What brain cells in a dish can reveal about MS

It is MS awareness week, which aims to raise awareness of multiple sclerosis, an autoimmune, neurological disease which affects one in 1000 New Zealanders and is the leading cause of disability in young adults.

MS is a disorder in which the immune system attacks the myelin sheath, an important fatty substance that lines the arms of neurons (axons). There is no cure for MS, but our research aims to help develop therapies that can promote remyelination and restore normal bodily functions to those with the disease.

Think of the myelin sheath as a protective and insulating cable of our central nervous system. Picture the wiring in your house, wires are protected and insulated by the cable, which are all very carefully and precisely connected to one another to allow safe and efficient transmission of electricity. That’s how neurons connect to and communicate with one another.

If the wires in your house are exposed, it is likely your electricity will trip and at least a portion of your electrical setup will no longer work. Similarly, if the myelin sheath is damaged and the neuronal axons are exposed, those neurons don’t communicate efficiently and are prone to damage themselves.

Because neurons are responsible for movement, speech, muscle control and so on, people with MS display a range of symptoms including movement and balance problems, slurred speech, chronic pain, extreme fatigue, vision problems, cognitive problems and bladder and bowel dysfunction.

Although there is no cure there are disease-modifying therapies, drugs that modulate the immune system to stop it from attacking the myelin sheath. They’re effective at slowing the progression of the disease.

However, people with MS have likely had it for about a decade before being diagnosed and so have a lot of damage and myelin loss. This damage is called lesions, and these are identified on an MRI scan. Disease modifying treatments won’t repair these lesions, but remyelination strategies should. This is the new frontier in MS treatment, therapies that combine the disease modifying drugs with a remyelination strategy, which enables the body to repair damaged myelin.

This is what my research is focused on; more specifically, oligodendrocytes (not a word anyone is likely to remember how to say or spell; I call them oligos). Oligos are fascinating little cells, found in the brain and the spinal cord and which produce myelin.

In fact, in MS the immune system doesn’t just attack the myelin sheath, but the oligos that produce it. The clever thing about oligos is that when they are under attack, their immature version, known as their precursors, can migrate to the site of damage and mature into new oligos to replace those that were lost and hence produce more myelin.

This process works quite well and in the predominant form of MS known as relapsing-remitting MS (RRMS); this recruitment and repair process is responsible for the remission phase in those with RRMS. But over time the immune system wins this battle, and the oligos can no longer replenish themselves or the myelin.

Over the last five to six years I’ve developed a method to convert human skin cells into oligo precursors and then oligos, which is called reprogramming. We do this for a living in our laboratory (led by Professor Bronwen Connor) but mainly focus on all the different types of neurons in the brain.

But I’ve jumped onto the oligo band wagon and figured out how to generate them efficiently from skin (research funded by the New Zealand Multiple Sclerosis Research Trust).

Now, thanks to my recently awarded HRC Emerging Researcher First grant, I’m going to set up a biorepository of MS skin cells. With the support of neurologist Dr Jennifer Pereira at Auckland hospital, we’re going to recruit individuals with MS who are willing to donate skin cells by biopsy which I’ll grow and turn into oligos.

My goal is to have the New Zealand MS community represented in this biorepository, those with relapsing-remitting MS, those with secondary progressive and those with primary progressive MS.

Once I’ve got the skin cells then I can make the brain cells. The aim is to turn those skin cells into oligos, and neurons; to grow the brain cells of the New Zealand MS community in a dish.

This research will determine if I could generate them with comparable efficiency and resulting yield irrespective of whether they came from someone with early stage RRMS versus the aggressive form of RRMS, and the rarer primary progressive MS.

The research will also involve studying them at a gene and protein level to understand what makes them vulnerable and at what stage along the developmental timeline of skin to mature oligo do things go wrong. This will be the foundation for the big picture, which is to then identify new therapeutic targets and test new drugs to promote remyelination.

The long-term goal is to work towards testing our reprogrammed human oligos as a transplant therapy for MS. By this, I mean that we would transplant human oligos to replace those that have been lost and thereby replenish the myelin. With this biorepository, we could have the potential for personalised medicine, whereby we could take skin from an individual with MS, turn it into oligos and then transplant back in.

Converting skin cells into brain cells is a big field of research internationally, but oligos are overlooked within this field, with the focus being on neurons.

Oligos are crucial to the functioning of the central nervous system and have been increasingly shown to play a part in the cellular pathology of many neurological conditions, not only MS. I hope my research will put New Zealand on the map and contribute to the international hope of developing a therapy that can restore neural function in people with MS, so they can recover the normal bodily functions most of us take for granted.