[{"command":"settings","settings":{"ajaxPageState":{"theme":"hm_theme","theme_token":"zYC4ObQDzUPSg4XOZZCAGJDhBIeBq7TEiOL9YuWXTy0","libraries":"eJwDAAAAAAE"},"ajaxTrustedUrl":{"form_action_p_pvdeGsVG5zNF_XLGPTvYSKCf43t8qZYSwcfZl2uzM":true},"pluralDelimiter":"\u0003","user":{"uid":0,"permissionsHash":"2af85631393b514cbde3779a1f71d92618d53b94b54ea1960d28b2e2d121ff12"}},"merge":true},{"command":"openDialog","selector":"#drupal-modal","settings":null,"data":"\u003Cdiv id=\u0022republish_modal_form\u0022\u003E\u003Cform class=\u0022modal-form-example-modal-form ecl-form\u0022 data-drupal-selector=\u0022modal-form-example-modal-form\u0022 action=\u0022\/en\/article\/modal\/7140\u0022 method=\u0022post\u0022 id=\u0022modal-form-example-modal-form\u0022 accept-charset=\u0022UTF-8\u0022\u003E\u003Cp\u003EHorizon articles can be republished for free under the Creative Commons Attribution 4.0 International (CC BY 4.0) licence.\u003C\/p\u003E\n \u003Cp\u003EYou must give appropriate credit. We ask you to do this by:\u003Cbr \/\u003E\n 1) Using the original journalist\u0027s byline\u003Cbr \/\u003E\n 2) Linking back to our original story\u003Cbr \/\u003E\n 3) Using the following text in the footer: This article was originally published in \u003Ca href=\u0027#\u0027\u003EHorizon, the EU Research and Innovation magazine\u003C\/a\u003E\u003C\/p\u003E\n \u003Cp\u003ESee our full republication guidelines \u003Ca href=\u0027\/horizon-magazine\/republish-our-stories\u0027\u003Ehere\u003C\/a\u003E\u003C\/p\u003E\n \u003Cp\u003EHTML for this article, including the attribution and page view counter, is below:\u003C\/p\u003E\u003Cdiv class=\u0022js-form-item form-item js-form-type-textarea form-item-body-content js-form-item-body-content ecl-form-group ecl-form-group--text-area form-no-label ecl-u-mv-m\u0022\u003E\n \n\u003Cdiv\u003E\n \u003Ctextarea data-drupal-selector=\u0022edit-body-content\u0022 aria-describedby=\u0022edit-body-content--description\u0022 id=\u0022edit-body-content\u0022 name=\u0022body_content\u0022 rows=\u00225\u0022 cols=\u002260\u0022 class=\u0022form-textarea ecl-text-area\u0022\u003E\u003Ch2\u003ENew findings about how a human egg matures may help prevent infertility and birth defects\u003C\/h2\u003E\u003Cp\u003EPhysiological changes known to trigger miscarriages and to increase the likelihood of carrying a child with a genetic condition start in a woman\u2019s early 20s, possibly earlier, and continue progressively through to her 40s, says Dr Agata Zielinska, a cell biologist at the Max Planck Institute for Biophysical Chemistry\u0026nbsp;in G\u00f6ttingen, Germany.\u003C\/p\u003E\u003Cp\u003E\u2018It was thought that things started to go wrong around the age of 35\/36, and you were safe before then, but we\u2019ve found that the chromosome structure deteriorates progressively,\u2019 said Dr Zielinska. \u2018Errors are detectible from the early 20s and by the age of 35\/36 they are so pronounced, you really start to see them. So the clock is ticking continuously.\u2019\u003C\/p\u003E\u003Cp\u003EFertility issues present an ever-growing problem around the world. The \u003Ca href=\u0022https:\/\/www.who.int\/reproductivehealth\/topics\/infertility\/perspective\/en\/\u0022 target=\u0022_blank\u0022 rel=\u0022noopener noreferrer\u0022\u003EWorld Health Organization (WHO) estimates\u003C\/a\u003E that one in 10 couples struggles to conceive. As the trend for women to delay motherhood continues, some scientists hope to fix the biological mechanisms underpinning infertility.