UAE researcher in breakthrough that could reduce problems associated with older women conceiving

A study co-authored by a New York University Abu Dhabi researcher has identified an enzyme that boosts meiosis, a natural chromosome process that sometimes encounters problems in older women, leading to miscarriages and potentially Down Syndrome in a newborn.

Obstetrician showing pregnant patient ultrasound on digital tablet

As a woman ages, it can become more difficult for her to fall pregnant, and the likelihood that a pregnancy will end in miscarriage tends to increase.

About 10 per cent of pregnancies end in miscarriage when the mother is in her 20s, while for women aged above 45, the rate of miscarriage is more than 50 per cent.

The effect of age on fertility is something that increasing numbers of couples around the world are having to face, because growing numbers of women now leave motherhood until their late 30s or 40s.

In Greece, for example, the average age at which a woman has her first child is 31.2 years, while in Australia the figure is 30.5 years and in Italy, Japan and South Korea it is 30.3 years.

Demonstrating how things have changed, in the United States the figure increased from 22.7 years in 1980s to 26 years in 2013, according to reports citing the Centers for Disease Control and Prevention. The UAE, too, is likely to have seen an increase, with the average age at which Emirati women marry having gone up from 23.7 years in 1995 to 26.8 years in 2012.

A key reason why fertility falls with age is that eggs are not produced continually throughout life but are already present, in immature form, when a girl is born. And older eggs are more likely to have abnormalities with the chromosomes, the bundles of DNA and protein passed from parent to child.

Under normal circumstances in an adult woman, an immature egg cell, called a primary oocyte, undergoes a type of cell division called meiosis, in which the normal complement of 46 chromosomes (made up of 23 pairs) is reduced to 23 chromosomes. In fertilisation, this egg fuses with a sperm cell to produce an embryo with 46 chromosomes.

In older primary oocytes, meiosis more often goes awry, sometimes resulting in a mature ovum with an abnormal number of chromosomes. It may have 24 chromosomes instead of 23 because an additional copy of one of the chromosomes is present.

Any resulting embryo, instead of having one pair of each type of chromosome, may have three examples of a particular chromosome. Known as trisomy, this is a form of aneuploidy (the presence of an abnormal number of chromosomes), which can affect about half of a woman’s eggs by the time she is 40.

A form of aneuploidy causes Down Syndrome, which results from a child having three copies of chromosome 21. More often, aneuploidy leads to embryos that are unable to implant into the uterus wall or are lost through miscarriage.

Given aneuploidy’s significant consequences, it would be of great value to understand better why it becomes more common in older eggs.

A newly published study co-authored by Dr Ibtissem Nabti, a researcher at New York University Abu Dhabi, does just this. Although it involved looking at eggs in mice, rather than people, it offers pointers as to how the frequency of aneuploidy could be reduced, something that could improve fertility in more mature women.

Central to the new study is an enzyme called securin, which helps to ensure that meiosis takes place successfully. When levels of securin are low, aneuploidy is more common because the activity of another enzyme, separase, which controls how chromosomes separate from one another, is not regulated properly, causing them to separate early.

In the new study, of which Dr Nabti is the senior author, a team of researchers looked at oocytes from mice that were young (aged one month) or old (aged 13 to 14 months). They found that there is less securin in the oocytes of older mice.

“In our manuscript, we demonstrated that injection of extra amounts of securin in eggs from older mice partially rescues the incidence of premature chromosome separation, which is the leading cause of aneuploid embryos and miscarriages in older women,” said Dr Nabti.

Crucially, this work on mice indicates a way in which problems of aneuploidy in people could be combated.

“This [injection of extra amounts of securin] can also be applied to human eggs, however, it is immensely challenging, given that human in-vitro egg maturation is not yet successful and therefore such treatment has to be applied while the egg is still in the ovary,” said Dr Nabti.

“Also, we have to make sure that any such treatments will be safe for both the egg and the subsequent embryo.”

The new study, called Maternal age-dependent APC/C-mediated decrease in securin causes premature sister chromatid separation in meiosis II, was published in the journal Nature Communications. Among the other authors is Professor John Carroll, of the School of Biomedical Sciences at Monash University in Melbourne, Australia, and several researchers at University College London, where Dr Nabti used to be based.

Prof Carroll and his group at Monash University are continuing to research the issues highlighted in the study.

“There are still a few questions that need to be answered, such as the mechanism behind the age-related decrease in securin levels and how this can be prevented,” said Dr Nabti.

Now, at NYU Abu Dhabi, Dr Nabti has turned her attention to a new area of interest, namely transport within cells and “molecular motors”.

“These proteins are responsible for the long-distance delivery of organelles [structures within cells], proteins, RNA granules [RNA, or ribonucleic acid, is a form of genetic material] and chromosomes within the cell. Therefore they are crucial for cell viability and any failure in their regulation or activity would lead to diseases, such as Alzheimer’s,” said Dr Nabti.

Alzheimer’s disease, a neurodegenerative condition, is the most common cause of dementia, affecting about 30 million people globally.

So, having previously looked at aneuploidy, which exert its effect from the very beginning of life, Dr Nabti is now focused on processes that can cause problems later in life. Although at opposite ends of the age spectrum, in both cases it is an understanding of the molecular biology that could provide the answers needed to combat the conditions.