COVID-19 and the CRISPR Community Response
Kevin Davies and Rodolphe Barrangou
On January 4, most of us were easing back into the research lab and teaching routine after a well-deserved holiday break. Few of us paid much heed to a 1,300-word essay in STAT by science writer Helen Branswell. We should have.
“Experts search for answers in limited information about mystery pneumonia outbreak in China,” read the headline.1 Branswell’s remarkable story not only sounded the alarm about the outbreak in Wuhan, but also raised concerns that a reticence to report statistics and transparently share information would prove catastrophic down the line. She quoted coronavirus expert Ralph Baric, Professor at the University of North Carolina, who said, “If the number of cases keeps increasing, then it becomes more and more of a global public health threat. The chance of [infected] people slipping through the screening platforms for international travel or travel elsewhere in China become greater as long as they don’t know what the pathogen is.”
Three months later, like all scientists around the world, the global CRISPR community has been rocked on its heels by the COVID-19 pandemic. “Rudderless, blindsided, lethargic, and uncoordinated, America has mishandled the COVID-19 crisis to a substantially worse degree than what every health expert I’ve spoken with had feared,” wrote Ed Yong in a thorough piece in The Atlantic.2
There will eventually be ample time to study and research the lack of preparedness, the price gouging and unfathomable competition to procure face masks and ventilators, and factors driving both the spread, impact, and human, political, and economic impacts of the pandemic. For now, we can only admire and thank our medical colleagues and all those on the front lines, literally putting their lives at risk to manage the flood of COVID-19 patients.
On the research front, it is gratifying to see scientists from so many disparate fields turning their attention to the pandemic, hatching new ideas and building platforms to diagnose, model, screen, and/or treat the disease. An army of scientists is working on solutions, encompassing diagnostics, antivirals, and next-generation vaccines, and willing to make themselves and their resources available as needed.
Our colleagues at Genetic Engineering & Biotechnology News have done a remarkable job of chronicling drugs and vaccines in development.3 The current tally already exceeds 150 drug and vaccine programs in active development. “There are 4–5 extremely promising candidate drugs in development for COVID-19,” says Sidhartha Muhkerjee. “We need to buy time to allow these drugs to be tested in (hopefully) randomized studies.”
The CRISPR community has been responding admirably to the COVID-19 pandemic. Here are just a few of the projects that are showing promise, and we would love to hear about others:
Feng Zhang, working with his former group members Omar Abudayyeh and Jonathan Gootenberg, published a protocol for the detection of the novel coronavirus (SARS-CoV-2).4 The protocol is based on the SHERLOCK platform, first reported in 2017, which uses Cas13 to detect the RNA virus in as little as 60 minutes. The readout is based on lateral flow using a paper dipstick. On a related note, Pardis Sabeti, Cameron Myhrvold, and colleagues (Broad Institute) used machine learning to design a point-of-care assay for SARS-CoV-2 and other viruses.5
Mammoth Biosciences, the CRISPR diagnostics company set up by members of Jennifer Doudna’s lab, published a white paper describing the use of its diagnostic DETECTR technology to detect the SARS-CoV-2 RNA in about 30 minutes.6
The group of Neville Sanjana (New York University) has published a Cas13 screen to identify guide RNAs that can be targeted against SARS-CoV-2.7 “We hope that this large-scale Cas13 dataset and machine learning framework will help rapidly predict optimal guide RNAs in these types of situations,” Sanjana said on Twitter.
Stanley Qi (Stanford University and our associate editor) and coworkers published a preprint on a CRISPR-Cas13 strategy called PAC-MAN (Prophylactic Antiviral CRISPR in huMAN cells) that can degrade SARS-CoV-2 sequences. The Qi lab screened a group of crRNAs aimed at conserved viral regions and identified sequences for cleaving SARS-CoV-2. A set of six crRNAs targets more than 90% of all coronaviruses. Qi says that the approach “is potentially a rapidly implementable pan-coronavirus strategy to deal with emerging pandemic strains.”8
Liu Changchun and colleagues (University of Connecticut) have developed a one-pot Cas12a sensing system that Liu hopes will prove a next-generation point-of-care molecular diagnostic.9
Speaking of diagnostics, two of the leading CRISPR research centers—the Broad Institute and the Innovative Genomics Institute (IGI) at the University of California, Berkeley—have both set up high-throughput COVID-19 testing pipelines.
