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By Dr. Radoje Drmanac, CSO of MGI and Complete Genomics Today marks the 20th anniversary of the completion of the first human genome sequence, which was mapped out on April 14, 2003. Initially a targeted effort to understand the impact of radiation on human beings, the Human Genome Project (HGP) set in motion countless advancements that have revolutionized healthcare and brought us the sub-$100 genome available today. Having spent north of three decades of my career contributing to our collective understanding of the human genome, I look back at my achievements and those of my peers with great pride. Working on the HGP My involvement with HGP began in 1987, precisely when the initiative was kickstarted, in the form of a $150,000 grant opportunity provided by the US Department of Energy, to improve technologies for genome analysis, including sequencing. As part of the HGP, I proposed to develop DNA sequencing by hybridization, which at the time enabled more efficient higher throughput sequencing. This led me to move to the U.S. Around this time, my idea of massively parallel sequencing (MPS) using DNA microarrays prepared by emulsion PCR on microbeads was also born. In essence, the HGP was about making a list of genome parts. At the time, we did not understand most of them, but nonetheless, there was a list. It prompted this important demand for the sequencing of more genomes. It made shorter reads more usable because we now had a reference. It allowed exome and panel sequencing using capture probe and primers based on the genome sequence. It proved that biology is entering larger scale projects, much like sending human beings to the moon. It was also the impetus for me to start my own company, Complete Genomics, to maximize the potential of MPS. The revolution of genomics MPS was critical in enabling routine, affordable, sequencing of individual genomes. I was motivated to bring this to life. In 2005, with my team I invented patterned arrays of DNA nanoballs (DNB) that expanded MPS’ capabilities to more efficient and larger-scale sequencing. Today, we call this core technology DNBSEQ. DNBSEQ sequencing arrays have no clonal errors or index hopping and generate higher signal density than regular DNA arrays for greatly improved detection accuracy. With advantages including increased accuracy, decreased duplicates and reduced index misassignments, it is the technology currently used in all MGI’s sequencing instruments. In 2010, another milestone was the first $5,000 genome using DNBSEQ. This achievement indicated that routine, affordable, and accurate whole-genome sequencing (WGS) is achievable and beneficial. I developed the CoolMPS sequencing chemistry in 2016, which incorporates bases by labeled antibodies. A fundamentally unique chemistry, CoolMPS avoids DNA "scars" that accumulate with traditional sequencing methods, which affect the accuracy of subsequent base readings. Instead, CoolMPS introduces unlabeled nucleotides and four fluorescent labeled antibodies in its sequencing process to recognize the incorporated bases. In this new process, the natural scarless bases are added in each sequencing cycle, enabling more accurate and longer reads, greatly expanding MPS applications. Improving public health by driving down sequencing costs Progress is being made in genomics at a breakneck pace, which allowed prices for genomic sequencing to steadily drop over the past decade. On that front, recently the sub-$100 human genome was introduced – a huge step forward from the $3 billion and 13 years spent for one human genome in the HGP. Indeed, from single-cell or spatial omics, sequencing applications will continue to grow. This downward trend in pricing shows that routine genome sequencing for everybody is possible and that there is value in individual genome testing. With a projected four times the DNB array density than today to reduce reagent consumption, combined with our single-tube long fragment read (stLFR) technology, which allows sequencing of data from long DNA molecules, we can provide affordable, fully-phased WGS and run deeper sequencing of the immune system and microbiome to holistically keep our health and aging in check. Since the 80s, there has always been this common goal within the field of achieving unlimited genome sequencing (because, in the end, there are so many things to measure and so many genomes to sequence). That said, we will not stop even at a $10 genome. Once dubbed “big science,” the HGP completed something few had imagined. Genomics for all In 2007, the first Asian personal genome was published in Nature, inaugurating a new era of large-scale personal genomics. Since then, more and more government-funded, population-scale sequencing programs have been launched. From the 1,000 Genome Project, which started in 2008, and the U.K.’s 100,000 Genome Project, to the Genomes of Icelanders, these efforts are playing a critical role in helping researchers identify genetic factors that contribute to the development and progression of specific health conditions, as well as the corresponding treatments and preventive measures. At MGI, we participate in several national genome projects, in Thailand, Indonesia and Brazil, providing these countries with a better understanding of the unique genomic complexities of their local populace. Our analyses serve as a foundation for developing personalized diagnostics, drug selection and treatment in the fields of cancer, infectious diseases, rare and undiagnosed diseases, non-communicable diseases and pharmacogenomic diseases, all of which are important areas of research that can contribute to extending human healthy life expectancy. Looking back from the HGP to now, the field of sequencing has massively advanced thanks to MPS. Because of this ability to conduct efficient sequencing in labs around the world, almost every omics today is done by sequencing. We can measure protein level in blood by sequencing barcodes and even evaluate gene activity all through sequencing. With that, the purpose of sequencing is also moving from understanding of genomes to disease prevention and treatment using omics assays. Soon, genetic sequencing will become part of our annual health checkups, where we will be able to monitor molecular health of our tissues. From seeing the applications of the first genome sequence, to discovering the first disease-causing mutation in personal genomes we sequenced, I have no doubt that genetic sequencing will do wonders as it touches every aspect of our lives.

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