What efforts have scientists and doctors made to solve human fertility problems?

Introduction:

Infertility has become a hot topic in recent years, and many married couples are facing the dilemma of being unable to have children. Why is this the case? What role will assisted reproductive technology play in solving human reproductive problems?

In this issue, we invited Professor Han Yibing from the Kiang Wu Hospital in Macau. Professor Han is mainly engaged in research and clinical work in reproductive biology, and has profound attainments in in vitro fertilization, microinjection, and stem cell isolation and culture.

Han Yibing ( Professor of Kiang Wu Hospital, Macau ) | Guest

Ye Shuisong | Interview

01 Embryo implantation and development process

Ye Shuisong: Teacher Han , can you tell us how embryo implantation and development occur under normal circumstances?

Han Yibing: Under normal circumstances, a woman's egg is discharged from the ovary, passes through the fallopian tube, and enters the ampulla of the fallopian tube. At this time, through sexual intercourse, sperm swims up to the ampulla and fertilizes the egg, and the fertilized egg goes down from the ampulla into the uterine cavity. It takes about four to five days for the embryo to implant from the fallopian tube to the uterine cavity.

02 Factors affecting embryo implantation

Ye Shuisong: According to statistics from the World Health Organization , approximately 17.5% of adults suffer from infertility . What are the factors that affect embryo implantation ?

Han Yibing : The infertility rate surveyed by the World Health Organization is currently getting higher and higher. In fact, there are many reasons for infertility.

One of the reasons is the problem of embryo implantation, which accounts for less than half of infertility. In fact, infertility is more caused by ovulation, and male infertility accounts for 30%-40%.

Ye Shuisong: What percentage do male and female factors contribute ?

Han Yibing: The real proportion is difficult to estimate. There is more than one factor that affects infertility, and there are many unknown causes. Using current methods to determine whether a woman has ovulation problems, we can get a clear answer. However, it is more difficult to judge the embryo implantation because it is a "black box."

For the problem of embryo implantation, it basically depends on whether you are pregnant. If you are pregnant, you can check the embryo implantation based on the thickness of the endometrium. In recent years, some genetic screening methods for endometrial receptivity have emerged, but these are some prospective and experimental diagnoses. At present, there is no clear diagnostic technology to show that infertility is a problem of embryo implantation. Solving the problem of embryo implantation and improving the success rate of IVF is still a very difficult task.

The barrier of embryo implantation is clinically called repeated implantation failure. Patients with repeated implantation failure are the group of patients that most affect the success rate of IVF. The success rate of IVF is not 100%, and basically the success rate in the world is around 50%.

The remaining 50% of patients face the problem of embryo implantation failure after embryo transfer. These patients may experience embryo implantation disorders or premature embryo death. At present, in vitro fertilization technology has made significant progress, which is used to check whether the embryo has developmental potential, and to use blastocyst culture to extend the in vitro culture time and improve the quality of the embryo, but it still cannot reach a 100% pregnancy rate. The difference in pregnancy rate lies in the receptivity of the endometrium.

Ye Shuisong: There are still many difficult problems in this field that we need to overcome, and there are still many clinical problems that still need to be solved by scientists and doctors.

03 The development of assisted reproductive technology

Ye Shuisong: When talking about infertility , assisted reproductive technology will definitely be mentioned . This technology has now developed to the third generation . Can you introduce the characteristics of each of these three generations of technology?

Han Yibing: The first, second, and third generations of assisted reproduction are all colloquial expressions used by the general public. In scientific terms, they are not standardized. The first, second, and third generations of assisted reproduction technology are not a technology that continues to develop over time. The first generation of test-tube babies (technology) now refers to ordinary IVF in vitro fertilization technology.

The second-generation test tube baby technology is intracytoplasmic sperm injection technology. Of these two technologies, IVF is indeed earlier than the second-generation sperm injection technology, but now both technologies are in use. They have different indications, which does not mean that the second generation is better than the first generation.

The so-called third-generation IVF technology refers to pre-implantation diagnosis of embryos, which is applied to patients with genetic diseases. The first-generation IVF technology is used to fertilize sperm in vitro with sperm from male patients with normal sperm, which is to put the egg and sperm together and let it fertilize on its own. Which egg is fertilized will be naturally selected.

The second-generation intracytoplasmic sperm injection technology is used to treat situations where the sperm count is insufficient. We process the sperm in vitro and then put it back into the body.

When sperm motility is weak or does not meet the standard, some auxiliary means are needed. We usually use a needle to selectively inject the sperm into the egg. At this time, the sperm is no longer competitive.

Because the three technologies have different indications, they are currently being used simultaneously.

04 Contributions of scientists and doctors

Ye Shuisong: In the field of assisted reproduction , many scientists at home and abroad have made important contributions . For example, Zhang Mingjue , Robert Edwards , Zhang Lizhu and others, can you briefly introduce their contributions ?

Han Yibing: Professor Zhang Mingjue's main contribution was to create test tube mice and test tube rabbits, and to discover the phenomenon of sperm capacitation. But current research has found that there are other molecular interactions in the fertilization process. Although the concept of sperm capacitation is now outdated, Mr. Zhang Mingjue discovered that after being treated by a certain method, sperm is in a state that he defined as capacitation. Only when the capacious sperm and egg are combined can fertilization occur. This is a milestone discovery.

Professor Edwards was an embryologist in Cambridge, England. His major contribution was the birth of the first test-tube baby, Louise Brown, on July 25, 1978.