At Berkeley, Doudna was overwhelmed with volunteers from academia and industry offering to help set up a 2,500-square-foot testing laboratory that will be able to handle 1,000 tests and more in 24 hours. The set-up is based on SARS-CoV-2 test kits from Thermo Fisher Scientific and features a customized automated workflow. “It’s unbelievable to see how fast this is coming together and people writing software just overnight to put such a complicated pipeline in place and ensure that it’s secure. It’s really quite amazing,” Doudna told STAT.10 The co-technical leads are Jennifer Hamilton and Enrique Lin Shiao, both postdocs in the Doudna lab.11
At the Broad Institute, Stacey Gabriel, Sheila Dodge, and colleagues converted the Institute’s Clinical Research Sequencing Platform (CRSP) into a COVID-19 testing center that is now part of the Massachusetts state reference lab. The Broad has immense expertise in processing genomic samples, but had no experience working with viral specimens. It aims to process 2,000 tests per day.
We’ll Meet Again
The current difficulties have severely curtailed our community’s ability to conduct research and to collect and share data (and drinks). We are sad to see the cancellation or postponement of several important conferences in the next few months, including the American Society of Gene & Cell Therapy in Boston (May), the FASEB Genome Engineering conference in Lisbon (June), and especially the CRISPR 2020 meeting this June in Paris. The Paris conference has been pushed back 12 months to June 1–4, 2021.
In the meantime, we will all learn to work from home, interface via online conferencing, and keep some sense of normalcy until we get the chance to socialize in person again. It remains unclear how this will impact work rituals (handshakes anyone?), travel habits and professional gatherings (what is the future of scientific conferences and online meetings?).
We have previously discussed how scientific skepticism has hampered public acceptance of genome editing technologies. Sadly, this extends to the difficulties some political leaders have with grasping scientific frameworks, recommendations, and processes. Sage and courageous leaders such as Dr. Anthony Fauci can rely on the support of all scientists, including those who are battling this disease in myriad ways. We salute their inspirational creativity and altruism as we confront a pandemic that has already claimed lives of talented physicians and scientists.
mediated cytotoxicity; antiviral agents
1. Branswell H. Experts search for answers in limited information about mystery pneumonia outbreak in China. STAT, January 4, 2020. Available online at: https://www.statnews.com/2020/01/04/mystery-pneumonia-outbreak-china/ (last accessed April 8, 2020). Google Scholar
2. Yong E. How the pandemic will end. The Atlantic, March 25, 2020. Available online at: https://www.theatlantic.com/health/archive/2020/03/how-will-coronavirus-end/608719/ (last accessed April 8, 2020). Google Scholar
3. Philippidis A. Vanquishing the Virus. GEN (in press). Google Scholar
4. Zhang F, Abudayyeh A, Gootenberg J. Protocol. Available online at: https://www.broadinstitute.org/files/publications/special/COVID-19%20detection%20(updated).pdf (last accessed April 8, 2020). Google Scholar
5. Metsky HC, Freije CA, Kosoko-Thoroddsen T-SF, et al. CRISPR-based surveillance for COVID-19 using genomically-comprehensive machine learning design. Available online at: https://www.biorxiv.org/content/10.1101/2020.02.26.967026v2 (last accessed April 8, 2020). Google Scholar
6. Broughton JP, Deng W, Fasching CL, et al. White paper. Available online at: https://mammoth.bio/2020/02/15/white-paper-a-protocol-for-rapid-detection-of-sars-cov-2-using-crispr-sars-cov-2-detectr/ (last accessed April 8, 2020). Google Scholar
7. Wessels H-H, Méndez-Mancilla A, Guo X, et al. Massively parallel Cas13 screens reveal principles for guide RNA design. Nature Biotech 2020 Mar 16 [Epub ahead of print]; DOI 10.1038/s41587-020-0456-9. Crossref, Google Scholar
8. Abbott TR, Dhamdhere G, Liu Y, et al. Development of CRISPR as a prophylactic strategy to combat novel coronavirus and influenza. Available online at: https://www.biorxiv.org/content/10.1101/2020.03.13.991307v1 (last accessed April 8, 2020). Google Scholar
9. Ding X, Yin K, Li Z, et al. All-in-one dual CRISPR-Cas12a (AIOD-CRISPR) assay: a case for rapid, ultrasensitive and visual detection of novel coronavirus SARS-CoV-2 and HIV virus. Available online at: https://www.biorxiv.org/content/10.1101/2020.03.19.998724v1 (last accessed April 8, 2020). Google Scholar
10. Herper M. CRISPR pioneer Doudna opens lab to run Covid-19 tests. STAT, March 30, 2020. Available online at: https://www.statnews.com/2020/03/30/crispr-pioneer-doudna-opens-lab-to-run-covid-19-tests/ (last accessed April 8, 2020). Google Scholar
11. Molteni M. How a CRISPR lab became a pop-up COVID testing center. WIRED, April 2, 2020. Available online at: https://www.wired.com/story/crispr-lab-turned-pop-up-covid-testing-center/ (last accessed April 8, 2020). Google Scholar