How To Birth A Billion-Dollar Industry

Having seen non-invasive prenatal testing grow from an idea to an actual product, Professor Dennis Lo shares why he thinks Asia is the best place to be for his next venture: liquid biopsies for cancer.

AsianScientist (Feb. 13, 2019) – For much of human history, pregnant women knew virtually nothing about the children they carried until the moment of birth. They had no way of finding out the sex of the child or even if they were carrying one, two or more babies; much less if those babies were developing normally behind the veil of the womb.

These days, however, women are able to find out a great deal about the children they carry well before birth. It all starts as soon as two weeks after conception, when home pregnancy tests begin to be able to detect the presence of human chorionic gonadotropin in urine. By about 12 weeks of pregnancy, a routine ultrasound should be able to reveal the gender of the child, and by 26 weeks, prospective parents can even get a sneak peek at their baby’s developing features with a 3D or 4D ultrasound.

Since 2011, would-be parents have had the option of going even deeper, finding out not only what their future child looks like, but uncovering profound and unalterable facts about the child: his or her very DNA. The test, called non-invasive prenatal testing (NIPT), allows parents to find out if their child has extra chromosomes, specifically chromosomes 13, 18 and 21, indicative of Patau, Edwards and Down syndrome respectively.

As it turns out, this is information that many parents are eager to find out. Since it was made commercially available, NIPT tests have been performed an estimated ten million times. For the vast majority of people who take the test, negative results bring relief and much-needed assurance to the uncertain process of pregnancy. However, as an expecting mother myself, I couldn’t help but wonder how I would handle it if I took the test and the results came back positive for any of the trisomies.

Naturally, my first instinct as a scientist was to search the literature. But being a journalist, I couldn’t stop there, so I picked up the phone and called the inventor of the test, a clinician-scientist at the Chinese University of Hong Kong by the name of Professor Dennis Lo. Here’s what I found out.

Stumbling into science

The story begins in 1987 with Lo as a 24-year-old medical student studying at Oxford University, UK. While studying obstetrics, he learnt that pregnant women who wanted to find out if their babies were genetically normal had only one of two options: chorionic villus sampling or amniocentesis. Both procedures are painful, and carry a small risk of miscarriage, infection or injury to the baby and the possibility of amniotic fluid leakage. Not ideal, to say the least.

Apart from preparing to be a doctor, Lo had also spent some time picking up laboratory skills, including a technique that had been invented just four years prior and would later go on to win its inventor the Nobel Prize: polymerase chain reaction (PCR).

“At that time, PCR was still relatively new, and I was thinking about what we could apply this technology to. One thing that we thought would be useful was to try and see if we could detect fetal cells in the mother’s blood as an alternative to the existing methods,” Lo explained.

The idea was simple, but its execution was more complicated. A unique organ formed during pregnancy, the placenta protects the fetus by shielding it from its mother’s immune system which would recognize it as a foreign object. For the same reason, it had been assumed that the placenta also effectively prevented fetal cells from crossing over to the mother’s blood stream. But as detection methods began to improve, it became possible to detect fetal DNA in the mother’s blood.

Taking advantage of the fact that PCR can specifically amplify the amount of DNA in a sample, Lo was able to detect male Y chromosome DNA in the blood of pregnant women (XX) carrying male fetuses (XY). Crucially for a technique that at the time was still plagued by false positives from environmental contamination, that male DNA did not show up in the blood of mothers carrying female fetuses.

Excited by these findings, which indicated that it was indeed possible to accurately detect fetal DNA in the blood of pregnant women, Lo and his colleagues quickly wrote up their results and in 1989, published their paper in The Lancet. For Lo, who had yet to graduate from medical school at the time, this early success sparked a lifelong fascination with science and encouraged him to take the somewhat unconventional path of pursuing a Doctor of Philosophy on top of his clinical training. But as he would soon find out, he was just at the beginning of the arduous journey of translating promising research into a clinically relevant tool.

Coming home to Hong Kong

Although PCR was able to amplify the amount of fetal DNA found in a mother’s blood, reliably finding enough fetal cells—the source of DNA—was a formidable challenge.

“The problem is that fetal cells in the mother’s blood are very rare, so even though I had started working on the project full-time, it wasn’t going very well,” Lo said.

After eight years of searching for fetal cells without a breakthrough, Lo began to wonder if a change in direction—and a change of scene—was necessary. It was now 1997, a landmark year for Lo’s hometown of Hong Kong: the handover of the former colony from British to Chinese rule. Driven by uncertainties about the transition, an estimated 800,000 people left Hong Kong prior to the official July 1 handover date, including many scientists and academics.

“Hong Kong is home for both my wife and myself,” Lo said of his wife Alice, a physicist he met while studying at Oxford. “The two of us have always thought that we would like to come back sooner or later and were basically waiting for the right moment. 1997 was a good time because many openings became available.”

1997 was a turning point for research reasons as well, Lo continued. Sensing that perhaps he was looking in the wrong direction, Lo came across a paper published in Nature Medicine in late 1996 that detailed the discovery of tumor DNA in the plasma of cancer patients.

“In my clinical practice, I’d never come across a tumor as large as an eight-pound baby,” he reasoned. “I thought that if others could detect a small tumor that way, then surely we would be able to do the same for a baby.”

Knowing that he would not have many resources at his disposal upon his return to Hong Kong, Lo was on the lookout for a project that could be conducted cheaply.

“We needed a method that would allow us to get DNA from plasma easily. So we thought about boiling the plasma for five minutes, just like what we do when cooking instant noodles,” Lo said. “We did that and took out just ten microliters for PCR and lo and behold, there was plenty of fetal DNA.”

