New Sperm Shaker Set To Improve IVF Success Rates

Scientists have developed a ground-breaking method for testing the quality of a sperm before it is used in IVF and increase the chances of conception.Researchers at the University of Edinburgh have created a way of chemically ‘fingerprinting’ individual sperm to give an indication of quality. Scientists can then consider whether the sperm is healthy enough to be used to fertilise an egg as part of an IVF treatment.

The sperm are captured in two highly focussed beams of laser light. Trapped in what are essentially ‘optical tweezers’, an individual sperm’s DNA properties are identified by the pattern of the vibrations they emit in a process known as Raman spectroscopy. This is the first time this process has been used to evaluate DNA damage in sperm.

Dr Alistair Elfick, lead scientist on the project, said: “In natural conception the fittest and healthiest sperm are positively selected by the arduous journey they make to the egg. What our technology does is to replace natural selection with a DNA based ‘quality score’. But this is not about designer babies. We can only tell if the sperm is strong and healthy not if it will produce a baby with blue eyes.”

In the past quality tests of sperm have mostly been carried out on the basis of shape and activity. While these do give some indication of health of the sperm they do not give its DNA status.

There are established tests for sperm DNA quality but they work by cutting the cells in half and tagging them with fluorescent dye – a process that kills the sperm and renders it useless. This new process does not destroy the sperm,

so if it is found to have good DNA quality, it can still be used in IVF treatment.

Conception rates in both IVF treatment and intercourse are at around one in four. By selecting the best quality sperm it is hoped this new process could both increase a couple’s chances of conception and give the child the best potential start in life.

The research is currently in a pre-clinical phase, and if successful could be available to patients in the next five to ten years.

This research was funded by the EPSRC (Engineering and Physical Sciences Research Council).

Researchers Identify Potential Cancer Target

Dartmouth Medical School researchers have found two proteins that work in concert to ensure proper chromosome segregation during cell division. Their study is in the January 2009 issue of the journal Nature Cell Biology.

This finding is relevant for treating solid cancerous tumors that lose the ability to accurately segregate their chromosomes. Tumors that shuffle chromosomes, a process called chromosomal instability, are known to have a poor prognosis.

"We show that the function of two proteins, called Kif2b and MCAK, is to correct improper attachments during cell division to prevent the mis-segregation of chromosomes" said Duane Compton, the senior author on the paper and a professor of biochemistry at Dartmouth Medical School. "The two proteins share the workload as Kif2b acts early in cell division and MCAK acts later. This cooperation underlines the importance of proper chromosome segregation for the healthy life of all cells." Compton is also director of the Cancer Mechanisms Research Program at Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center.

Compton explained this finding follows a study his team published in the February 2008 issue of The Journal of Cell Biology that showed that the main cause of chromosomal instability is that chromosomes make improper attachments to the spindle apparatus during cell division. "These improper attachments occur normally during cell division in all cells, but in the tumor cells, the improper attachments fail to get corrected and cells attempt to divide with persistent improper attachments," said Compton.

The current study shows the two proteins complete their job by regulating the attachment between the chromosomes and the spindle apparatus. Based on these results, the team also determined that increasing quantities of either Kif2b or MCAK in tumor cells restored nearly normal accuracy of chromosome segregation.

"We discovered how to make the tumor cells faithfully segregate their chromosomes every time the cell divides," said Compton. "Chromosomal instability has been studied for over a decade in tumor cells; this is the first time anyone has suppressed it in tumor cells indicating a strong causal relationship between correction of improper attachments of chromosomes to the spindle apparatus and chromosomal instability. These results give us insight into the overall mechanisms of cell division in tumor cells compared to normal cells, and we may be able to exploit that, leading to new therapeutic strategies or treatments that might prevent tumor progression."

Compton and his team will now work to directly test the contribution of CIN to tumor development.

