AsianScientist (Aug. 28, 2015) – In 1965, Singapore had a total fertility rate (TFR) of 4.66 children per woman and an average household size of about six, according to the Singapore Department of Statistics.
By the time Samuel Lee was born in 1983, however, the situation had changed drastically, with the TFR dropping to 1.61, below the generally-accepted replacement rate of 2.1. But Mr Lee was no ordinary baby: he was Singapore’s—and Asia’s—first “test-tube baby”, brought into the world by a team led by the late S. S. Ratnam.
Since then, thousands of babies have been born in Singapore through assisted fertility techniques, with 1,158 in 2009 alone [the most recent publicly-available datum]. Although these numbers are not high enough to cause a discernible rise in birth rates, perhaps more importantly, in vitro fertilisation (IVF) has given many infertile couples a shot at parenthood.
Much of the credit for this should go to Ariff Bongso, professor of the department of obstetrics & gynaecology at the National University of Singapore, who has made several pivotal research breakthroughs that have improved IVF success rates.
“I have watched some of the children born through IVF grow up and enter university. To me, it is overwhelming to know that a technique conceptualised in the lab ultimately results in so much happiness and joy,” says Professor Bongso, who is a faculty member at the Yong Loo Lin School of Medicine and the National University Health System.
Over the course of his still active career, Professor Bongso has also been at the forefront of one of the most exciting fields of the last decade: stem cell research.
Reaching peak productivity in Singapore
Like many other IVF pioneers in his time, Professor Bongso, a native of Sri Lanka, first perfected his skills on animal embryos before making the jump to humans. Although offered a place to pursue medicine overseas, he chose to study veterinary medicine instead, completing a five-year programme at the University of Ceylon in 1970.
“The initial shift from human to veterinary medicine turned out to be a defining moment in my education,” Professor Bongso recalls. “My strong background in comparative mammalian reproduction has in fact been an asset in understanding and providing solutions to some of the problems in humans.”
He went on to complete a master’s and PhD in mammalian reproductive biology at the University of Guelph in Ontario, funded by a Canadian Commonwealth Scholarship. He then returned to Sri Lanka to work but after ten years, and in inauspicious circumstances, felt the pull of Singapore.
In 1987, while attending the funeral of his close friend, S. M. Ratnam, in Kuala Lumpur, Professor Bongso met the deceased’s brother, Professor S. S. Ratnam, who persuaded Professor Bongso to join him in Singapore. Professor Bongso and his family liked Singapore so much that he took up citizenship in 1991.
“Without a doubt, the most productive part of my career has been during my stay in Singapore,” he muses. “In those early years of my career in Singapore, I spent less time on writing and winning research grants… manpower, material and funding were all provided by the department. These to me were the key ingredients that resulted in several breakthroughs and world firsts.”
Living proof of a life’s work
Although the very first IVF baby was born in 1978, IVF techniques were still relatively crude in the late 1980s and had a very low success rate of 10-15%.
Conception begins when a sperm cell meets an egg cell in the fallopian tubes. Each sex cell has only one copy of the pair of chromosomes found in non-reproductive cells. When sperm and egg fuse, the resulting embryo has a full set of chromosomes. If all goes well, it starts developing into a baby.
However, getting the sperm and egg to meet in the first place is challenging. For roughly one-third of infertile couples, the male’s sperm is lacking in either quantity or quality. In another one-third of cases, the female experiences hormonal imbalances resulting in the egg not being released into her fallopian tube; or she has structural defects in her fallopian tubes which prevent the sperm and egg from meeting. In all other cases, both male and female partners have one or more issues resulting in infertility.
IVF can be thought of as speed dating, concentrating sperm and egg cells outside the body to increase their chances of meeting and fusing. The embryos thus formed in “test tubes”—or, more likely, petri dishes—are then transplanted into the womb where they hopefully begin to grow.
“Back then, the culture conditions for the growth of human embryos in the laboratory were suboptimal,” Professor Bongso explains. “As a result, IVF specialists were transferring fertilised embryos after culturing them for only two days, whereas in natural conception the embryos reach the uterus from the fallopian tube on day five—at the blastocyst stage.”