The beginnings of a billion-dollar industry

The 1997 Lancet paper describing Lo’s discovery made a splash in the research community, but it would take more than a decade for those results to find their way to the clinic. Once there, however, NIPT would become a whole new industry worth billions of dollars.

The first company to launch commercial NIPT tests was Sequenom, which released its MaterniT21 test in 2011 in Hong Kong. Sequenom was followed hot on its heels by Illumina, Ariosa Diagnostics and Natera, which all launched their own versions by 2012. A flurry of new entrants, acquisitions and lawsuits ensued, one of the most recent developments being a US$26.7 million patent infringement suit won by Illumina against Roche-owned Ariosa Diagnostics in 2018. Lo’s NIPT portfolio, assigned to the Chinese University of Hong Kong, has been licensed to Sequenom and Illumina, which have in turn sublicensed the technology to other companies.

“When we first developed the technology, many people didn’t believe that it would work. One of our very first patents was licensed to a company in the UK. That company did not realize the significance of the patent and sat on it for three years before eventually returning it to the university,” Lo said. “[Returning the patent to us] is unimaginable today because people have subsequently spent millions to fight this patent.”

As women in developed countries continue the trend of delaying pregnancy, demand for NIPT is steadily growing. The current market is estimated to be well over half a billion US dollars and, driven by double-digit growth figures, is expected to reach US$5.67 billion by 2028 according to a report by BIS Research.

Beyond specific conditions, it is now even technically possible to piece together a baby’s entire genome from a NIPT sample. However, just because something can be done does not mean that it necessarily should, Lo cautioned.

“There are interpretive problems when it comes to looking at a fetus’ whole genome; we still do not know the significance of most of the variants that we are likely to find,” he said.

“I suspect that for the foreseeable future, NIPT will be used to look for diseases that are common in particular locations, such as thalassemia in Hong Kong or Singapore, and cystic fibrosis in Caucasian populations. There just aren’t enough genetic counselors for us to recommend whole genome sequencing for every child screened.”

Circling back to liquid biopsies

The same population-specific approach has helped Lo to use NIPT’s underlying technology in an entirely different group of people: cancer patients. When used to analyze circulating tumor DNA rather than fetal DNA as in the case of pregnant women, Lo’s technique can screen for cancers such as nasopharyngeal carcinoma (NPC), dubbed ‘Guangdong cancer’ for its high frequency in Hong Kong.

Also known as liquid biopsy, studying tumor DNA in patient plasma has been used to track the progression of certain types of cancers and assess the outcome of treatment. However, until Lo’s study was published in the New England Journal of Medicine in 2017, it was unclear if liquid biopsies could also be used to screen for cancers that had not clinically manifested.

In the case of NPC, which is known to be caused by the Epstein-Barr virus, many cases are only detected at a late stage, resulting in a high mortality rate. Based on a clinical trial of over 20,000 ethnic Chinese men, Lo and his team found that liquid biopsy screening could detect NPC at an earlier stage, and in doing so improve their survival rate by ten times.

“We are quite optimistic; we think that if this technology is introduced, the mortality of NPC will be halved,” he added.

Returning to the field that first inspired his change of direction, Lo is now working on developing markers for other cancers including liver, lung and colorectal cancer and has licensed the technology to develop a multi-cancer test. He is also the scientific co-founder of GRAIL, an Illumina spin-off that in 2017 merged with Hong Kong-based Cirina, a company Lo founded in 2016. GRAIL, which counts Bill Gates and Jeff Bezos among its investors, has raised US$1.5 billion in funding to date and is said to be considering an initial public offering in Hong Kong.

A little bit of luck

Described by his colleagues as “doggedly determined,” Lo nevertheless recognizes the role of chance at multiple points in his scientific career. “We were very lucky,” he said of the first company that he licensed the NIPT patent to.

“Them returning the patent to us allowed us to find another partner and successfully commercialize the technology in the end.”

Lo also counts himself fortunate to have had the support of his friends and colleagues over the two decades it took to commercialize the NIPT.

“If you listen to my story, you will see that it took us 22 years to turn an idea into a commercial product. As you can imagine, if people didn’t have faith in us during those 22 years, we would not be where we are today,” he shared.

But his greatest stroke of luck was perhaps being at the right place at the right time. Although research funding in Asia was poor in the past, the economic rise over the last two decades and increased government interest in science and technology personally benefitted him, Lo said. Most of all, coming back to Asia has had a profound impact on his research direction, ultimately affecting the lives of millions of pregnant women and possibly millions more cancer patients.

“I’ve always wondered what would have happened if I didn’t decide to come back to Hong Kong,” he mused. “When you are in one place for too long, you tend to do what you have always been doing. If I didn’t decide to come back, I might not have been brave enough to try a new line of research. Coming back to Asia forced me to take a new direction.”

For Lo, returning to Hong Kong is more than about feeling at home or doing his best work; he also feels a sense of responsibility towards the next generation of scientists living and working in Asia.

“What I have learnt about science during my training in the UK is that it is important for Asia to have a strong scientific base. For that to happen, somebody has to come back and train the students,” he said.

“We need to be humble because I think there is a lot to do before our level of science can catch up with that of the US or the UK, or other parts of Europe. I hope that we will be able to create an environment whereby our best students will choose science as a career. For me, this is crucial.”

This article was first published in the January 2019 print version of Asian Scientist Magazine.
Click here to subscribe to Asian Scientist Magazine in print.


Copyright: Asian Scientist Magazine; Photo: Peter Wong/Asian Scientist Magazine.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

Rebecca did her PhD at the National University of Singapore where she studied how macrophages integrate multiple signals from the toll-like receptor system. She was formerly the editor-in-chief of Asian Scientist Magazine.

Related Stories from Asian Scientist