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North research offers hope to infertile couples.

Byline: Helen Rae

ABREAKTHROUGH in medical science is offering new hope to infertile couples. Human sperm have been created using embryonic stem cells for the time in a scientific development which will lead researchers to a better understanding of the causes of infert y. But it will not be used to create human babies - and will not mean the end of men, they said. A team of 20 researchers, led by Prof Karim Nayernia at Newcastle University and the NorthEast England Stem Cell Institute (NESCI) have developed a new technique to grow sperm from embryonic stem cells. Researchers saw the cells, which were treated with acid, begin to split and dive then eventually push out a tail and begin to move.

They called for the introduction of laws "sooner rather then later" to control how the research is used. Prof Nayernia said: "This is an important and exciting development as it will allow researchers to study in detail how sperm forms and lead to a better understanding of infertility in men - why it happens and what is causing it. "This understanding could help us develop new ways to help couples suffering infertility so they can have a child which is genetically their own. "It will also allow scientists to study how cells involved in reproduction are affected by toxins, for example, why young boys with leukaemia who undergo chemotherapy can become infertile for life - and possibly lead us to a solution." It is believed that within the next five to seven years infertile men could be helped by the pioneering research. The team also believe that studying the process of forming sperm could lead to a better understanding of how genetic diseases are passed on. "Infertility in men has been rising in the last 20 years, particularly in the Western world, and this could be down to a number of environmental and genetic factors," explained Prof Nayernia. "This research is the first system which is able to look at the genetic and environmental influence, which is a key issue when looking into infertility." In the technique developed at Newcastle, stem cells with XY chromosomes (male) were developed into germline stem cells which were then prompted to complete meiosis - cell division with halving of the chromosome set. These were shown to produce fully mature, functional sperm called scientifically, In Vitro Derived sperm (IVD sperm). In contrast, stem cells with XX chromosomes (female) were prompted to form early stage sperm, spermatagonia, but did not progress further. This demonstrates to researchers that the genes on a Y chromosome are essential for meiosis and for sperm maturation.

The IVD sperm will not and cannot be used for fertility treatment. As well as being prohibited by UK law, the research team say fertilization of human eggs and implantation of embryos would hold no scientific merit for them as they want to study the process as a model for research. Prof Nayernia added: "While we can understand that some people may have concerns, this does not mean that humans can be produced 'in a dish' and we have no intention of doing this. "This work is a way of investigating why some people are infertile and the reasons behind it. If we have a better understanding of what's going on it could lead to new ways of treating infertility. "This is not the end of men. We need at least a Y chromosome from the man for sperm maturation. "I also see the need for the biological process and social process in human production and we cannot just rely on biological aspects." Prof Nayernia showed the potential of the method in 2006, when he used sperm derived from male embryonic stem cells to fertilise mice to produce seven pups, six of which lived to adulthood, though the survivors did suffer problems.

He said the work was in its early stages and more investigation needed to be done to decide whether IVD sperm would be safe or suitable as a fertility treatment. He said he believed that in at least a decade such a treatment could be offered to, for example, men who had received chemotherapy which can leave them infertile. "When combined with other pioneering stem cell techniques, specifically somatic cell nuclear transfer, it could also allow men who are currently infertile the chance to have a child which is genetically their own but again, this will be many years away," he explained. "Given the speed of progress in this area of work, legislation needs to be put in place sooner rather than later to allow for the technique to be licensed as a treatment in the future for infertile men." But pro-life groups say they are against the research. Marileine Ollerenshaw, North East development officer for Society for the Protection of Unborn Children, said: "This is another way of destroying the naturalness of family life. "Trying to cure an illness through the use of embryonic stem cells is something we are not in favour of. "A lot of scientists are giving false hope to so many people who are looking to cures to help them and these scientists are using embryonic stem cells to fuel that hope. "It's not right and it will have huge implications on society in the future." Comment 10 TEAM DEVELOPED NEW METHOD THE Newcastle University team developed a method for establishing early stage sperm from human embryonic stem cells. The embryonic stem cells were cultured in a new medium containing vitamin A derivative (retinoic acid), in a technique established by the team. Based on this technique, the cells differentiated into germline stem cells. These expressed a protein which was stained with a green fluorescent marker and they were separated out by FACSTM (Fluorescence-activated cell sorting) using a laser. After further differentiation, these in vitro derived germline stem cells expressed markers which are specific to primordial germ cells, spermatogonial stem cells, meiotic (spermatocytes) and post meiotic germ cells (spermatids and sperm). These results indicated maturation of the primordial germ cells to haploid male gametes - called IVD sperm - characterised by containing half a chromosome set (23 chromosomes). Prof Nayernia said: "In the lab, we prompted embryonic stem cells like these, to develop into many different cell types.

