“Conventional thinking said that the blood circulation of the mother and that of the baby are separate and that the exchange of materials is limited to the nutrients that the mother provides to the baby,” recalls Dennis Lo (Hong Kong, 60 years old). The researcher explains that his findings showed that the exchange is much more intimate. “There is an exchange of genetic information between the baby and the mother,” he points out.
Since the late 1997s, Lo searched for fetal DNA in the pregnant woman’s blood and developed techniques to analyze it and detect diseases before birth. Her work allowed the development of a non-invasive test to identify Down syndrome, a disorder that until then could only be detected with techniques that could endanger the life of the fetus. The technology was launched in 2011 and has changed the practice of prenatal diagnostics, reducing the need for invasive testing.
This week, Lo visited Madrid to receive the Commemorative Lecture Award from the Conchita Rábago de Jiménez Díaz Foundation in recognition of his research work. The professor at the Chinese University of Hong Kong is also one of the world leaders in the development of liquid biopsy, a technique that allows tumors to be diagnosed through a blood test.
Ask. In addition to detecting alterations in a chromosome, such as Down syndrome, prenatal diagnostic techniques can obtain DNA to sequence the baby’s entire genome. Can this be useful to prevent diseases?
Answer. There is work showing that it is possible to obtain the complete genome, but people use this technique for more selective purposes. If you have a number of genetic diseases that you want to test, this technology can be used. In the UK NHS they have a service like this. But if you talk about the whole genome, there is something that we have to discuss and debate. Personally, I believe that during pregnancy, a woman already has many things to worry about, so we should not burden her with information that she does not need. The information she needs is to know if the baby may suffer from any serious illness that threatens her life at that time, during the pregnancy or immediately afterward.
If you talk about complete sequencing of the baby’s genome, you can learn things about his health in the distant future. I don’t think the mother needs to know that her child has a high chance of developing diabetes in 40 years. Furthermore, our knowledge of the implications of that information is not complete. You may see the whole genome and not know what it means, and that will worry the mother too. So I think for now it is best to limit this information to looking for important and early diseases.
Q. Will it be interesting to combine the information offered by prenatal diagnosis to identify genetic disorders with genetic editing techniques that allow them to be corrected?
R. Currently, ethical and legal guidelines say that you cannot change a baby in such a way that that change will be heritable. You have probably read about the case of a Chinese scientist who modified the genome of babies to make them resistant to HIV. That case has been condemned globally and the question remains whether these changes that confer resistance to HIV will have other effects later in the lives of these babies, making them, for example, more susceptible to other viral infections. That said, when this scientist did gene editing on him, he used Non-Invasive Prenatal Diagnosis (NPD) to check if editing him had worked.
Q. Now, there are still tumors, such as lung or pancreas, that are often detected too late. Is it possible that liquid biopsies will change that situation?
R. There are tests for a single type of cancer and others for multiple types. In those of a type of cancer, I have developed one for head and neck cancer. For one type of tumor it is easier to do clinical trials because you only have one cancer and one risk group. In that case, the results can be impressive. In Hong Kong, I have focused on nasopharyngeal cancer, which is very common in southern China. A Cantonese like me has a lifetime risk of getting this type of cancer of one in 39. We have used liquid biopsy for this type of cancer and we have seen that, if you do not do the test, around 75% of cases are detected in stage three or four [muy avanzados], but if you do the test, 70% are discovered in phase one or two, and can be treated earlier. Survival increased tenfold, so that’s a big improvement. We published the article in 2017, in the New England Journal of Medicineand now we are implementing this technology in Hong Kong.
For analysis of many types of cancer, as each cancer has different genomic changes, it is difficult to do a test for all types of tumor, which have their own mutations. What we have done is develop a test that looks at epigenetic change. 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 [por el formateo] you can find out where the cancer is. A few years ago, we developed this technology, which has now been licensed to Grail, [una compañía] of which I was a scientific co-founder. Grail now has a test for 50 types of cancer. According to the latest data published by them, if the test is positive, the probability that that person has cancer at that moment is 75%. If it is negative, the probability is 2.5%. And they can tell where the cancer is with 86% accuracy. The current weakness of this test is that for stage one cancer, the sensitivity is 25% and for stage two, around 57%. So we have to improve.
Q. Can’t so much information generate stress, make us feel that we are always preventive patients waiting for cancer to be detected?
R. I think health education and the ability of health systems to follow people and treat them appropriately is important to eliminate stress. If you have technology that points out a risk, but you can’t treat it, it’s useless, but we can see what happens with blood clots and cholesterol control. Many people, especially over a certain age, take medications to control this problem and do not live with much worry. They take their statins and monitor themselves regularly. With cancer it would be something similar.
Q. Can liquid biopsies also be used to better follow the treatment of the disease?
R. The idea of liquid biopsy is that blood absorbs DNA from different parts of the body, in it there is a mixture that offers an overview of what is happening in the body at a moment. And it allows us to look at multiple clones of a tumor at the same time and see how it evolves and adapt treatments. In lung cancer there is a gene called EGFR (epidermal growth factor receptor) and if you have an EGFR mutation, you can treat the tumor with drugs called tyrosine kinase inhibitors. Afterwards, the tumor can evolve and develop resistance and develop metastasis, and there you will also see more DNA circulating in the blood.
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