China Health Trip takes you through the latest medical breakthroughs in China, showcasing the possibilities of advanced healthcare. Read on for more insights.

In the golden month of September 2024, a special birthday celebration was held at Peking University Third Hospital to celebrate the birth of a unique life ten years ago – the world’s first test-tube baby screened for single-gene genetic diseases by MALBAC genome amplification high-throughput sequencing. Her arrival not only brought happiness and joy to a small family, but also set a new milestone in the history of reproductive medicine in the world, and also marked the leap from following to leading in my country’s assisted reproductive technology.

As the carefully produced growth video slowly played, everyone witnessed the growth of the protagonist of the birthday – “MALBAC- Baby” over the past ten years. At the birthday party of this ten-year-old girl, the relatives, friends and teachers present gave her the most sincere and beautiful blessings, and her parents could not hide their excitement and gratitude.

Thank you to Teacher Xie Xiaoliang’s team for the advanced technology (MALBAC) developed, and thank you to the doctors and scientific research team of Peking University Third Hospital. It is you who have opened the door to happiness for us with your superb medical skills and selfless love. We will always remember this kindness and pass on this love and hope to more people, so that everyone can benefit from the rapid development of medical technology.

History of the first MALBAC-Baby

In September, Beijing was suppressed by the continuous autumn rain and the chill gradually rose. But on the 19th, it was like summer and the sun was particularly bright. A special 10th birthday party was held at Peking University Third Hospital (PKU 3H), with a lovely and lively little girl who showed talent in painting and sports. PKU 3H’s assisted reproduction is well-known throughout the country, and it is not surprising to send new life to infertile families. However, ten years ago, the first cry of a baby girl was of extraordinary significance in the history of reproductive medicine in the world. A father who suffered from a serious single gene genetic disease since childhood and an elderly mother, this family reversed their fate because of the emergence of MALBAC technology and had a healthy child as they wished. China’s first “test tube baby” was ten years later than the world, but the first “MALBAC-Baby” brought China to the forefront of the world.

Looking back ten years later, we can still feel the impact of the technological revolution brought by MALBAC and the miracle of life created by this disruptive innovative technology.

The story starts at the end of 2010. With the support of his alma mater, Peking University, Xie Xiaoliang, a famous biophysical chemist and then Mallinckrodt Professor at Harvard University, jointly established the “Biodynamic Optical Imaging Center” (BIOPIC) with Professors Su Xiaodong and Huang Yanyi of Peking University. It was later renamed the “Biomedical Pioneering Innovation Center” (BIOPIC). After more than a year of preparation, this new scientific research institution aimed at promoting multidisciplinary cross-disciplinary cooperation and driving the development of life medicine with technology was officially established in December. Since then, Xie Xiaoliang, who served as the director of the center, began to travel frequently between Peking University and Harvard, bringing back the world’s most cutting-edge scientific and technological concepts and experiences to his motherland. With the technological revolution of the new generation of sequencers, the cost of DNA sequencing has dropped significantly, showing the broad application prospects of personalized medicine. The research focus of BIOPIC began to shift to genomics. When he was a postdoctoral fellow at Cambridge University, Tang Fuchou pioneered the single-cell transcriptome sequencing technology, and he became the first young talent introduced from overseas to the center.

At that time, Xie Xiaoliang’s research team was conducting cutting-edge research in genomics at Harvard. He and his postdoctoral fellow Zong Chenghang and doctoral student Lu Sijia invented a new single-cell gene amplification technology – MALBAC, which is the multiple annealing circular amplification method. This technology cleverly uses the principle of quasi-linear amplification, and only a single cell is needed to complete high-precision and high-coverage whole genome sequencing. Using this technology, they tried to sequence and analyze single-cell genomes of human haploid germ cell samples. The initial sample came from a professor whose students were more concerned about the health of the mentor’s sperm than the mentor himself. Through cooperation with Li Ruiqiang, a researcher at BIOPIC at the time, the research team found that, like normal men, the genomes of most sperm in the sample were completely normal, and less than 5% of sperm cells had a complete chromosome loss or an increase in the number of copies. If the research is to continue, a sperm motility report is also needed.

After hearing about this, Tang Fuchou took Xie Xiaoliang to Peking University Third Hospital to ask Qiao Jie for help. After returning to China, Tang Fuchou has been working with Qiao Jie’s team to study the single-cell transcriptome of human early embryos. Qiao Jie is a famous reproductive medicine expert in my country. For many years, she has been engaged in clinical and basic research related to obstetrics and gynecology and reproductive health. She has conducted in-depth research on the mechanism of human early embryonic development from the perspective of genetics and epigenetics, and successfully applied the results of basic research to clinical preimplantation genetic diagnosis; revealing the pathogenesis of difficult infertility, optimizing assisted reproductive technology methods, and improving the success rate of treatment for difficult infertility patients. After learning about the MALBAC technology, Qiao Jie smiled and said: “Don’t just study sperm, you must also study eggs, because studying women is much more interesting than studying men (meaning that the development process of egg cells is more complex and interesting than the development process of sperm).” Xie Xiaoliang, who originally went there for a report, gained two allies. With the addition of Tang Fuchou and Qiao Jie’s team, the MALBAC technology invented by Xie Xiaoliang’s team quickly moved from the laboratory to the clinic. At the end of 2013, the results of the three people’s cooperation were published in the journal Cell, showing for the first time the possibility of clinical application of MALBAC technology in IVF.

