Past and present
The genomics research field is undoubtedly one of those areas where technology developments have demonstrated to be key enablers for progressing fundamental scientific insights, but also the translation into routine practice including improved clinical care. While scientists embarked upon decoding the human genome already in the early seventies, it was the development of the ABI3700 capillary sequencer (which evolved from sequencing principles as developed by Nobel prize winner Fred Sanger in the early 70s) in the late 90's that made it possible to generate the first draft of the human genome in 2001. The first so-called 'next-generation' sequencer, which was based on different principles and allowed for massively parallel sequencing, allowed for the generation of the first 'personal genome' in 2005. Since then, technology has developed rapidly, both in terms of throughput and read lengths and sequencing genomes of individuals, including tumors, is possible in just a few days and with a price tag of several thousands of euros (while the first reference and personal human genome did cost billions and millions of dollars, respectively). Currently, international projects have used large-scale sequencing approaches to identify causes of congenital diseases, genetic contributions to common disease, drivers of cancers, etcetera. Treatment and drug development by academics and pharma are increasingly driven by these findings.
While next-generation DNA sequencing technologies are now widely accessible and commonly used for many genome analyses and tag-based approaches (e.g. ChIP-seq, RNA-seq) in most Life Sciences institutions, clear technological challenges remain. In addition, novel DNA sequencing principles are continuously developed by various vendors with the primary goal to drive down costs, increase throughput and reduce analysis time. Parallel with these developments and the wide-spread adoption and ongoing development of NGS-based techniques, demand for capacity is growing and users are driving down analysis units from people to single cells. Besides the need for increased throughput, also miniaturization and increased sensitivity are required for this and need to be optimized for each NGS-based application.
Another key difficulty is that biomedical researchers often have no capacity to carry out analyses of modern data sets using appropriate tools and computational infrastructure in a way that can be fully understood and reused by others. Finally, sustaining the growing application of genomics in biomedical research will require that data interpretation becomes as accessible as data generation. Increased reproducibility through the adoption and implementation of a FAIR framework, together with increased throughput, will spur the progress of genomics.
Challenges to be addressed by the infrastructure
There are currently four main challenges that need to be addressed to efficiently advance the genomics field and establish even more breakthroughs. There are currently four main challenges that need to be addressed to efficiently advance the genomics field and establish even more breakthroughs.
(1) higher throughput, lowering costs and sample needed to improve scaling of whole genome sequencing analysis and tag-based approaches.
(2) higher accuracy and sensitivity for e.g. structural variant detection using long-read technology.
(3) improve coverage of analysis towards more complete (human) genomes and transcriptomes.
Edwin Cuppen is professor of Human Genetics and runs his research lab at the Centre for Molecular Medicine, University Medical Centre Utrecht. He is an expert in DNA sequencing and applies next-generation sequencing for both research and diagnostic purposes. In 2005, Edwin Cuppen received a European Young Investigators Award and in 2013, he was awarded a prestigious NWO Vici grant for dissecting the molecular mechanisms behind and functional consequences of structural variation in genomes. He is also one of the initiators of the nationally operating Center for which he oversees the centralized genome analysis and bioinformatic data integration efforts. To this end, the Hartwig Medical Foundation, an independent not-for-profit organization that was made possible by philanthropy, was established in 2015. Edwin is scientific director at HMF.