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The Jellyfish That Never Dies

The Jellyfish That Never Dies

We humans, we’re not all that keen on dying. Ever since the stories of the Fountain of Youth bewitched sailors and explorers in the 16th century, we have been fixated on finding a way to outsmart the reaper. Now, though, it seems like that solution to our darned mortality has been drifting through the oceans all this time.

The lucky animal that has developed this trait is Turritopsis nutricula – a relatively small species discovered floating through the Mediterranean in 1883. Once this species has reached sexual maturity, it can return to a youthful form. This is achieved by a process called transdifferentiation, whereby the jellyfish’s cells are able to return to their stem cell progenitors, which can in turn essentially re-start the organism’s life cycle.

Understanding the life cycle of Turritopsis nutricula is key to understanding how transdifferentiation can revert it back to a youthful stage. It starts its life as a larva, that sinks to the bottom of the ocean, where it develops into a polyp. At this point, you would be forgiven for mistaking it for just another plant on the ocean floor. Eventually, it will develop into the medusa – the conformation that we all recognise as a jellyfish. All riveting stuff so far, you’ll agree.

Where it does get exciting though, is when the sexually mature mature medusa reverts to the polyp stage under times of stress or lack of food. This reversion back to a more youthful state is through the work of transdifferentiation.

The life cycle of the Turritopsis nutricula jellyfish, including its transdifferentiation from the adult medusa stage to the secually immature polyp stage.
The life cycle of the Turritopsis nutricula jellyfish, including its transdifferentiation from the adult medusa stage to the secually immature polyp stage.

I’m going to digress for a moment here to quickly talk about stem cells. I’ll be using the development of blood cells as an example. The key to our development is the fact that the hugely diverse range of cells in our body can all be derived from the few cells that make up the earliest developmental stage of a foetus – the zygote. Cells that have this ability to specialise into numerous cell types are called stem cells. The amount of different types of cell a stem cell can mature into defines the stem cell’s ‘potency’.

For example, those early embryonic stem cells are described as ‘totipotent’ – they are able to become any cell in the body, depending on both the environment the stem cells finds itself in and chemical signals delivered to that stem cell. However, each time a stem cell gets slightly more specialised, it loses potency – it becomes committed to a certain pathway. Let’s take the development of blood cells as an example. The cell that can give rise to all the cells in your blood is referred to as a haemopoietic stem cell (HSC). It has been derived from a totipotent stem cell that has become slightly specialised. Therefore, it is not totipotent, but multipotent. It is still relatively unspecialised, but is committed to producing only the cells found in the blood.

The process of haematopoises. All the specialised cells in your blood are derived from HSCs. As you go down this chart, the cells are becoming more and more specialised and are losing potency.
The process of haematopoises. All the specialised cells in your blood are derived from HSCs. As you go down this chart, the cells are becoming more and more specialised and are losing potency.

Now, there are an awful lot of cells in your blood – you’ve got to pack in all the red blood cells, platelets and all the hugely varied cells of the immune system. Therefore, there has to be slightly more differentiation of the HSC, into either a common myeloid progenitor or a common lymphoid progenitor. These progenitors will then give rise to highly specialised cells, such as those red blood cells or platelets. These cells are unipotent – they can’t get any more specialised. The cellular machinery that allowed the different types of specialisation in stem cells has been switched off, and when these cells divide, they will only produce the same type of cell.

Transdifferentiation flies right in the face of this fact, as it relies on the fact that a non-stem cell can differentiate into another type of cell, or can give rise to cells of a different lineage. One form of transdifferation involves the de-differentiation of cells back along their lineage into the multipotent stem cells. These multipotent stem cells can then be influenced – by those environmental factors I talked about earlier – to become another cell line.

Another less well understood method of transdifferentiation is the direct production of one cell type from another terminally differentiated cell. A simple example of this – and thus far, the only other example of natural transdifferentiation – is found in newts and salamanders. If the lens is removed from the eye, it can regenerate. However, it has been shown that this regeneration comes from epithelial pigmented cells on the iris. Though this link was clearly outlined in a paper published in Nature by Tsonis et al, they did not go on to describe how this process occurred.

The regeneration of a newt’s lens, from epithelial pigment cells in the iris.
The regeneration of a newt’s lens, from epithelial pigment cells in the iris.

So, to recap, the Turritopsis nutricula is able to return to its youthful polyp stage once it has reached sexual maturity. It is able to this because a process of transdifferation – which can be achieved either by a reversion back to a stem cell or by the less well understood process of direct cell conversion.

But how can such a characteristic be harnessed to benefit humans?

The work of Dr. Deepak Srivastava’s group at the Gladstone Institute of Cardiovascular Disease at the University of California is the best example of how transdifferentiation could be used in medicine. By switching on three genes GATA4, MEF2C, TBX5 in fibroblasts – structural cells in cardiac tissue – Dr.Srivastava’s group managed to induce transdifferentiation to cardiomyocytes, the cells that contract and result in the rhythmic beating of the heart. It is the loss of cardiomyocytes and the scarring that is associated with this that leads to complications following a heart attack. There is great hope then, that this relatively simple process – the switching on of three genes, can lead to the treatment of seriously debilitating illnesses.

The induced transdifferentiation of fibroblasts into cardiomyocytes. This technology has great potential for use in regenerative medicine. From: Ieda, M., et al. (2010). “Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors.” Cell 142(3): 375-386.
The induced transdifferentiation of fibroblasts into cardiomyocytes. This technology has great potential for use in regenerative medicine.
From: Ieda, M., et al. (2010). “Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors.” Cell 142(3): 375-386.

But what does the future hold for this technology? Seeing as our bodies slowly grind to a halt as we age, can we induce our cells to replace our increasingly damaged cells? Will this transdifferentiation technology provide what, say, botox treatments don’t – that being a literal rejuvenation as well as an aesthetic one?

Watch this space…

‘Til next time…

Joe

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