He retrieved the egg through laparoscopy, then fertilized it in vitro, and moved it back into the fallopian tube on the first day of embryo fertilization. Although it was only one day in vitro, it solved the problem of Louise Brown's mother's fallopian tube blockage, and eventually the test-tube baby was born. In 2010, he won the Nobel Prize in Physiology.

Professor Zhang Lizhu is an obstetrician and gynecologist at the Peking University Third Hospital. She successfully gave birth to China's first test-tube baby in 1988. Although her entire invention process copied foreign experience, she overcame many difficulties.

At that time, there were technical barriers, and we did not have the opportunity to study abroad. We just knew that this method was feasible. It is said that she ground the egg retrieval needles herself. She overcame many difficulties, including the fact that many of our reagents, instruments, and equipment were domestically produced. Under such circumstances, the first test-tube baby in our country was born in 1988, Zheng Mengzhu, which was very remarkable.

05 Cutting-edge work in the field of reproductive medicine in China

Ye Shuisong: There are many scholars in China who have done a lot of cutting-edge work in the field of reproductive medicine . Can you briefly introduce them ?

Han Yibing: China is a latecomer in the field of assisted reproduction. Although our first test-tube baby was ten years behind the rest of the world, we currently have many technologies that are ahead of the rest of the world, such as pre-implantation diagnosis of embryos (third-generation test-tube baby technology).

The third-generation test-tube baby (technology) is divided into several types. One is the pre-implantation diagnosis PGT-A on chromosomes, another is PGT-M for single-gene diseases, and the last one is PGT-P for multi-gene diseases.

PGT-A

PGT-M

PGT-P

Chromosome abnormality PGT-A was first widely used abroad, and our country has also carried out a lot of work in PGT-A. Our country first did PGT-P, which is a multi-gene diagnosis. For example, Professor Huang Hefeng did a study on infants in diabetic families last year. Professor Huang's team screened out a specific gene in a baby in the diabetic family, making the baby's risk of diabetes very low.

Academician Huang Hefeng holds a low-risk diabetic test-tube baby

The second is embryo PIMS technology, which is methylation screening for preimplantation diagnosis of embryos. This is also the first technology developed in our country. It is different from the three types of PGT mentioned above. It diagnoses epigenetic changes in embryonic DNA. Epigenetics does not involve the sequence of DNA, nor does it involve changes in single genes or multiple genes. It is just that there are some changes in methylation on DNA. DNA modification is carried out through AGCT. AGCT is the same, but their methylation conditions are different. Some are methylated and some are not. Using the PIMS technology invented by Professor Chen Zijiang and Professor Liu Jiang, the success rate of IVF can be increased to more than 80% through the diagnosis of epigenetic modifications.

The third advanced technology in our country is the non-invasive pre-implantation diagnosis invented by Professor Xie Xiaoliang. He collects the culture medium of the blastocyst, detects the DNA in the culture medium, and after splicing it out, it can represent the DNA level of the embryo. This non-invasive diagnosis has also been carried out in our country.

Ye Shuisong: At present, there are indeed many scholars in our country who have done a lot of cutting-edge work in the field of reproductive medicine.

06 What is three-parent baby technology?

Ye Shuisong: At the beginning of this year, a three-parent baby was born in the UK . A healthy baby was born through mitochondrial replacement . Can you introduce what this technology is ?

Han Yibing: Three-parent baby mainly refers to the source of DNA. We know that test-tube babies have a father and a mother. The father represents one parent in one gene, and the mother represents one parent in one gene. It represents the DNA in the nucleus of the egg cell. The egg itself contains a mitochondria. Mitochondria are a very special organelle that provides nutrients for the respiration of human body cells.

There is DNA in mitochondria, and our mitochondria are all of maternal origin. Whether it is a boy or a girl, the DNA is all maternal DNA, so three-parent babies are for female patients with mitochondrial diseases. The eggs released by these patients cannot develop into embryos after fertilization due to mitochondrial diseases, and the mitochondria cannot provide enough nutrients for the development of the embryo. In order to realize the dream of these patients to become mothers, embryologists try to inject the mitochondria of healthy women into the eggs of mothers with mitochondrial diseases. When the sperm enters the egg, the fertilized egg contains DNA from three sources, forming an embryo, which makes up for the dysfunction of mitochondria, and thus a three-parent baby is obtained.

07 Recommendations for infertile couples on assisted reproduction

Ye Shuisong: For infertile couples , what factors should they consider if they want to undergo assisted reproduction ? As a clinical expert , what suggestions do you have ?

Han Yibing: For patients who want to seek IVF services, they must first roughly know the causes of infertility. We will use targeted means to do IVF. Some people think that "since we are doing IVF anyway, we don't care about the causes", which is unscientific.

For example, sometimes patients only need to take a little medicine to get pregnant naturally, without the need for IVF. Therefore, we need to know whether it is a male factor or a female factor.

If it is a female factor, then is it an ovarian factor, a fallopian tube factor, or an endometrial factor? Is it related to genetic factors? If there are genetic factors, then a genetic diagnosis is needed. If not, then you can give up the genetic diagnosis method and go directly for in vitro fertilization.

The IVF service technology we currently provide is becoming more and more natural, with the less intervention the better.

Ye Shuisong: Thank you very much to Teacher Han for giving us some popular science knowledge on infertility and assisted reproduction today.

This article is a work supported by Science Popularization China Starry Sky Project

Team/Author: Deep Science

Audit:

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.

Source: Deep Science