Title: The role of the human sperm in healthy live birth
Funder: Health Education England

Abstract: BackgroundAcross Europe around 1 in 6 couples resort to fertility treatment in their struggle to have a child, over half of these will have a male partner who factors in the fertility problem. However the techniques currently used to move towards conception rely on a series of procedures for the female partner, which all carry risk. It is therefore not just of financial interest, but also of female health interest that successful healthy live birth can be achieved with as few rounds of treatment as possible. Aims Sperm provide a number of unique points of interest when considering ways to improve the outcome for subfertile couples: Sperm are amenable to improvements in laboratory diagnosis / assessment New sperm are produced constantly, therefore interventions and changes in lifestyle have measurable, assessable effects within reasonable treatment periods As sperm are (usually) supplied in excess numbers for treatment elements, cell selection can be employed to help identify the best' sperm to use in any treatment modality. During normal' in vivo fertilisation, cells migrate through the female tract. They therefore may induce signals that prepare the uterus for implantation. Plan of investigation & summary of the potential benefitsThe proposed fellowship will incorporate three workpackages of research to examine how the above sperm-related features can be exploited to help deliver the very best, and healthiest, live birth rates. Workpackages A & B will focus upon the genetic integrity of the male gamete. Surplus sperm from the samples provided for assisted conception will be used to assess measurements of DNA quality and whether the cell population present can be skewed to enhance the treatment population. As part of this program I aim to assess and validate a locally developed variant of the well-accepted Sperm Chromatin Structure Assay, involving a microscope modification. If robust, this would make assessment of sperm DNA cost-effective within standard diagnostic semen analysis pathology lab work regimes and budgets. Comparisons will be made between our novel technology and the published reference-standard Comet and TUNEL tests. I will utilise our recently published observations that sperm swim in the corner', and that sperm head morphology selects for swimming pattern, to examine how microchannel-mazes might be employed to actively select sub-populations of motile cells, driven by their own motility. The ploidy and DNA integrity of selected cells will be examined. If they are improved this should provide a novel method for selection of better' sperm for IVF, improving ongoing pregnancy and live birth rates saving the NHS money and risk on females requiring repeated cycles. Finally, in workpackage C, preliminary data indicate that the cells of the human endometrium (womb lining) signal on exposure to human sperm. Sperm normally pass through the womb on their journey to fertilise the egg 6-12 days prior to the embryo implanting. The potential importance of sperm in preparing the endometrium for implantation in the human has not been studied. In animals key changes are induced by the introduction of sperm to the uterus. Recent publications have demonstrated that stimulating the uterus in the cycle before embryo transfer, by scratching' the surface. This may provide a dramatic improvement in implantation and pregnancy rates, but with a major drawback of significant pain. I will identify sperm molecules involved in inducing endometrial signals, alongside performing a preliminary study of pregnancy rates after surplus-sperm-insemination at the time of egg-collection, after which I will develop a clinical trial. If we can identify an active molecule in our assays this will become a vital addition to assisted reproductive treatment, and then couples with low sperm numbers will benefit.

Lay abstract: In the human fertilisation process millions of sperm are selected down to hundreds reaching the egg. On the sperms' journey their presence may also alter the female tract environment, helping to prepare the womb for embryo implantation. This research aims to help improve outcomes in assisted conception by: delivering an affordable way of assessing sperm DNA quality in any laboratory; Improving how the best' sperm are selected for IVF using recently developed microchannel maze-on-a-chip technology; Identifying whether sperm-derived molecules can be used to revolutionise how we prepare the womb for effective embryo transfer, meaning more couples can have healthy children.

Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH