Biological enigma: encrypted messages to deliver gene therapies 

During the Second World War, German armed forces used a code called Enigma to encrypt secret messages sent over radio waves. Famously broken by mathematicians including Alan Turing, the Enigma machine scrambled communications so only those with the right tools and settings could get the message.

A similar challenge faces drug developers today – how to ‘transmit’ medicines around the body that are only ‘understood’ by cells that need treatment, leaving healthy cells unaffected.

This is the principle for an innovative technique being developed by Pietro Fratta and Oscar Wilkins, who are jointly based at the Crick and UCL. They’re developing a modified type of gene therapy (a therapy that introduces new DNA into cells to correct defects) which is only activated in the cells which really need it. Essentially, it’s encrypted.

They’ve developed this method to try to treat cells affected by motor neuron disease (MND), a rare but truly devastating disease that causes a gradual worsening of a person's ability to move and control their body, and eventually fatal paralysis. There’s no cure, and current treatments only modestly slow down the disease’s advance.

“MND affects a type of nerve cells called motor neurons. Because they’re essential for us to move, speak, swallow and breathe, they’re probably the most critical cells in our body,” says Oscar. “Despite MND affecting the whole body, less than 0.00001% of someone’s cells are affected. The challenge is targeting treatments to this minuscule fraction of affected cells while avoiding the 99.99999% of cells which are healthy.”

Breaking the code in diseased cells  

Pietro and Oscar centred their approach around a protein called TDP-43, known to be involved in MND and other neurodegenerative diseases. In cells from healthy people, the protein resides near the DNA, helping correctly interpret genetic instructions. But in someone affected by MND, TDP-43 proteins clump together in distant parts of the cell.

“Under normal circumstances, TDP-43 ensures that the DNA gets correctly ‘photocopied’ into RNA, the messenger carrying the instructions to make proteins,” said Pietro. “But when TDP-43 forms clumps at the corners of the cells, the photocopying process goes wrong: random sequences, called ‘cryptic exons’, get included in the RNA. This means that a wide range of proteins that cells produce become faulty, with serious consequences.”

“TDP-43 is often described as a ‘goldilocks’ protein,” says Oscar. “Its levels have to be just right. So we can’t allow the encrypted message to be read by every cell because we’d end up with too much TDP-43 in otherwise healthy cells.”

Pietro and Oscar have found an ingenious way around this. Their novel gene therapy is activated by the presence of cryptic exons, which are only found in cells where TDP-43 has stopped working – in other words, they’re using cryptic exons as a ‘decryption’ tool.

Burn after reading

Because the gene therapy restores levels of functioning TDP-43, it can then stop the decrypted message from being read further – a very smart way of self-regulating that could lead to safer therapies in the long run. “We think encrypting these messages so that healthy cells can’t process them is an elegant way to reduce the risk of toxic side effects,” says Oscar.

Focusing on MND is just a start. The researchers say their new finding could be tweaked for similar conditions such as frontotemporal dementia, which is also characterised by faulty TDP-43.

Whether in neurodegenerative disease, cancer or heart disease, a key challenge facing drug developers is to find something unique about the diseased cells that can be exploited. And Pietro and Oscar’s encryption system is, like the messages sent over radio waves using Enigma, a way to deliver a therapy that only cells with the correct decryption tools can use.