Pioneering lab at Bourn Hall Clinic uncovers secrets about the biology of human eggs
Dr Melina Schuh is exploring why older women find it harder to fall pregnant
Dr Melina Schuh’s new laboratory at Bourn Hall Clinic is carrying out ground-breaking research into human eggs.
It is seeking to uncover the secrets of why older women find it harder to fall pregnant – and why they are more likely to have children with chromosomal abnormalities.
The laboratory is the first in Europe to use a light sheet microscope to take images of live, developing human eggs.
It has helped the team to discover that chromosomes – the DNA molecules containing the instructions for life – are more likely to fall apart in the eggs of older women.
Dr Schuh, a director at the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany, established the lab at Bourn Hall to continue work she began in 2012 at the Medical Research Council Laboratory of Molecular Biology (MRC LMB) in Cambridge.
“I was a group leader at the LMB and was starting to study how mouse eggs develop,” she told the Cambridge Independent.
“There are some differences between mice eggs and human eggs. One is that human eggs are much more likely to be abnormal – they often carry too many or too few chromosomes. It was unclear why.”
At that stage, there were no imaging studies of the critical process of cell division – known as meiosis – in human eggs.
“It was not possible to follow directly in the eggs how the chromosomes become separated in meiosis and where these errors came from,” explained Dr Schuh.
She contacted Bourn Hall Clinic – famed for its IVF treatment – and carried out the first studies that visualised how chromosomes separate in human eggs.
They also compared immature egg cells, known as oocytes, from young and older women to understand what defects occur with age. It is these defects that make it harder for older women to conceive and increase the likelihood of their children having Down’s syndrome.
“When I moved to Germany, we thought why can’t we use the opportunity to set up the lab at the clinic?” said Dr Schuh, who appointed senior PhD student and embryologist Bianka Seres to set it up and optimise the technique of light sheet microscopy.
It employs a ‘sheet’ of light to illuminate a single plane of the sample at a time and a 3D reconstruction of the egg is built up from the images it creates.
Recording an image takes just milliseconds – meaning this method captures changes in real time, yielding an animation that reveals biological processes in a cell in great detail, without casting as much light on the egg as standard microscopes.
“Reducing the light is particularly important with a human egg because they need more than an entire day to develop,” explained Dr Schuh. “If you put lots of light on them, they may not develop well.”
The novel technique revealed how older eggs were less stable.
“In a 40-year-old woman, you will have 40-year-old eggs, as they are first formed in the embryo when they develop. It already has all its chromosomes then,” said Dr Schuh.
“There is evidence from mouse work that proteins in these eggs associated with chromosomes are also very long-lived. So it’s very likely in a 40-year-old woman that there are also proteins that are 40 years old.
“What we found is that the chromosomes are falling apart when women get older.”
The pairs of chromosomes should only divide during the process of meiosis.
“This is what happens once every menstrual cycle: an egg divides and it is ovulated into the oviduct. Only then should the chromosomes come apart. But what we saw is the chromosomes start to come apart in older women much earlier. That’s a problem because then they can’t be separated correctly – they’ve already fallen apart,” said Dr Schuh.
This means the eggs are released during ovulation with an incorrect number of chromosomes – something known as aneuploidy.
If these eggs are fertilised, the resulting embryos will also have an incorrect number of chromosomes. Severe chromosomal errors either prevent implantation in the lining of the womb or cause early miscarriage.
The process of cell division is a fascinating one – and could be envisaged as lots of little tug-of-wars going on, tearing apart the chromosomes.
It involves spindle fibres forming a protein structure to divide the genetic material.
First, at opposite ends of the cell, structures called centrioles form cell polls. Then long protein fibres known as microtubules extend from these to form the spindle. Some of these connect the poles to the chromosomes at attachment points. Others connect elsewhere - and then the tugging begins.
“There are normally four attachment points on chromosomes called kinetochores,” explained Dr Schuh. “The structure of these attachment points is also changing as women get older – they are coming apart too.
“That creates problems as the chromosomes can’t be separated by the machinery – the spindle. They start to rotate around on the chromosomes and take on abnormal positions within the spindle and that leads to errors.
“So the main changes we saw are in the chromosomes themselves – they are not as strongly tied as they should be – and the attachment points, the kinetochores, are coming apart.”
The team also learned that the spindle is much more fragile in humans than other species.
“We recorded the first videos of the spindles and the chromosomes and this is something we were really surprised to see,” said Dr Schuh. “Instead of the spindle forming very rapidly and being stable, it was fragile and formed over a very long time. That’s very unique about human eggs.
“In mouse eggs, the spindle is very rapidly assembled and is normally stable.
“In human eggs, this doesn’t seem to the case. We found the degree of instability of the spindle correlates very well with the probability of seeing errors when the chromosomes are separated.”
Mice have microtubial organising centres that help to make the spindle rapidly. Humans don’t have these. Dr Schuh speculated that evolution plays a part.
“Human meiosis is very error prone,” she said. “Since humans have a long lifespan and relatively few progeny, in evolutionary terms it may not be a problem if one in four eggs fail to give rise to a viable embryo. For mice this rate of failure would have a much greater impact.”
But she added: “Occasionally you can still get an egg with chromosomes intact so our work gives a bit of hope. Even with older women there may still be good eggs. That’s an important finding.”
Many questions still remain for the team.
“I think we need to understand more about the ageing process and see if there are things that can be done to diagnose errors at an earlier stage or to give the cell more time or enhance mechanisms for error correction.
“We are also just trying to understand the basic biology,” said Dr Schuh.
Some women are considering freezing their eggs at an earlier age. This is primarily done for health reasons – cancer patients can be left infertile, for example – but some are considering it out of choice.
“Our work can help define age ranges when this is best done,” said Dr Schuh.
The lab is a satellite to Dr Schuh’s Department of Meiosis at the Max Planck Institute and is funded by the Max Planck Society, along with funds from the prestigious Lister Research Prize, which she was awarded in 2014.
Patients who are undergoing IVF at Bourn Hall who have immature eggs not suitable for treatment can donate their eggs to the research.
Dr Schuh said: “We really hope to develop tools that could potentially be used in the clinic in the longer term. Of course, the basic research must first be carried out, but we are already starting to look at methods that could potentially help with some of these problems.”