\u003C\/p\u003E\u003Cp\u003EFor a project called \u003Ca href=\u0022https:\/\/cordis.europa.eu\/project\/rcn\/111198\/factsheet\/en\u0022 target=\u0022_blank\u0022 rel=\u0022noopener noreferrer\u0022\u003EChromOocyte\u003C\/a\u003E, led by principal investigator Dr Melina Schuh, Dr Zielinska was part of a team that set out to discover why genetic faults affect such a high proportion of ageing human eggs, or oocytes, resulting in pregnancy loss, birth defects and infertility. \u003Ca href=\u0022https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/11283700\u0022 target=\u0022_blank\u0022 rel=\u0022noopener noreferrer\u0022\u003EDNA or chromosome errors\u003C\/a\u003E are found in 50-70% of older human eggs, along with 20% of eggs of women in their early 20s, says Dr Zielinska.\u003C\/p\u003E\u003Cp\u003EA growing number of trisomic foetuses, which have 47 chromosomes instead of 46, have been reported in the past decade. Down syndrome, Edwards syndrome and Patau syndrome are common forms of\u0026nbsp;trisomy.\u003C\/p\u003E\u003Cp\u003E\u2018We wanted to see what was happening at a cellular level so that eventually it would be possible to design tools to correct (or prevent) these errors and eradicate aneuploidy (the presence of an abnormal number of chromosomes in an egg cell),\u2019 said Dr Zielinska.\u003C\/p\u003E\u003Cp\u003E\u003Cblockquote class=\u0022tw-text-center tw-text-blue tw-font-bold tw-text-2xl lg:tw-w-1\/2 tw-border-2 tw-border-blue tw-p-12 tw-my-8 lg:tw-m-12 lg:tw--ml-16 tw-float-left\u0022\u003E\n \u003Cspan class=\u0022tw-text-5xl tw-rotate-180\u0022\u003E\u201c\u003C\/span\u003E\n \u003Cp class=\u0022tw-font-serif tw-italic\u0022\u003EWe wanted to see what was happening at a cellular level so that eventually it would be possible to design tools to correct these errors and eradicate aneuploidy (the presence of an abnormal number of chromosomes in an egg cell).\u003C\/p\u003E\n \u003Cfooter\u003E\n \u003Ccite class=\u0022tw-not-italic tw-font-normal tw-text-sm tw-text-black\u0022\u003EDr Agata Zielinska, Max Planck Institute for Biophysical Chemistry, Germany\u003C\/cite\u003E\n \u003C\/footer\u003E\n\u003C\/blockquote\u003E\n\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EMeiosis\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003EIn a study that started at the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK, and ended earlier this year in G\u00f6ttingen, Dr Schuh\u2019s team was able to do something unprecedented. Using super high-resolution cameras that illuminate microscopic structures, they were able to study and document \u003Ca href=\u0022https:\/\/science.sciencemag.org\/content\/348\/6239\/1143.long\u0022 target=\u0022_blank\u0022 rel=\u0022noopener noreferrer\u0022\u003Elive human egg cells in the moments preceding fertilisation\u003C\/a\u003E, as these cells hurtle towards the completion of meiosis.\u003C\/p\u003E\u003Cp\u003EMeiosis is the two-step division process culminating in the fertilisation of a gamete \u2013 a mature sex cell. The second meiotic step starts when an egg leaves the ovary and takes a number of hours to complete in humans. This process has long been viewed as error-prone, though until now, it was not fully understood why.\u003C\/p\u003E\u003Cp\u003EIn meiosis, a cell with two sets of chromosomes, called a diploid cell, splits its DNA in half, forming new cells with half the number of chromosomes. During successful fertilisation, a split egg cell joins a sperm cell that has also split its DNA. The task of dividing the sex cell\u2019s DNA falls to a protein structure called a spindle, which binds to \u2018handles\u2019 on chromosomes called kinetochores. By pulling on these handles, the spindle drags chromosome strands in opposite directions as the egg divides.