Hannah De Jong

Stanford University

Hannah De Jong’s heritage is in plant breeding. Her grandfather worked with potatoes, as does her father, a Cornell University professor. Her mother studies tomato genetics.

De Jong did undergraduate work in plant biology, but she “was always curious about research that could have an impact on human health care.” When she started her doctoral studies at Stanford University, De Jong switched from plants to human genetics.

The project De Jong (pronounced “De Young”), a Department of Energy Computational Science Graduate Fellowship (DOE CSGF) recipient, works with advisor Euan Ashley to address a damaging genetic heart condition.

Hypertrophic cardiomyopathy, or HCM, enlarges and thickens part of the heart muscle, making it work harder to pump blood. “It’s one of the main causes of sudden death in young people,” says Ashley, a professor of cardiovascular medicine, genetics and biomedical data science, and affects around one in 500 people in the United States. Ashley says he and De Jong hope understanding the genetics “will allow us to take a more precision approach to their condition and their treatment.”

De Jong concentrates on MYH7, a gene that encodes beta cardiac myosin, a protein that is part of the motor that makes heart cells contract. “We believe that when that contraction doesn’t occur properly the heart cells respond by making more of that contractile structure,” enlarging the organ, she says.

Researchers know it takes only one MYH7 mutation – one altered DNA letter, called a single nucleotide polymorphism (SNP) – to alter beta cardiac myosin. The trick is finding which SNPs of hundreds do it.

De Jong’s research focuses on a section of MYH7’s DNA that’s thought to be especially important. That means she must create and examine around 600 mutations.

Her main tool is saturation mutagenesis, which makes multiple copies of pieces of the gene’s DNA. Each contains a different SNP. De Jong uses computers to design chemical reagents that generate the mutations.

Once De Jong produces the mutations, she’ll insert those not already seen in HCM patients into stem cells. After they grow into heart muscle cells, De Jong will sort them into three groups – small, large and in between – since those with HCM-associated mutations generally grow bigger.

DeJong: cells

Finally, De Jong will decipher the cells’ DNA and use computers to search the results for frequent mutations. Those that appear more in DNA sequences from enlarged cells probably are hypertrophic alterations that cause HCM.

There are many obstacles, especially inserting the DNA into stem cells. To simplify that step, De Jong is exploring another new technology: CRISPR/Cas9, which employs genetic machinery that bacteria use to defend their genome from foreign DNA, such as that from a virus. It can be programmed to target specific DNA segments, letting scientists edit genes at precise locations. “With CRISPR, you can make changes in the DNA of a living organism” rather than in a test tube, De Jong says.

With luck and skill, the researchers will have gigabytes of DNA sequencing data from cells exhibiting hypertrophic characteristics. De Jong then will spend less time in the wet lab and more at a computer.

Analyzing her data, however, requires different computing capacity than the usual focus on maximum operations per second. “In genetics, generally the computational limitations are not processing-based, they’re memory-based,” De Jong says.

De Jong might get additional computer power through connections made during her 2016 Lawrence Livermore National Laboratory practicum. The lab’s Catalyst system is optimized for her research, with high memory capacity and a top speed of 150 trillion operations per second.

In the practicum, De Jong focused on detecting signs of DNA alterations rather than creating them. The group she worked with, headed by bioinformatics researcher Tom Slezak, studies bioterrorism. His team developed a system that analyzes air samples and identifies deadly viruses and bacteria.

But the technique can spot only previously known pathogens. Scientists fear adversaries could genetically engineer microorganisms to make them more virulent or impossible to detect. So De Jong has developed software to identify artifacts that gene-engineering tools – particularly CRISPR/Cas9 – may leave in DNA sequences. The downside: There’s no modified pathogen sequence data – thankfully – to test her technique. “As it stands, it’s essentially my best guess.”

Meanwhile, De Jong’s Stanford research will inform scientists’ fundamental understanding of beta cardiac myosin’s nature, Ashley says, but also could be immediately relevant to patient treatment.

De Jong’s DOE CSGF appointment ends in 2018, but she expects to take an additional two years to finish her research.

Read the entire article in DEIXIS, the DOE CSGF annual. [PDF, pages 10-12]

Image caption: This microscope image shows heart cells derived from stem cells and stained to show the contractile structure. Credit: Hannah De Jong.