Have a cystic fibrosis or BRCA mutation, or maybe a dangerous variant of the Huntington’s gene dangling in your cells? The Center of Human Genetics (CME) in Leuven will clear this out for you. As the biggest diagnostic unit in Belgium, CME is a major player at the European level in terms of genetic diagnosis. They perform close to 50,000 genetic analyses and over 12,000 cytogenetic tests per year. The center has over 10,000 patient contacts annually and mainly serves Flanders and, for acquired disorders, parts of the Walloon area. They can trace over 100 rare disorders and are world-renowned for their research in neurofibromatosis, heart diseases and several syndromes. Joris Vermeesch, head of the Department of Human Genetics and the Laboratory for Cytogenetics and Genome Research at KU Leuven, gives us some insight into how the tremendous amount of information hidden in our DNA can be used for tumor detection and embryo selection.
From prenatal screening to tumor detection (liquid biopsy)
“About 13 years ago, my laboratory developed comparative genomic hybridization (CGH) to detect genome-wide copy numbers,” Vermeesch says. “We now perform genome-wide copy number profiling and detect developmental disorders via non-invasive prenatal testing, independent of big companies.” Non-invasive prenatal testing can be performed on a blood sample of the pregnant woman, i.e., a liquid biopsy. Vermeesch adds: “We are pushing technology to give a postnatal diagnosis based on prenatal data and try to identify new genes related to different disorders.”
Concerning cancer, tumor cells release small amounts of DNA in the blood circulation, which can be used to detect these tumors. Vermeesch confirms: “My team demonstrated that liquid biopsies can be used to detect tumors, even before symptoms pop up. This became a major emphasis of our laboratory, too.”
Single cell analysis to increase baby-take-home rate
“Another area where we have been making big process is in the analysis of single cells, mainly for fertility problems,” Vermeesch explains. “We apply this to improve the diagnosis of IVF embryos, where (one of) the parents possess recessive or dominant genes for heritable diseases.”
For example, if both parents are carriers of a mutation in the cystic fibrosis gene, the child will have a 1 in 4 risk of developing the disease. We perform a genome-wide screen and select those embryos that don’t carry the mutation, or at least are not homozygous. This can be done on day 3 after the conception of the embryo.
Traditional genetic diagnostic tests to screen for mutations have some great disadvantages . For example, an assay needs to be optimized for a particular family, which takes 3 to 6 months. Moreover, some chromosomal rearrangements are impossible to detect with the classical techniques, such as small deletions or duplications. Another major issue is that 1 of the 2 alleles might drop out during PCR amplification.
Vermeesch acknowledges these problems and explains how his new technology is able to tackle them: “Over the last 2 to 3 years , we developed an innovative assay that is able to determine the genome structure. It not only allows genome-wide copy number profiling of a single cell, but also it allows us to define the origin of the copy number, i.e., maternal or paternal. In combination with the analysis of SNP areas, the haplotype — the sequence of allele variants on a single chromosome — can be resolved. The haplotype allows us to identify which chromosome was inherited from which ancestor. This information enables us to assess the risk for monogenic disorders in a fast and reliable manner. Moreover, we can detect with high accuracy whether aneuploidies are present in the embryo. If a trisomy or monosomy is present, it is less likely that the embryo will develop into a healthy baby.”
Of course, we also have information on the hair color and the color of the eyes, but we don’t use this from an ethical point of view.
Vermeesch’s team also discovered that embryos are not chromosomally stable until day 5, and therefore structural analysis of the genome should not be performed before this day (1). Now that the proof of concept of this new technology has been realized, it sets the stage for a rapid worldwide implementation.
Many of the methods developed in Vermeesch’s laboratory have been patented and licensed to companies for marketing in the near future. Cartagenia — a spin-off from the Department of Human Genetics and ESAT at KU Leuven that was recently sold to Agilent — received the rights on the patents on single cell analysis, which can be used for preimplantation genetic diagnosis. The non-invasive prenatal test (NIPT), developed by Vermeesch’s group to screen for aneuploidies, is also being licensed to and commercialized by Agilent. They amended the protocol slightly, and since March 2016 they have been marketing it under the name OneSight.
In Belgium, thanks to the healthcare system, genetic testing can be offered to everyone at virtually no cost, and also the cost for counseling is low compared to other countries. Vermeesch remarks: “Genetic diagnostic tests are performed in university hospitals, which allows researchers to address outstanding genetic questions and inquire about novel diagnostic approaches at the same time. This is a perfect breeding ground for product development and, eventually, new companies. The sequence of our genome has a great predictive potential, but exploiting it is a major challenge. My long-term ambition is to leverage full genome sequencing in the healthcare system. I want to facilitate a transformation from curative to preventive medicine.”
Joris Vermeesch studied bioengineering at Ghent University before moving to the US and obtaining a PhD in chemistry and molecular biology (Lincoln, Nebraska). After his PhD, he came back to Belgium and joined Peter Marynen’s team as a postdoctoral fellow, studying chromosomal stability in humans for 5 years. Next, he worked at Aventis CropScience as the head of the genomics unit. In 2001, he became responsible for the Constitutional Cytogenetics unit at the Center of Human Genetics at KU Leuven and was appointed as professor. As of August 1, Vermeesch will be the department head of the Center of Human Genetics.
(1) Vanneste, Evelyne, et al. "Chromosome instability is common in human cleavage-stage embryos." Nature medicine 15.5 (2009): 577-583.