In 1988, Professor Bongso and his team attempted to develop a co-culture system in the lab that would mimic the conditions of the human fallopian tube. They grew the embryos on a bed of human fallopian tubal cells in a plastic dish in the presence of a synthetic formulation of fallopian tube fluid that they developed.
“This allowed us to prolong the growth of human embryos to the blastocyst stage and doubled the IVF pregnancy rates,” he says.
Professor Bongso’s co-culture technique soon spread from Singapore to IVF programmes all around the world, where it remained the gold standard until recently, when a new cell-free liquid culture medium formulated on the knowledge gained by the co-culture system replaced it.
Apart from co-culture, Professor Bongso has also been involved in developing IVF techniques ranging from microinjection—a procedure enabling men with poor sperm counts to father children—to zona-free blastocyst transfer, whereby the outer shell of the embryo is enzymatically removed to increase the chance of implantation in older women.
Entering the stem cell fray
While his success in the field of IVF made him something of a household name in Singapore and the region beyond, Professor Bongso’s next discovery launched him onto the world stage. In 1994, he became the first scientist in the world to report the isolation of human embryonic stem cells (hESCs), which have the potential to develop into any human cell.
Building on his IVF-related knowledge, Professor Bongso used a fallopian feeder culture, in which he was able to maintain the hESCs for two generations. In contrast, a group in Wisconsin using mice cells as a feeder culture succeeded at maintaining their hESCs for over 40 generations, receiving a patent for their work in 1998.
By this time, stem cells had evolved from a purely academic research interest to an intensely commercial one, with many companies realising their vast potential for treating diseases such as Alzheimer’s and diabetes.
Arguing that patents on hESCs restricted access to the potentially revolutionary cells, several groups sought to overturn the patent held by the Wisconsin group. In the ensuing legal battle, Professor Bongso’s work was cited as evidence that the Wisconsin group was not necessarily the first to have discovered hESCs.
However, culturing hESCs on mouse feeder cells is not without its limitations.
“Cell lines grown on mouse or other animal cells could possibly be contaminated with viruses and bacteria from the feeder cells,” Professor Bongso says. “This risk seriously curtailed the possible downstream applications of hESCs.”
In 2002, Professor Bongso and his team succeeded in establishing a “pure” stem cell line grown in completely animal-free conditions, by using embryonic muscle and skin cells rather than adult fallopian tube cells for the feeder culture. This removed a major obstacle to the progression of stem cells from lab to clinic.
Riding the wave
But the problem of mouse feeder cells was only one of many. Still, unfazed by the challenges and convinced that the opportunity was promising, Professor Bongso co-founded ES Cell International (ESI), a biotechnology startup supported by the Economic Development Board of Singapore.
Incorporated in 2000, the company had early success, including the patenting of Professor Bongso’s human feeder method and its selection by the US National Institutes of Health as one of ten groups to have its stem cell research eligible for federal funding. Th e company also scored a coup with its recruitment of Alan Colman—famous for cloning Dolly the sheep—first as chief scientist and then as CEO.
But in the wake of that early euphoria, the stem cell industry at large was about to experience its first boom and bust cycle. By 2007, ESI had given up its research on treatments for diabetes and heart failure, switching instead to the less risky option of licensing hESC lines and using them in screening assays for drug development. A US company eventually acquired ESI in 2010 and renamed it ESI BIO.
Professor Bongso has continued slowly chipping away at the hurdles in stem cell research. In particular, his research group has focussed on cells isolated from the Wharton’s jelly of the human umbilical cord, a much less controversial and more readily available source of stem cells than discarded embryos.
As excited as Professor Bongso is about his current research, he has not neglected to train the next generation of scientists. Fong Chui Yee, for instance, was once his student and is now a respected researcher in her own right. She has worked closely with Professor Bongso over the years and is poised to take over his lab when he retires.
“I strongly believe that in the biomedical field, research teams should comprise a mix of clinicians, basic research scientists and clinician-scientists working together,” Professor Bongso says. “Synergy between all these three types of specialists in a complementary manner will draw in diverse ideas and fruitful results.”
Copyright: Asian Scientist Magazine; Photo: Cyril Ng.
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