Co-authors on the paper include: Samuel Bakhoum, Sarah Thompson, and Amity Manning, all with the Department of Biochemistry at Dartmouth Medical School and the Norris Cotton Cancer Center.

This research is supported by funding from the National Institutes of Health.

New Hope For Diabetes Patients?

Researchers have identified a signal pathway that could be involved in the occurrence of Type 2 diabetes. If it is deactivated, it may be possible to delay the illness by many years.

Diabetes, a metabolic disease, affects about 246 million people throughout the world, about a quarter of a million of them in Switzerland. Obesity and lack of exercise often play a decisive role in the illness. During his thesis work in collaboration with researchers from Oxford and the University of Lausanne, Jens Zehetner, a doctoral student with Wilhelm Krek, Professor at the Institute of Cell Biology of ETH Zurich, has identified one of the mechanisms that may play a part in diabetes. The study reveals that the signal pathway for the secretion of insulin is controlled by the pVHL and HIF1a genes, which are familiar from cancer research and are known to play an important role in growth and in the cell’s energy supply. Not only do the results help understand the origin of diabetes, the knowledge could also be used to combat the illness.

Signal pathway for insulin production

Wilhelm Krek explains that, “Cells need energy in the form of adenosine triphosphate (ATP), the cell’s energy currency, to enable them to maintain their functions. In a healthy person, the b-cells of the pancreas, which are responsible for insulin production, recognise when food is ingested. Sugar is burnt in the mitochondria of the b-cells by what is known as oxidative phosphorylation, producing ATP which, in turn, initiates insulin secretion in the b-cells. This stimulates the muscle cells, among others, to absorb sugar, thus regulating and normalising the level of sugar in the blood. Krek says that some diabetics may have an abnormality in this signal pathway. The plan now is to investigate this in a follow-up study.

Changeover to glycolysis

In their study of the pVHL and HIF1a genes, the scientists began by modifying mice genetically to end up with four kinds of mice with different gene combinations: those in which both genes were intact and those in which one, or the other, or both had been deactivated.

Under normal conditions with an adequate oxygen supply, HIF1a is constantly suppressed and destroyed by pVHL. However, if there is a shortage of oxygen, ATP cannot be formed in the mitochondria, which in turn activates HIF1a to enable the cells to produce the necessary ATP via glycolysis – independently of the mitochondria. The researchers now studied what happens in the b-cells if HIF1a is activated in mice.

Zehetner says, “Even when the amount of ATP produced was equal to that in “normal” mice, the insulin secretion profile in the animals without pVHL changed dramatically.” The secretion of insulin is increased at basal glucose levels but is less efficiently upon glucose stimulation. He says that this shows that the ATP production taking place in the mitochondria activates yet more factors – at present unknown – that are important in regulating the secretion of insulin. ATP production on its own is not enough.

Oxygen deficiency as the cause

In obese mice, the mass of the b-cells increases. This causes newly formed b-cells to have a worse blood supply at first, due to a lack of oxygen. Krek explains that, “Our hypothesis states that this oxygen deficiency is exactly what leads to activation of the suppressed HIF1a gene to keep the oxygen-starved cells alive.” The result is a changeover from a regulated, effective secretion of insulin to a physically increased but less efficient glucose-stimulated insulin secretion – the possible start of Type 2 diabetes. The illness becomes apparent when all the b-cells gradually die off through permanent overloading.

Gene deactivation as a therapy

Krek explains that “The study enabled us to show that pVHL and HIF1a play an important part in insulin secretion and that they are decisive in the strategy of ATP production.” One of the next steps will now be to utilise this knowledge in the form of a treatment for diabetes, although this has yet to be developed. If one were to be able to inactivate the HIF1a signal pathway in the b-cells of diabetes patients, it might be possible to delay the outbreak of the illness perhaps for many years. This is because experiments in mice whose HIF1a was inactivated showed that their insulin secretion was stimulated by the ATP formed in the mitochondria and functioned with no problems.