red blood cells, edit them to correct a disease-causing mutation, then infuse them back into the body.

But this “ex vivo” approach has downsides. It’s complex to administer, expensive, and has limited uses. Most diseases occur in cells and tissues that can’t be easily taken out of the body, treated, and put back in. So the next wave of Crispr research is focused on editingin vivo”—that is, directly inside a patient’s body. Last year, Intellia Therapeutics was the first to demonstrate that this was possible for a disease called transthyretin amyloidosis. And last week, the Cambridge, Massachusetts-based biotech company showed in-the-body editing in a second disease.


The Brain In Your Gut

From moods to memory, the brain in our guts has a big impact on the brain in our heads. Pioneering neuroscientist Associate Professor Elisa Hill-Yardin from RMIT in Australia has spent years delving deep into the gut-brain connection, an emerging field in health research. Here she shares the five critical things we should know about our “gut brain”.

The gut has similar types of neurons to the brain. The gut brain is a big nervous system, about the same size as the spinal cord, which controls the contractions of the gut and its secretions. There are very rare gene mutations that affect brain connectivity and we’ve learned that the vast majority of those gene mutations are also found in the gut. If those mutations change the wiring in the brain, they’re also likely to change the wiring and the action of the gut brain – the enteric nervous system. To date, we’ve only ever examined the effect of those mutations in the brain. Now we’re starting to look at them in our second brain, the gut.

We now know that microbes in the gut do change our mood and behaviour, and microbes even change brain activity. There’s a great study that looked at women, doing MRI brain scans and showing that if they ate yoghurt for a certain number of days their resting brain activity was different – which is amazing! But we also know from animal studies that microbes have an impact on mental health. You can breed mice that are germ free and we know that those mice show differences in their anxiety behaviours – in other words, they’re less anxious without the microbes. So you could say we’re being controlled by the microbes in our gut. They’re much more important to our feelings than we ever thought.

What’s come out in research in recent years, though it’s been known for a long time in the autism community, is that the majority of children with autism have serious gut problems. Now we don’t know the cause of autism but we do know that there are hundreds and hundreds of rare gene mutations that alter brain connectivity. And we now know that some of those mutated genes are also found in the gut. We’re also learning that diseases that affect cognition and memory, like dementia, may also have a gut component. Researchers are starting to look at traditional brain diseases like Alzheimer’s, Parkinson’s, Multiple Sclerosis, and finding difference in the microbes in the gut. So they’re starting to think about how we can make changes in our microbes to make changes to our brain health.

The Gut-Brain Axis team that I lead at RMIT is focused on understanding how the enteric nervous system is altered in neurological disorders such as autism. This includes researching how the gut nervous system interacts with microbes in the intestine and changes in inflammatory pathways. We’re trying to identify the basic mechanisms, examining the connections between the gastrointestinal tract and changes in mood and behaviour, including the impact of genetics on microbiota in the gut. The ultimate the aim is to find novel therapies that can improve daily life for people with autism, but our work also has broader application for other neurological disorders, such Parkinson’s disease.

Many of the great enteric physiologist pioneers are in Australia and they were the first to describe different types of neurons based on their activity and neurochemical content. This work has been done on animal models, due to the possibilities of emulating human genetic diseases in these models. So, a lot of basic anatomy and physiology has been studied. But what we need now is to move the field towards using the latest sophisticated techniques and capitalising on the recent interest in the gut-brain axis, which of course involves understanding how the gastrointestinal tract works in concert with the trillions of microbes that live inside it.

Professor Elisa Hill-Yardin has presented her work to the US Air Force Office of Scientific Research