Credited to Hong Kong. The underlying discovery of fetal DNA in maternal plasma was made in 1996 to 1997 while Lo worked at Oxford in the United Kingdom. Hong Kong is where the clinical test was developed, and Stephen Quake in the United States showed sequencing-based counting independently in 2008.
How it began
In 1996, while Dennis Lo was working at Oxford, reports of tumor DNA in blood plasma led him to reason that a fetus might also release DNA into the cell-free part of its mother's blood. He extracted DNA from plasma and serum, used PCR to look for Y chromosome sequences and found cell-free fetal DNA. Lo moved back to Hong Kong in 1997, and at the Chinese University of Hong Kong he turned the finding into a test. In 2008 he showed that massively parallel sequencing of maternal plasma could detect trisomy 21. The discovery step therefore belongs to Oxford and the development of the test to Hong Kong.
Before it existed
Chromosomal abnormalities in a fetus were confirmed with amniocentesis or chorionic villus sampling. Both required a needle to collect fetal tissue or fluid, and both carried a small but real risk of miscarriage. A test that needed only the mother's blood would remove that risk.
How it works
A simple blood draw gives a plasma sample that holds a mix of maternal and fetal DNA fragments. Random stretches of this DNA are amplified, sequenced and mapped to the chromosomes they came from. A fetus with Down syndrome carries an extra copy of chromosome 21, so slightly more fragments than expected map to chromosome 21 compared with reference chromosomes. Counting millions of fragments makes that small excess measurable. Lo found fetal DNA as early as the seventh week of pregnancy and showed that it cleared from the mother's blood within two hours of birth.
What changed first
In his 2008 report Lo tested 28 maternal plasma samples from the first and second trimesters and correctly identified all 14 fetuses with trisomy 21 and all 14 without. Stephen Quake showed independently in the same year that sequencing could count the molecules. Tests for Down syndrome reached the market in 2011.
What lasted
The Lasker Foundation states that the test was adopted in more than 60 countries and that 10 million tests were performed in 2018, sparing large numbers of women invasive procedures. The same principle was extended to Rh factor, trisomy 18, trisomy 13 and sex chromosome imbalances, and in 2010 Lo's group mapped a genome-wide fetal profile from maternal plasma. Reading cell-free DNA in blood also fed into liquid biopsies for cancer and monitoring of transplants. Lo received the 2022 Lasker-DeBakey Clinical Medical Research Award.