\u003C\/p\u003E\u003Cp\u003E\u003Cfigure role=\u0022group\u0022 class=\u0022@alignleft@\u0022\u003E\n\u003Cimg alt=\u0022To get ready for fertilisation, the DNA in a human egg is split in two when a protein structure called a spindle (in pink) binds to kinetochores (white) on the chromosomes (blue) and pulls them apart. Image credit - Dr Agata Zielinska, MRC Laboratory of Molecular Biology\u0022 height=\u0022561\u0022 src=\u0022\/research-and-innovation\/sites\/default\/files\/hm\/IMCEUpload\/young%20egg_1.jpg\u0022 title=\u0022To get ready for fertilisation, the DNA in a human egg is split in two when a protein structure called a spindle (in pink) binds to kinetochores (white) on the chromosomes (blue) and pulls them apart. Image credit - Dr Agata Zielinska, MRC Laboratory of Molecular Biology\u0022 width=\u0022819\u0022\u003E\n\u003Cfigcaption class=\u0022tw-italic tw-mb-4\u0022\u003ETo get ready for fertilisation, the DNA in a human egg is split in two when a protein structure called a spindle (in pink) binds to kinetochores (white) on the chromosomes (blue) and pulls them apart. Image credit - Dr Agata Zielinska, MRC Laboratory of Molecular Biology\u003C\/figcaption\u003E\n\u003C\/figure\u003E\n\u003C\/p\u003E\u003Cp\u003EThe ChromOocyte team captured chromosome deterioration in detail. By filming and photographing the moments before fertilisation, the team observed that the spindle is \u2018unstable\u2019 in human oocytes and often attaches itself incorrectly to chromosome strands, increasingly so with age, leading to genetic errors, according to Dr Schuh.\u003C\/p\u003E\u003Cp\u003EExperiments on mice have shown that the function of the \u003Ca href=\u0022http:\/\/europepmc.org\/articles\/PMC4755749\u0022 target=\u0022_blank\u0022 rel=\u0022noopener noreferrer\u0022\u003Ekinetochores deteriorates with age\u003C\/a\u003E. \u2018In young (human) females, you will find two handles close to each other, near the middle of the chromosome, but as they get older, the handles separate,\u2019 said Dr Zielinska. \u2018This contributes to the spindle not being able to attach properly and then missegregation of the chromosomes occurs.\u2019\u003C\/p\u003E\u003Cp\u003EIn the course of the project, the team observed that \u003Ca href=\u0022https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/26670547\u0022 target=\u0022_blank\u0022 rel=\u0022noopener noreferrer\u0022\u003Eage-related errors\u003C\/a\u003E were far more abundant in humans than in mice. \u2018In women \u2013 even young women in (their) early 20s \u2013 these handles are already quite apart. And the degree of deterioration is much higher as the woman gets older,\u2019 said Dr Zielinska.\u003C\/p\u003E\u003Cp\u003EAneuploidy, where there is an abnormal number of chromosomes, is most likely linked to this, she says.\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003ECohesin \u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003E\u003Ca href=\u0022http:\/\/europepmc.org\/articles\/PMC4791431\u0022 target=\u0022_blank\u0022 rel=\u0022noopener noreferrer\u0022\u003ECohesin\u0026nbsp;\u003C\/a\u003Eis another cell component that scientists suspect may be responsible for chromosomal errors arising in an ageing oocyte. Cohesin is a protein complex\u0026nbsp;that holds sister chromosomes together until the egg is ready to divide its DNA prior to fertilisation. It is special among proteins in that \u003Ca href=\u0022https:\/\/www.sciencedirect.com\/science\/article\/pii\/S0960982216301415?via%3Dihub\u0022 target=\u0022_blank\u0022 rel=\u0022noopener noreferrer\u0022\u003Eit stays unchanged throughout its lifespan\u003C\/a\u003E. It forms at the very start of life \u2013 mammals create their entire pool of immature egg cells before they are born \u2013 and soldiers on without regeneration until an oocyte leaves the ovary at the start of its journey down the fallopian tube.