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Wednesday, 17 October 2012

Open Questions in Embryo Development

There are many things we still don't know about the very first hours of an embryo's development. In this time, does an embryo separate its back from front? Left from right? Or is this decided later?

We know about certain pathways that are involved in the early development of embryo.  But do we have the whole picture? And how can we even try to look at it?

This is what I am interested in my work. On my daily commute people often ask what it is that I work with. I tell them I use a technique to try to look at all the proteins at once within early embryos, mass spectrometry proteomics.

"What kind of embryos?  Human (with varying tones)? Mouse? Rat?"

"No."  I reply.  "Frogs."
A frog embryo, or 'Frogspawn'
A frog embryo, more commonly known as 'Frogspawn'.
Image credit: Andrew Michaels (Creative Commons)
Frogs may seem a strange animal to be working with for scientific work.  After all, whoever heard of any serious work being carried out in frogs?  Until, that is, a week or so ago, when John Gurdon was a joint winner of the Nobel Prize in Physiology or Medicine.  His work followed up on the work of Briggs and King to show that sexually mature Xenopus laevis (the African claw-toed frog) could be derived from transfer of a nucleus from the somatic cell of an embryo to an enucleated unfertilized egg (Gurdon et al., Nature, 1958).  But Gurdon went further – up to this point nuclei for transplantation had been taken from cells that were differentiating rather than differentiated i.e. developing and not yet fully developed; and so, from the intestinal epithelium cells of tadpoles, Gurdon took nuclei and transplanted these into enucleated unfertilized eggs (Gurdon, J Embryol Exp Morphol, 1962) to found the field of "cloning" as we know it today.

In particular for our interests, the early frog embryo is very useful.  The first 12 divisions of cells in the Xenopus embryo occur with no growth at all in-between cell cycles – the cells divide, divide, divide incredibly rapidly – every 30 minutes at room temperature, with the exception of the first cell division which takes 90 minutes (we don't know why).  So to look at what's going on in the early embryo – and across the whole embryo – I and others am turning to a method of looking at the whole protein complement of a sample – mass spectrometry proteomics.

So what exactly is "Proteomics"?  It's OK, these people didn't know either.  It's the study of proteins – the suffix "-Omics" is probably more familiar from "genomics" (although a whole range of 'omes has been appearing recently as discussed in this article from the Wall Street Journal). The role of "-Omics" in developmental biology is a timely issue – a recent essay in Development briefly covers the topic but unfortunately makes no reference to proteomics.  For a quick summary of the world of computational proteomics please see this cool stop-motion video by my colleague Dr Oliver Serang. Mass spectrometry measures the masses of fragments of proteins to determine what proteins are present in a sample and there are even ways of telling how much of a protein there may be in a particular sample.

Egg mass of small frogspawn embryos
Many small embryos in one egg mass.
Image credit: Taylor Gosforth/USFWS (Creative Commons).
Where Xenopus brings great value particularly to the field of proteomics is in the abundance of protein material that a researcher has available.  Working with tissue culture and in particular stem cells, a major constraint is culturing enough cells to provide material for proteomics experiments.   20 eggs can provide enough material for a sample, compared to several flasks of cells from tissue culture (with all the investment that takes).  Xenopus lay clutches of 1000 eggs and in terms of microinjection of drugs, nucleic acids or proteins, or embryo manipulation, 20 embryos is an easily achievable number.

And what do we hope to achieve by this work?  The possibilities really are endless.  Greater understanding of the development of embryos, most obviously – which is relevant for animals from fish to humans as development occurs in incredibly similar ways in vertebrate species.  I've already mentioned that cells cycle very quickly in the early embryo and so finding out what exactly is the minimum environment for cells to divide is important in fields from stem cells to cancer.  And as frogs are such an easy system to work with to manipulate the embryos, all sorts of drugs can be injected into the early embryo, to see the effects on embryo development and growth as perhaps an easy basic screen before carrying out larger studies using mice, rats, or clinical trials in humans.

The importance of basic science in model organisms is often forgotten.  But these systems, and these questions, are incredibly important for all sorts of complications and diseases that we can run into in our lives.  There are many areas where we just don't know what happens and what goes on, and the beauty of these studies is that we can find out so many things not only to answer the questions we already had, but to present new questions we didn't even know existed.

Gary McDowell is a Research Fellow at Harvard Medical School, and can be found on twitter as @BiophysicalFrog