June 4, 2021 –
Team at Gene Editing Institute Develop DECODR to Detect Unintended Mutations
On nearly an hourly basis, most of us edit a text, document or social media post. We delete one word or replace another to best express our thoughts.
Similarly, CRISPR-Cas9 removes, adds or alters regions of DNA. The gene-editing tool could help cure such illnesses as sickle cell disease and cystic fibrosis. It is also a gamechanger in agriculture.
No wonder CRISPR is the subject of news articles, radio segments and TV programs. Last October, for instance, Jennifer Doudna of the University of California, Berkley, and Emmanuelle Charpentier of the Berlin-based Max Planck Unit for the Science of Pathogen made headlines for winning the Nobel Prize in Chemistry. The researchers were honored for the discovery of CRISPR-Cas9 genetic “scissors.”
But no matter how precise the cut, CRISPR can also negatively impact the areas near the repair site. To find and categorize these genetic scars, ChristianaCare’s Gene Editing Institute released DECODR, an affordable software application.
“We developed DECODR to accelerate the development of CRISPR gene therapies by providing a way to detect these changes rapidly so we can determine whether they pose a risk to patients,” explains Eric Kmiec, Ph.D., director of the Gene Editing Institute in Newark, Delaware, and principal author of a study on the app published in The CRISPR Journal.
Short for deconvolution of complex DNA repair, DECODR is the brainchild of a high school student and a Ph.D. candidate who, in many ways, reflect Delaware’s talent pool in cutting-edge fields.
CRISPR — which stands for clustered regularly interspaced short palindromic repeats — is part of an antiviral system in certain bacterial species. Thanks to the Nobel Prize winners and their associates, CRISPR is also a gene-editing tool.
At the ChristianaCare Gene Editing Institute, located in the Helen F. Graham Cancer Center, researchers are studying how CRISPR-Cas9 can delete the gene responsible for chemotherapy-resistant lung cancer tumors, decrease a solid tumor’s volume and stop its growth.
Using CRISPR safely is paramount as studies move into clinical trials.
“Like many medical interventions, CRISPR gene therapies are likely to come with a mix of risks and benefits,” Kmiec says. “More information is needed to ensure patients can make an informed decision.”
Pinpointing the potential for problems requires painstaking DNA sequencing — no easy feat. “Targeting deep sequencing is generally used for large patches of DNA like the entire genome of a person. It can take weeks to months,” explains research fellow Kevin Bloh, lead author of the study published in The CRISPR Journal and a Ph.D. candidate at the University of Delaware. It’s also costly.
Sanger sequencing takes less than 24 hours but may not reveal all the possible mutations, Bloh notes. It could take up to 40 minutes for a person to manually analyze one CRISPR-edited sequence
Enter Rohan Kanchana, a high school intern who cut his teeth on computer coding in sixth grade. Kanchana was not permitted to work in the Institute’s actual lab, but he could use his savvy software skills outside it.
While at Newark Charter School, Kanchana was intrigued when Bloh and researcher Brett Sansbury told him that a single gene edit could produce volumes of DNA data. Afterward, DNA sequences appear like a stack of sentences piled atop each other. “You can’t read it,” notes Kanchana.
DECODR’s algorithms separate the sentences one by one from the messy pile so researchers can read each sequence, Kanchana says. The program also quickly and accurately finds a wide range of DNA code insertions and deletions that might happen after a CRISPR-directed gene repair.
The results indicate specific mutations and highlight genes that have fixed themselves. However, it is up to the clinician to interpret the results and analyze accidental mutations’ risk.
The software is easily updated. While a variety of platforms can support the web-based application, it runs best on computers or desktops, Kanchana said.
A free version of DECODR is available online at decodr.org/analyze. The Gene Editing Institute is pursuing a licensed commercial version that could offer more options while still providing highly accurate data.
Bloh, who is studying medical and molecular sciences, has used DECODR both at work and for his academic research. The alumnus of Salesianum High School in Wilmington earned a master’s degree at nearby Drexel University in Philadelphia.
Having the Gene Editing Institute within a patient-based healthcare system makes Delaware special, he says. “It is the only place where this type of research [on lung cancer tumors] could make [a direct] impact.”
Kanchana adds that Delaware is the ideal learning environment for students who want to pursue software development.
“Computer programming is valuable anywhere, but especially in Delaware,” he says. “If you reach out to people [in the STEM community] and say you can work with computers and develop software, they are very open and welcoming. It’s special about Delaware.”
For proof, consider that his father, a gastroenterologist, reached out to Kmiec about the internship, saying the student’s talent with a computer might prove useful.
Kanchana has benefited from the active STEM program at his school, which has career pathways for biotechnology and computer science. “They offer very specialized and very intensive tracks,” he notes.
He hopes to study computational biology in college. DECODR has put him on the right path toward the degree. “It’s the perfect application of using computer code and algorithms to analyze biological data,” he says. “The Gene Editing Institute was a wonderful opportunity for me. “
He is not the only one. “Our projects tend to attract outstanding young scientists, and we have been fortunate to retain many of those who have trained with us as graduate students,” Kmiec says. “DECODR will only amplify this since the analysis of the type of genetic footprint CRISPR leaves behind after it edits the DNA is at the heart of therapeutic development.”
The release of DECODR could lead to the expansion of the institute’s analytical team, he says. Meanwhile, it’s back to business as usual — breaking new ground.
“We have been fortunate to be part of the CRISPR revolution,” says Kmiec, “and believe we’ve contributed some important discoveries on the fundamentals of how CRISPR actually edits human DNA.”