\u003C\/p\u003E\u003Cp\u003E\u2018It\u2019s a mystery how cohesin can still bind the chromosomes, stopping them from falling apart, in a woman of 40,\u2019 said Dr Kikue Tachibana, principal investigator of the \u003Ca href=\u0022https:\/\/cordis.europa.eu\/project\/rcn\/110851\/factsheet\/en\u0022 target=\u0022_blank\u0022 rel=\u0022noopener noreferrer\u0022\u003EChromHeritance project\u003C\/a\u003E\u003Cstrong\u003E. \u003C\/strong\u003E\u2018How does a protein complex that starts its function in foetal development do so for such a long time?\u2019\u003C\/p\u003E\u003Cp\u003EAs it happens, cohesin isn\u2019t infallible. It gradually falls away, causing degradation of the chromosome \u2013 a molecular process that Dr Tachibana has been studying in her lab at the Institute of Molecular Biotechnology in Vienna, Austria. \u2018We think this is one of the causes of the \u201cmaternal age effect\u201d,\u2019 said Dr Tachibana.\u003C\/p\u003E\u003Cp\u003EDr Tachibana is hopeful that her research will eventually lead to clinical interventions that will ensure chromosomes are separated accurately at meiosis. \u2018We are testing a new hypothesis about cohesin deterioration that may provide insights into what triggers oocyte ageing,\u2019 she said.\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EGenetic reprogramming \u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003EAnother finding from Dr Tachibana\u2019s lab involves paternal DNA, and potential errors that creep in as this is being reorganised in the fertilised egg. In the hours after fertilisation, the one-cell embryo goes through a process of genetic reprogramming, forgetting its history as an egg or a sperm and starting a fresh life as a whole organism.\u003C\/p\u003E\u003Cp\u003EThis reprogramming process is fundamental to the start of life for any sexually reproducing species but\u0026nbsp;how exactly DNA is reorganised remain largely unknown. Dr Tachibana\u2019s work has started to explain some of the mysteries around these mechanisms.\u003C\/p\u003E\u003Cp\u003EShe was keen to test the idea that \u003Ca href=\u0022http:\/\/europepmc.org\/articles\/PMC5161750\u0022 target=\u0022_blank\u0022 rel=\u0022noopener noreferrer\u0022\u003Etears occur in the paternal DNA\u003C\/a\u003E as an essential part of this reprogramming process, and that the maternal DNA directs the surveillance system that registers and then repairs these lesions.\u003C\/p\u003E\u003Cp\u003E\u2018We (genetically) knocked out the DNA repair machinery (in mouse oocytes) and discovered that indeed there is DNA repair occurring during this process, and the zygote (the fertilised egg) actually has a tightly controlled surveillance mechanism that monitors the whole process,\u2019 Dr Tachibana said. She adds that there is no further development of the zygote unless these tears are repaired.\u003C\/p\u003E\u003Cp\u003EThe team hasn\u2019t yet investigated the link between ageing and reprogramming, Dr Tachibana says.\u003C\/p\u003E\u003Cp\u003E\u2018But we would consider the hypothesis that with an aged oocyte, the repair mechanisms might not be very efficient, and if there\u2019s an aged sperm as well \u2013 because sperm can also accumulate DNA damage over time \u2013 then the two together could be a particularly detrimental combination.\u2019\u003C\/p\u003E\u003Cp\u003E\u003Cem\u003EThe research in this article was funded by the EU\u0027s European Research Council. 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