Dennis Lo – TRANSCRIPT
When I first learned about the molecule of DNA I became fascinated by how such a seemingly simple molecule could uncode the genetic program of life. However this program, like many other programs could be corrupted and could cause life threatening disease like cancer and genetic diseases. And to diagnose these diseases, a doctor would frequently have to gain access to the cells with such mutations. But those cells could reside deep within one’s body.
Now, for example, to diagnose a cancer a doctor might have to do invasive biopsy of an internal organ. But every time he does this, there is a chance of bleeding. As another example to test for a baby before he was born a doctor would have to do pre-natal testing.
But typically, that method is performed by sampling the fluids from baby from deep within the uterus. And every time we do this, there is a chance that the baby might miscarry. And over the last few years there is a lot of effort to try to develop non-invasive methods which do not have such a risk. In particular researchers are interested in sampling the fluids that circulate in our body, like blood. And this field is generally referred to as liquid biopsy.
I first became interested in this field when I was a medical student studying obstetrics in Oxford. As a young student I wondered why did grown up doctors do dangerous things, such as sticking needles in the abdomen of pregnant women. And I was thinking that maybe we can do something better and safer. Why not just sample the mother’s blood and try to detect any fetal cells which might have entered into a mother’s circulation?
I even managed to persuade a professor in Oxford to let me work in his laboratory for a few months. I had no idea actually how long medical research could take. I actually initially naively thought that I could crack this in a few months’ time. But before I knew it, I spent eight years working on this project without a lot of success. I was lucky I wasn’t fired.
And then in the autumn of 1996 I came across two papers in a journal which said that cancer cells somehow release DNA into the blood plasma of cancer patients. Now plasma is this yellow fluid in which our blood cells swim in. And then I suddenly had a strange idea. I thought that a baby growing inside pregnant mother is actually a little bit like a cancer growing in a patient. And I thought that the placentural baby, which implanted in the uterus is a little bit invasive.
So I thought that if a smallish cancer can release enough DNA for us to see in the plasma, then surely a baby who to us at the end of the pregnancy could be like eight pounds, will surely deliver enough DNA for us to see. But the problem is that at that time I had just returned from Oxford to Hong Kong to start a new career. And I was born in Hong Kong so I had particular affiliation and attachment back there.
So at that time I really didn’t have a lot of resources, so I could only do something which was very readily available and cheap. And then I suddenly recalled when I was back in Oxford, being fed up as a medical student of the college food, I would actually sometimes cook instant noodles, back in my room. I actually got quite good at it. So what I did, is to boil some water to prepare soup base and then put the noodles in and a few minutes later you have a lovely dinner. And I was thinking what could be simpler than if I just boil some plasma and then maybe test a little bit of that boiled soup.
Now surprisingly, even with this crude preparation I was able to detect the male chromosome, that a male baby has released into his mother. And I saw no signal if a mother is carrying a baby girl. So this was the first demonstration of the presence of fetal DNA in maternal plasma. It hasn’t been shown before because previously, when people tried to look for fetal cells in the mother’s blood, plasma is the very first thing they throw away. And then even though the baby is so small compared with the mother, I was very surprised to find that actually the fetal DNA maternal plasma reached a mean of some 15%. And you can detect it as early as seven weeks of pregnancy which is very early.
And then I spent the next few years trying to develop new diagnostic method based on this technology. And the first thing I did – was because the first marker I found was on the male chromosome – so this technology can be used for sexing the baby, which is medically important, because some genetic diseases preferentially affect boys. They are the so called sex linked disease in which the disease gene is present on chromosome x and males have only one copy of this chromosome so we don’t have any back-up.
And one example of a genetic disease which is sex linked is hemophilia, which is a genetic disorder causing clotting problem of the blood. As another example I used this technology to detect the blood group type of the baby. And this could be important because sometimes the mother and baby’s blood group type do not match and a mother could produce antibody which could cause the placenta to attack the red blood cells of the baby.