News, Culture & Society

Human immunity can KILL the CRISPR gene-editing system

The gene-editing technology some thought would change the nature of medicine  may not be able to withstand the attacks of the human immune system, a new study suggests.

The biotechnology, called CRISPR-Cas9, has been hailed as one of the greatest scientific developments of the last decade for its promising ability to edit or fix genetic mutations to treat – and perhaps some day prevent – diseases.  

Researchers at Stanford University sought to find out if the human body would reject cells after they had been edited using Cas9, an enzyme derived from bacteria, and reintroduced to the body. 

In the experiment, the human body recognized  and destroyed the bacterial cells,  but the scientists say we shouldn’t write the technology off so quickly. 

The human immune system attacks the much-anticipated CRISPR-Cas9 gene therapy, but researchers say that the system can be salvaged 

Mutations, deletions and extra copies in the human genome cause or make us more at risk for countless diseases, so the ability to fix these errors in the composition of our code could be a virtual cure-all. 

The CRISPR system is science’s most viable step in that direction yet. 

CRISPR is a system that occurs naturally in bacteria to commit information about viruses to their cellular memories, so they can fight the viruses better if they intrude again.  

So scientists re-purposed that system, found in two common bacteria constantly present in the body, to recognize and hunt down faulty areas of DNA sequences.  

Once CRISPR locates the problem, the Cas9 enzyme goes to work, cutting the faulty section out so that the DNA can repair itself. 

The Cas9 is not the only enzyme that could theoretically do this job, but so far it’s been the most effective and commonly used one. 

Both of the bacteria that scientists get the Cas9 enzyme from, streptococcus and staphylococcus, exist in the human body. 

So, before even undertaking the experiment, the researchers knew ‘it was quite possible that we would have a preexisting immunity to Cas9 as part of what keeps us from getting sick from strep and staph’ infections, says Dr Ken Weinberg, study co-author and Stanford University stem cell researcher. 

Bacteria is still bacteria, to the human body 

When he and his team tried using the CRISPR Cas9 system to edit the genome in cells from samples of human blood, and reintroduce the ‘fixed’ cells after they’d come into contact with Cas9, the original blood cells responded as they would to an infection. 

‘Half of healthy people already have antibodies to Cas9,’ Dr Weinberg said of the study samples, and, ‘more importantly for CRISPR is that the other limb besides antibodies is the ability of T cells to recognize cells that have Cas9 inside them.’

T cells are a crucial part of the immune system that quickly and effectively attack and kill bacteria and foreign bodies. 

‘Healthy people, at high frequency, have T cells that recognize Cas9 and [the immunity cells] are doing things that make it seem that they would try to kill a cell that had that protein inside it,’ Dr Weinberg says. 

But he isn’t overly-concerned, and said: ‘I think there may be ways to get around that.’ 

Alternative routes: The immune system’s response can probably be waited out or re-engineered 

His strongest suspicion is that he and other CRISPR researchers just need to get time on their side. 

The bacterial-based Cas9 that the human immune system is rejecting ‘is not a permanent part of gene-editing,’ Dr Weinberg says. 

The Cas9 enzyme is only expressed, or turned on, for a short time and ‘is not a permanent part of the gene-editing process,’ says Dr Weinberg.

Scientists turn it on, send it into the genome to snip out the defective piece, and then they can turn it off. 

So, after extracting cells from the larger body and editing them, doctors might just have to wait, incubating the fixed genetic material until there were fewer traces of the deactivated Cas9 enzyme. 

Then, reintroducing the edited cells might not sound any immunity alarms. 

Dr Weinberg says there are two other approaches that seem immediately possible to him: re-engineer Cas9 to ‘humanize it’ so that it doesn’t prompt an immune response, or to suppress the immune system itself. 

But the first is labor-intensive and the second could be dangerous to patients. 

‘Immunosuppression [would probably be the] least fruitful because if you have a therapy that was otherwise going to be okay to give in two or three days, why would you want to suppress immunity and make the patient subject to infection if you didn’t have to?’ says Dr Weinberg. 

Overall, his study’s findings are ‘a hiccup more than an enormous road block,’ to the evolution of gene-editing technology, he says, but acknowledges that finding out this small failure of the current technique is ‘important because it would have been terrible if we started clinical trails, and it didn’t work.

‘It would bet blamed on “CRISPR doesn’t work,” rather than something about the way it grafts [back into the body] that needs to change.’ 

‘I don’t think this is the death nail for Cas9, and certainly not the death nail for CRISPR,’ Dr Weinberg says.