Zebrafish and their leading role in regeneration research

Monash University’s stem cell detectives at ARMI – the Australian Institute of Regenerative Medicine – are just one part of a long quest by humankind to understand how we are built and how we repair. A very long quest.

“The first literature or citation you can point to on the regeneration of the brain and the spine came from ancient Egypt 3500 years ago,” says ARMI’s Dr Jan Kaslin. “A broken spine or neck in a human has no possibility of recovery. There is still after all these thousands of years not a clear, single strategy in the medical clinic. We have not advanced that much. We’re much better at treating infections and trauma medicine, but there’s basically nothing we can do to repair the brain and spinal cord – which is quite remarkable.

We have to resolve this problem first, and we’re nowhere near that.”

However, in something of a biological riddle, some animals can repair and regenerate themselves quickly and effectively. But how?

Monash’s ARMI is at the forefront of international research on regenerative medicine. The humble zebrafish is one of its main study tools because they have remarkable regenerative abilities, breed a lot and don’t mind living in the Institute’s Clayton aquarium of 6200 tanks of 100,000 fish, which is called Fishcore. The fish share about 70 per cent of their important genes with us, making them relevant for human biology and disease.

"We know a lot more about how animals are built and how stem cells are made. We’re starting to bridge the gap between expectation and reality.”

For ARMI, they’re a kind of superfish. Stem cells live throughout their bodies, allowing them to regenerate so well.

The regeneration is extraordinary. If a baby zebrafish’s spinal cord or brain is damaged, it can swim and function again within a few days. “It’s a good party trick,” says ARMI’s director, Professor Peter Currie. “We want to understand why they can do it and we can’t. Brain and spinal cord injuries are a catastrophic problem for human health, because quality of life is severely affected and it’s a massive healthcare burden.”

Dr Kaslin began his work in regeneration through the opposite – degeneration. That was more than decade ago, for his PhD, looking into degenerative conditions such as Parkinson’s disease, in which cells are lost to the body over a period of time. “One of my findings was that we saw the fish lost cells but then after a while they recovered. I asked myself how. Degeneration is important, but asking ourselves how we can regenerate is important too, because this tells us how to fight degeneration and repair.”

Life's building blocks

Stem cells are the building blocks of life, the base. Their job is to make other cells by dividing into more stem cells, or cells for growth and repair of tissues and organs. The three kinds of stem cell are embryonic (from embryos; they can become any kind of cell), adult and induced pluripotent (embryonic cells made in the lab from real cells). These stem cells are integral to regeneration – but the problem is humans can only regenerate certain parts of themselves. Skin, for example. It grows back. The liver is good at it, too.

This is why the ARMI team looks at stem cells to understand the molecules and cellular behaviour within regeneration. In the future it may mean human organs can be repaired more quickly, and cellular therapies could be used on patients with Alzheimer’s, Crohn’s or Parkinson’s.

Professor Currie calls it the “golden age” of biology and, specifically, regenerative medicine.

“I think it’s starting to approach the promise,” he says. “There’s been a coming together of understandings in the last decade. We know a lot more about how animals are built and how stem cells are made. We’re starting to bridge the gap between expectation and reality.”

Dr Kaslin and Professor Currie presented new findings on stem cell regeneration to a major international conference in July.

In the research presented to the conference, Dr Kaslin and his colleagues’ methods were explained. Using sophisticated microscopy, they tracked and documented the regeneration of living nerves in real time in zebrafish with severed spinal cords. They were able to see precursor stem cells moving and working to repair the spinal cord. They identified two “waves” of cell regeneration – the migration of precursors, then activation of the stem cells. The study suggests there may be ways to speed up how stem cells work in repair, which would greatly help treatment in humans with brain or spinal cord injury.

The sharks' part

While the humble but remarkable zebrafish is the main study model, ARMI does some interesting work with sharks from Port Phillip Bay, specifically the embryos born from female sharks.

“Sharks are intriguing,” says Professor Currie. “They’re a very ancient vertebrate species, so how they do things tells us a lot about how things started in the first place, what genes were initially involved, how genes are initially deployed to make tissue and stem cells – a ground state. Which processes are new, which are ancient?”

Essentially, what ARMI looks at is evolution. How it has worked, what it has meant, how it might be tailored to increased human health, potentially. “We’re getting a feel for how evolution has acted to make regenerative capacities,” Professor Currie says. “Why don’t we regenerate as well as some of these animals? To understand that, we have to track that character state throughout evolutionary history. If an animal is truly ancient or basal in the tree of life it helps us understand how those properties have evolved. How have animals been put together? How have different regenerative capacities evolved?”