In early 2013, a letter for help from Beijing caught Xie Xiaoliang’s attention. The letter writer suffered from hereditary multiple exostoses (HME). Since childhood, he had to undergo a resection surgery every three to five years due to the proliferation of chondromas, which was very painful. The cause of the disease was that his EST1 gene had a single base mutation inherited from his father. His wife was 36 years old. Although her genome was normal, the probability of chromosome copy number mutation in her egg cells was high. In order to give birth to a healthy child, the couple consulted countless materials and visited famous doctors at home and abroad. Even though they encountered setbacks everywhere, they still did not give up hope. After the advent of MALBAC technology, they rushed here, hoping that this most advanced embryonic gene diagnosis technology could help their family realize their dream. The couple became the No. 1 case family of the clinical trial. Lu Sijia’s team from Yikang Gene also joined the project, and worked with Xie Xiaoliang, Tang Fuchou, and Qiao Jie’s teams to apply the new generation of sequencers and precise single-cell genome amplification technology to pre-implantation embryo screening for IVF, and developed the “triple diagnosis” MARSALA technology that can simultaneously detect pathogenic gene loci, aneuploidy, and linkage analysis. On September 19, 2014, the world’s first test-tube baby screened for single-gene genetic diseases by MALBAC genome amplification high-throughput sequencing was successfully born.

The birth of MALBAC-Baby in 2014 marked the breakthrough of PGT-M from “zero” to “one” in the Department of Reproductive Medicine of Peking University Third Hospital, and is a perfect example of the combination of basic scientific research and clinical application. Over the past ten years, the PGT-M project of the Department of Reproductive Medicine of Peking University Third Hospital has included 1,800 families, involving nearly 700 genetic diseases, of which more than 420 couples have healthy offspring. A mature and complete full-process system has been established from pre-enrollment gene variation assessment → pre-experiment → embryo testing → prenatal diagnosis → post-birth follow-up. While continuously improving its own technical level and perfecting the clinical service system, the Department of Reproductive Medicine has joined forces with enterprises to achieve technology transformation and promote the application of MARSALA technology.

In 2016, Xie Xiaoliang and Lu Sijia, a master and apprentice, teamed up with two doctors to successfully screen for non-invasive chromosome copy number abnormalities in embryos before artificial insemination implantation. This is based on the sensitive detection of trace free DNA released into the culture medium by a single embryo using MALBAC technology. In 2019, Xie Xiaoliang and Lu Sijia worked with Professor Catherine Racowsky of Harvard Medical School to verify the safety, accuracy and applicability of this method. In 2021, by sequencing the micro-DNA methylome of 194 in vitro cultured embryos, Tang Fuchou and Qiao Jie’s team identified the exact cell source of free DNA in the culture medium, providing new support for non-invasive pre-implantation embryo aneuploidy genetic detection. Recently, Xie Xiaoliang, BIOPIC researcher Ge Hao, Lu Sijia and Qiao Jie successfully realized the non-invasive detection of single-gene genetic diseases in the culture medium.

Application of MARSALA technology

So far, MARSALA technology, as a model of industry-university-research-medicine integration, has been promoted to more than 110 units around the world, blocking the intergenerational transmission of more than 1,200 pathogenic genes, and has tested more than 12,000 families in total, helping about 6,000 families with genetic diseases realize their desire to have healthy babies.

Ten years have passed, and the newborn baby who used to grin when she saw everyone has now grown into a smart, lively and active little girl. At the birthday party, the scientific research team and medical staff who created the miracle together reviewed the extraordinary journey with the birthday girl and her parents, and sent the most sincere and beautiful blessings to the child.

Qiao Jie said: “In this fruitful season, we celebrate not only the healthy growth of a child, but also the beautiful chapter of the interweaving of medical wisdom and human emotions. Thank you for the persistence and hard work of the child’s parents. Your understanding and trust, courage and responsibility have accelerated our pace towards successful clinical application, and thus promoted the promotion of technology and the rapid development of the entire industry.”

Tang Fuchou hopes that the child can practice the scientific spirit and grow up happily in his future study and life. In his view, MALBAC technology is a milestone in the field of single-cell sequencing. Its clinical application in IVF has created a miracle of China’s speed-it took less than two years from the publication of MALBAC technology at the end of 2012 to the birth of the first “MALBAC-Baby” in September 2014. Moreover, MALBAC technology and subsequent MARSALA technology kill two birds with one stone, solving the two major problems of single-gene genetic diseases and chromosomal abnormalities at the same time.

Xie Xiaoliang was very pleased to see his child grow up healthily. “‘MALBAC-Baby’ has become a successful example of precision medicine,” he said. “The revolution of high-throughput DNA sequencing technology has brought new opportunities for the development of biomedicine. I am glad that I caught up with the dividends of this technological revolution. The first attempt to apply single-cell amplification technology to reproductive medicine clinical practice has achieved world-leading results.” It was inspired by this that Xie Xiaoliang decided to return to China full-time in 2018. BIOPIC was officially renamed “Biomedical Frontier Innovation Center”. He firmly believes that he can do world-leading work at Peking University and BIOPIC. Benefiting mankind is the mission of a scientist, and it is also the greatest happiness and satisfaction.