"A temporary green marker stained those which had the characteristics of early sperm and they were separated out by laser. "Growing in a medium containing vitamin A derivative, these early stage sperm are called spermatagonia. We saw some of them later develop to form spermatocytes - where the chromosome set halves... And they then went on to form spermatid. "In our research, some of these spermatid continued to grow, elongating and pushing out a tail which enabled it to move - forming the in vitro derived sperm or IVD sperm. They can be seen moving under the microscope in film from our original research project." For a video of the professor talking about the research, go to Controversy over medical history claims CONTROVERSY last night surrounded claims by Newcastle scientists that they have made medical history by creating human sperm in the laboratory. Experts cast doubt on the claim, arguing that the cells did not constitute "authentic" sperm with all the necessary biological characteristics. Dr Allen Pacey, senior lecturer in andrology at the University of Sheffield, said: "As a sperm biologist of 20 years' experience, I am unconvinced from the data presented in this paper that the cells produced by Professor Nayernia's group from the embryonic stem cells that can be accurately called 'spermatozoa'. "While the cells produced may possess some of the distinctive genetic features and molecular markers seen in sperm, fully differentiated human spermatozoa have specific cellular morphology, behaviour and function that are not described here."

Professor Azim Surani from Cambridge University said: "These sperm-like cells made in a dish from embryonic stem cells are a long way from being authentic sperm cells. "First, they need to test if a normal male pronucleus with appropriate chromosome numbers and without mutations can form when introduced into an animal egg; and there has to be evidence that these sperm-like cells are properly reprogrammed with male-specific imprints, without which they cannot function properly in early embryos." Professor Robin Lovell Badge, from the Medical Research Council Institute of Medical Research, said the work was a follow-up to animal research in which laboratory-made mouse sperm was used to produce offspring. However, all the mice born died after a few months, suggesting a problem with the sperm.

The Newcastle scientists had not produced robust evidence that the human sperm they created was normal, said Prof Lovell Badge. He said: "Although they find that some of the sperm cells have tails and can swim, this is not evidence of normality." Only a small proportion of the cells were "haploid" - having the necessary reduced genetic material following meiosis. Dr Evan Harris MP, who tabled amendments to the 2008 Human Fertilisation and Embryology Bill on laboratory-made eggs and sperm said: "While the Newcastle team is not seeking at present to use stem cell derived sperm as a treatment for infertility, it is clearly a possible future application. It is very sad that the recent Human Fertilisation and Embryology Act did not take the opportunity to provide a power for Parliament to approve clinical trials of stem cell (IV) derived sperm as a treatment for male infertility by regulations. "Instead the actual use of these gametes - even when derived from adult stem cells where no embryo is used - in the treatment of infertile couples will require primary legislation.

This makes it more difficult to attract funding for the application of this research despite the Government always banging on about the importance translational research." Approximately one in seven couples have fertility problems. The NorthEast England Stem Cell Institute (Nesci) is a collaboration between Newcastle and Durham Universities, Newcastle NHS Foundation Trust and other partners.

This does not mean that humans can be produced 'in a dish' and we have no intention of doing this Cases can be cured MORE and more men aged 50-65 are now attending fertility clinics, with men over 40 making up nearly a quarter of consultations. Up to half of all cases of infertility involve problems with the man. In fact, about 20% to 30% of the time, a man's low fertility is the main obstacle to conception. Causes of male infertility may include: low sperm count, sperm that are abnormally shaped or that don't move correctly, undescended testicle or an underlying medical problem. Sometimes the cause of male infertility cannot be identified. In these cases, there may be an underlying genetic problem. More than one-half of cases of male infertility can be corrected.
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Publication:The Journal (Newcastle, England)
Date:Jul 8, 2009
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