Nature is capricious. Sometimes, processes as antagonistic as a life growing inside its mother’s body and a disease like cancer developing in the body follow similar paths. And both processes leave a mark in the blood, specifically in the blood plasma, which contains DNA released by different types of cells. Discovering these connections is only within the reach of bold scientists who seek the most disruptive answers. It is the case of molecular biologist Dennis Loconsidered the father of non-invasive prenatal screening, which has been widely extended to clinical practice in the monitoring of pregnancies in the general population and in some high-risk pregnancies due to their history. But also from the liquid biopsy,the method that is revolutionizing cancer diagnosis. The Chinese scientist visited Madrid this week to collect the “Jiménez Díaz Commemorative Lesson” award, awarded annually by the Conchita Rábago de Jiménez Díaz Foundation.
When I was just a student at Oxford, The Lancet le published a writing in which you talked about false positives in PCR tests. Was it well received?
Everything I knew about the subject was taught to me by Sir John Bell, at that time a famous researcher at the University of Oxford. In a presentation of his he said that the polymerase chain test (PCR) would change the world. After that, I asked him to teach me everything he knew about that technique, and I started working with him. One of the things I learned was precisely that, that PCRs can generate false positives. Bell and I wanted to publish it but we shared it with other researchers and they told us we shouldn’t because we would look stupid. However, we believed it was important and we did it. And they published it. After a few months, this was confirmed in a study published in the journal Nature by the team itself that had started working with the technique. The reaction at the end was very good, even though we were discouraged at first.
When did the idea of prenatal genetic testing begin to develop in your head?
It started when I was studying Medicine. She was teaching different subjects, including Obstetrics, and, reading about the subject, I found the Kleihauer-Betke Test, (a test used to determine if there were red blood cells from the fetus in a pregnant woman with an Rh-negative blood group). That way I thought that if you look in the microscope and you can see the red blood cells of the fetus, you could do the same with the PCR test.
When was the first time you managed to find DNA-free cells in maternal plasma?
Initially I worked with cells from the fetus, but I realized that the number of cells was very low. I worked on it for 8 years. So, in 1997 (the year the United Kingdom returned sovereignty of Hong Kong to the People’s Republic of China) my wife and I decided to return to Hong Kong. I gave up Oxford and had time to think about different ways to get a greater number of cells. The fetal DNA in the maternal plasma is free, that is, outside the nucleus of the fetal cells since they pass through the placenta into the maternal bloodstream, and are quickly recognized and destroyed by the mother’s immune system. And we started working on it that same year, although it would still take two more to discover the circulating DNA.
Were you able to discern in those moments the implications that this would have on prenatal diagnosis?
Going back to that time when I was working with fetal cells, at that time I had to collect a lot of blood from the mother to be able to find a very small number of cells. But, when I started working with plasma, I did it with 10 microliters (1 cubic cm) and, in that very small sample, I was able to find many fetal cells. That’s why I realized that this step was very important. Although there were still problems to solve.
A great controversy was created due to the influence of prenatal screening on the parents’ decision not to carry the pregnancy to term if the baby had genetic diseases. How did you experience it?
I have always been very aware of the ethical implications of the discoveries of these investigations. But we must keep in mind that amniocentesis already existed, which determined the probability that the baby could be born with genetic alterations, such as Down Syndrome. The difference was that This test carried risks for both the fetus and the mother. What technology to analyze circulating DNA has done is eliminate that risk. Likewise, there are always people who do not use technologies properly. For example, the countries in which it was used to determine the sex of the unborn child (China among them), and to abort it if it was a girl. That is the reason why, when we find the pattern to determine genetic risk conditions, we specify that it could not be used to screen sex.
Apart from prenatal screening, what are the main clinical uses of circulating DNA, for example, in transplants?
Basically you have to understand that plasma receives materials from all over the body, so it contains a “still photo” of what is happening in the body at that moment. The way we discovered circulating DNA was by seeing that there was fetal DNA in the mother’s blood, so we asked ourselves: under what other conditions can there be male DNA in female blood (plasma)? For example, in a transplant. Let us consider that, in transplants, an important cause of cell death is the rejection of the transplanted organ. Thus, analyzing circulating DNA is a good way to monitor what is happening in the patient’s body after receiving the organ.
And in cancer?
Basically, cancer grows in a person much like a baby does in the placenta inside its mother. That’s why there are a lot of parallels in these two fields. Mutations can be detected in the blood, and these mutations can tell us what type of treatment is best for a patient. For example, many lung cancers have the EGFR mutation. But, before these genetic tests were done in plasma, it was very complicated to find out this. Therefore, thanks to these tests, which are increasingly widespread, precision oncology can be performed. And once we are treating them we can monitor whether the mutations decrease and when the tumor shrinks, so it is very useful.
In addition, there is the great advance of liquid biopsy…
Correct. A non-invasive test that allows us to know if a person – without symptoms and who may not have had cancer detected with other tests – may have it hidden somewhere in their body. This test It can be done in two ways: looking for a specific cancer at a time or testing for multiple types of cancer. The first is simpler. In Hong Kong, I and my team have been focusing on nasopharyngeal cancer, which is very common in southern China. A Cantonese like me has a risk of having this type of cancer of one in 39. We have used liquid biopsy to detect this type of cancer in a screening in the at-risk population and we have seen that, if you do not do the test, around 75 % of cases are detected in very advanced stages but, if you do, 70% are discovered in phase I or II, and can be treated earlier. Survival increased tenfold, so that’s a big improvement. We publish Article with these results in 2017, in the New England Journal of Medicine.
And they have developed a test that can detect up to 50 types of cancer…
In 2013 we developed an epigenetic test to detect different types of cancer with a single test. How did we do it, if we have to look for different mutations, some present in one type of cancer and others in others? We decided to use an epigenetic test instead of a genetic one. Epigenetics is when the DNA sequence does not change, but the formatting of the sequence does. The interesting thing is that different organs in the body have a different format, so you can find out where the cancer is
In 2015 we evolved it so that it could also identify exactly the place where the tumor originated.This technology is now available in the US, only with a prescription and to complement other existing detection methods. Grail is the biotechnology company that markets it and, currently, the test It can detect up to 50 types of cancer. In a pilot study, the test correctly diagnosed 2 out of 3 cancers among 5,000 people who had visited their GP with suspicious symptoms. In 85% of those positive cases, it also identified the place of origin of the tumor.
The Lasker Award for Clinical Medical Research – which was awarded in 2022 – is the prelude to the Nobel Prize. Do you have hope? What would it mean to you?
At the outset, I will tell you that one of the things that made me most excited about getting that award was meeting Katalín Karikó, to whom they also gave it, and to whom last year He was awarded the Nobel Prize in Medicine for his work with mRNA vaccines. As a scientist, the only thing I can do is continue to develop my work as best as possible. But the decision is up to the experts. The Nobel is the epiphany of a scientific career and It would be a great honor for my family, my city and my country. When I was a student I read “The Double Helix” by Dr. James D. Watson (which is the story of the process that led to the definitive decipherment of the human genetic map, made firsthand by James D. Watson, the scientist who deciphered it together with the British Francis Crick in 1953, and who received the Nobel Prize in Medicine in 1962 for it). At that time I couldn’t even imagine that, at any stage in my career, I could find myself in a situation that even remotely resembled it. That already makes me tremendously happy.