While genome sequencing has given us a picture of the order of nucleotides—and the rearrangements that lie behind variation and disease—it has not provided a complete illustration of the complex interactions of genes, RNA, and proteins.
William Lai is working to change that, with help from Element’s AVITI™ system. An Assistant Research Professor in the Department of Molecular Biology and Genetics and Director of The Epigenomics Core Facility at Cornell University, Dr. Lai presented his research and his core activities at the Element Biosciences Road Show’s New York City stop.
He also shared why he was more than happy to switch from Illumina to AVITI sequencing.
Lai’s own research focuses on designing novel assays that will further our understanding of the fundamental mechanisms of gene regulation. “DNA sequence, local and distal chromatin (protein) and RNA all play both cooperative and antagonistic roles in when and how often any gene is transcribed. Understanding how these biological networks make decisions is the key bottleneck in understanding how perturbations to these systems result in a disease phenotype,” his Cornell research focus states.
Lai now uses chromatin immunoprecipitation (ChIP) to investigate protein-DNA interactions. This technique allows him and his colleagues to see where proteins bind to the genome, how they turn functions on and off, and how “gene regulation gets messed up.” Gene sequencing is critical to this research. Since about 2006, Lai said he has always had access to a gene sequencer. “If you want to make an assay, you need access to a sequencer,” he says.
The recent acquisition of an Element AVITI platform at Cornell has helped Lai accelerate his research. “With 24-hour turnaround around and better readouts, this allowed me to advance my research and develop new technologies.” Using AVITI will also help the core lab slash its sequencing costs from about $130,000 to $15,000 for the same number of reads.
Lai presented results his lab has produced recently, combining sequencing on the AVITI platform with improved bioinformatics tools and the appropriate biochemical techniques. The system is now part of a robotic platform in his lab and in the core lab he directs. Now, he can survey 96 target proteins on a single plate and generate 1.2 billion reads “in one go,” he said. This allows the simultaneous testing of multiple drugs, and of more factors that influence drug action, faster. “Because the AVITI is right here, I can get an answer in a week instead of a month.”
Pharmaceutical research, and cancer drug research in particular, has suffered from discovery that’s based more on brute force than a careful elucidation of functions. Lai has been looking at the perturbations caused by two anti-cancer drugs: flavopiridol, a CDK9 inhibitor which has been used in dozens of clinical trials (and failed most of them), and triptolide, a transcription initiation inhibitor which is now in a phase II clinical trial.
The two drug candidates stop RNA expression in cancer cells. But the way they stop transcription is very different. “You see a buildup of proteins,” Lai said. “The three-dimensional structure of DNA and protein changes depending on the drug perturbation. We want to see what is actually happening, because these actions have implications for how well the drug will work as a cancer therapeutic. Epigenomics of protein-protein, protein-DNA interactions…if we understood this, it would be easier to design a therapeutic at that point.”
We’re proud that AVITI sequencing is helping advance his knowledge (as well as that of his core lab customers) in this important area of research. “You’re either innovating or being left behind,” he added.
Why did the Cornell Epigenomics Core Facility leave Illumina?
Making a decision like purchasing a sequencer can be expensive and risky. For high capital expenditures, researchers understandably look for a trusted supplier, reliable operations and great customer support and service. Illumina looked like a logical choice for Cornell, until, according to William Lai, it didn’t.
Lai was looking to see what other sequencing technologies offered, and he came upon Element and AVITI. “One thing was shocking during the demonstration,” he said. “Our libraries broke the AVITI platform!” After a substantial amount of research, debugging and consultation with Element’s team, they found the problem—a synthesis flaw, specifically a truncation--in oligos they had ordered. The AVITI System and the Element support team found the synthesis error in a critical assay component, which the Illumina outsourcing provider had previously been sweeping the under the rug.
“We had expected 400 million reads but were only getting 200 million. We weren’t getting those all at once, but something seemed off,” Lai recalled. Illumina was filtering the errors, and not indicating them as such.
On top of that, runs on Illumina systems cost $7.85 per one million reads, while AVITI cost 90 cents per one million reads. Once the truncated oligo errors were resolved, the cost difference became even greater. Lai estimated that sequencing on Illumina cost $130,000 in 2023. AVITI costs for the same reads? Just $15,000.