One of the biggest breakthroughs in Neural Tube Defects research was the discovery that Folic Acid supplementation reduces the prevalence of these conditions.

Nonetheless, they continue to affect 1:1,000 pregnancies. So what are the biggest challenges we face in finding new preventative strategies?

In today’s lecture to third year BSc students I asked them to rate some of the challenges we faced according to which they felt are the biggest. Here’s what they came up with.

As we adapt to lecturing in this Covid era we are increasingly needing to use online activities to support university teaching. This activity not only made the students think about research, but have also forced me to think about their answers!

Our research depends on our ability to visualise embryonic structures using 3D (confocal) microscopy. We’re pretty good at that by now.

One challenge we face is the need to image tiny cell structures and knowing their position in much larger embryonic tissues. The image below shows the closing spinal region of the mouse spinal neural tube. The entire structure shown is nearly half a millimetre. That’s big enough to see without a microscope, just. Nonetheless, we can image the whole structure with sufficient detail to see individual cells, with cell nuclei shown in cyan.

Finding that balance between visualising a big chunk of tissue yet still having enough detail to seen minuscule structures requires a really good microscope!

Cell shape is very important in studies of biomechanics.

In isolation, detached from their substrate and neighbours, most cells round up into a spherical shape. But when they are densely packed in tissues, cells push on each other and deform their neighbours and tissues.

One measurement we use to describe this packing is Solidity, which is defined as an object’s area divided by the area of a convex hull drawn around the object:

Eirini spent a very long time looking at chick neuropores closing during live-imaging on our two-photon microscope yesterday. By the end of the session it felt like they were talking to her…

Sometimes you really need to look away from the monitor/eyepiece.

Check out this new pre-print from our lab. In it we show that mutations which happen during embryonic development, and only affect a small proportion of cells, can be enough to cause spina bifida. It turns out that each mutated cell in our model prevents several other cells from biomechanically contributing to neural tube closure.

Pre-prints are repositories of papers which have not yet been fully peer reviewed and should therefore not be viewed as definitive. We decided to share our findings in this format while they are being formally reviewed because we are excited about the implications of our findings for the diagnosis and prevention of spina bifida as well as for genetic counselling of parents and patients.

Closing mouse spinal neural tube. The green dots are mutant cells. This small number of mutant cells is enough to cause spina bifida.

When a mechanical force is applied to an object, that object deforms and withstands physical stress.

Think of applying a force to stretch a rubber band. It stretches and withstands mechanical tension. If you cut it, that tension is relaxed and the rubber band pings back to its preferred length.

If you understand that, you’re well on your way to understanding a central tenant of biomechanics. Each cell in the embryonic neural tube acts like a little rubber band, stretching its neighbours. To work out how much tension a cell is withstanding we have to cut it and measure how far it pings (we call this “recoil”).

So how do you cut a cell? Cells are far too tiny to cut them with anything physical like a scalpel. Instead we use a high-powered laser to very precisely cut a cell border. In the image above you will see the laser cut indicated by a red line as the white borders around cells ping apart. These cells should be pulling the neural tube closed, so by cutting them we can infer whether they were doing their job correctly.

Neural Tube Defects are severe congenital disorders. They happen in early embryos when primary neurulation stalls. The process of primary neurulation turns a flat layer of cells on the back of the embryo into a closed neural tube, which then forms the central nervous system. By “closing”, the neural tube gets covered by cells which eventually become the skin.

The (mouse) fetus below has two different Neural Tube Defects. Its neural tube has remained open in the future head, producing exencephaly (also called anencephaly, highlighted in magenta), and in the spinal region, causing spina bifida (cyan). Both these defects were caused by the same genetic mutation in future skin cells.

Unexpectedly, this fetus also has an abnormally-formed eye – that’s the tiny, black pin-prick in the middle of its head which is normally much bigger. We did not know the specific mutation this fetus has would cause defects in the eye, but that’s how new findings are made!

Welcome to the Neurulation Biomechanics Lab!

We’re a growing group of scientists at the UCL Great Ormond Street Institute of Child Health studying how our brain and spinal cord form while we are tiny embryos.

Specifically, we study how embryos change their shape to cover the brain and spinal cord with skin which protects them during development. If that doesn’t happen, the embryo develops a birth defect known as a Neural Tube Defect. Examples of Neural Tube Defects include Spina Bifida. We study this using genetic models and advanced microscopy, which allows us to watch the neural tube close in model species including mice and chicks.

In the image on the right you can see the tail-end of a mouse embryo. Click on it to watch it move. The cyan region is the future skin, which you will see encircles a folding region of red cells. These red cells will form the future spine and you can see how, over around two hours of live-imaging, the embryo makes a lot of progress in covering it. Clearly, the embryo needs to change its shape quite a lot! What you’re seeing is the embryonic process of neurulation.

How do embryonic cells generate, withstand and transmit the mechanical forces required to change the shape of this tissue? This is what we mean by Biomechanics – the mechanics of biological systems.

Do abnormalities in these processes cause Neural Tube Defects? Can we apply what we learn to prevent, or at least explain the causation of, conditions like Spina Bifida? These are many of the questions our lab is interested in and we hope to share our findings here over years to come.