Tag Archives: Intellia Therapeutics

Congratulations to winners of 2020 Nobel Prize for Chemistry: Dr. Emmanuelle Charpentier & Dr. Jennifer A. Doudna (CRISPR-cas9)

It’s possible there’s a more dramatic development in the field of contemporary gene-editing but it’s indisputable that CRISPR (clustered regularly interspaced short palindromic repeats) -cas9 (CRISPR-associated 9 [protein]) ranks very highly indeed.

The technique, first discovered (or developed) in 2012, has brought recognition in the form of the 2020 Nobel Prize for Chemistry to CRISPR’s two discoverers, Emanuelle Charpentier and Jennifer Doudna.

An October 7, 2020 news item on phys.org announces the news,

The Nobel Prize in chemistry went to two researchers Wednesday [October 7, 2020] for a gene-editing tool that has revolutionized science by providing a way to alter DNA, the code of life—technology already being used to try to cure a host of diseases and raise better crops and livestock.

Emmanuelle Charpentier of France and Jennifer A. Doudna of the United States won for developing CRISPR-cas9, a very simple technique for cutting a gene at a specific spot, allowing scientists to operate on flaws that are the root cause of many diseases.

“There is enormous power in this genetic tool,” said Claes Gustafsson, chair of the Nobel Committee for Chemistry.

More than 100 clinical trials are underway to study using CRISPR to treat diseases, and “many are very promising,” according to Victor Dzau, president of the [US] National Academy of Medicine.

“My greatest hope is that it’s used for good, to uncover new mysteries in biology and to benefit humankind,” said Doudna, who is affiliated with the University of California, Berkeley, and is paid by the Howard Hughes Medical Institute, which also supports The Associated Press’ Health and Science Department.

The prize-winning work has opened the door to some thorny ethical issues: When editing is done after birth, the alterations are confined to that person. Scientists fear CRISPR will be misused to make “designer babies” by altering eggs, embryos or sperm—changes that can be passed on to future generations.

Unusually for phys.org, this October 7, 2020 news item is not a simple press/news release reproduced in its entirety but a good overview of the researchers’ accomplishments and a discussion of some of the issues associated with CRISPR along with the press release at the end.

I have covered some CRISPR issues here including intellectual property (see my March 15, 2017 posting titled, “CRISPR patent decision: Harvard’s and MIT’s Broad Institute victorious—for now‘) and designer babies (as exemplified by the situation with Dr. He Jiankui; see my July 28, 2020 post titled, “July 2020 update on Dr. He Jiankui (the CRISPR twins) situation” for more details about it).

An October 7, 2020 article by Michael Grothaus for Fast Company provides a business perspective (Note: A link has been removed),

Needless to say, research by the two scientists awarded the Nobel Prize in Chemistry today has the potential to change the course of humanity. And with that potential comes lots of VC money and companies vying for patents on techniques and therapies derived from Charpentier’s and Doudna’s research.

One such company is Doudna’s Editas Medicine [according to my search, the only company associated with Doudna is Mammoth Biosciences, which she co-founded], while others include Caribou Biosciences, Intellia Therapeutics, and Casebia Therapeutics. Given the world-changing applications—and the amount of revenue such CRISPR therapies could bring in—it’s no wonder that such rivalry is often heated (and in some cases has led to lawsuits over the technology and its patents).

As Doudna explained in her book, A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution, cowritten by Samuel H. Sternberg …, “… —but we could also have woolly mammoths, winged lizards, and unicorns.” And as for that last part, she made clear, “No, I am not kidding.”

Everybody makes mistakes and the reference to Editas Medicine is the only error I spotted. You can find out more about Mammoth Biosciences here and while Dr. Doudna’s comment, “My greatest hope is that it’s used for good, to uncover new mysteries in biology and to benefit humankind,” is laudable it would seem she wishes to profit from the discovery. Mammoth Biosciences is a for-profit company as can be seen at the end of the Mammoth Biosciences’ October 7, 2020 congratulatory news release,

About Mammoth Biosciences

Mammoth Biosciences is harnessing the diversity of nature to power the next-generation of CRISPR products. Through the discovery and development of novel CRISPR systems, the company is enabling the full potential of its platform to read and write the code of life. By leveraging its internal research and development and exclusive licensing to patents related to Cas12, Cas13, Cas14 and Casɸ, Mammoth Biosciences can provide enhanced diagnostics and genome editing for life science research, healthcare, agriculture, biodefense and more. Based in San Francisco, Mammoth Biosciences is co-founded by CRISPR pioneer Jennifer Doudna and Trevor Martin, Janice Chen, and Lucas Harrington. The firm is backed by top institutional investors [emphasis mine] including Decheng, Mayfield, NFX, and 8VC, and leading individual investors including Brook Byers, Tim Cook, and Jeff Huber.

An October 7, 2029 Nobel Prize press release, which unleashed all this interest in Doudna and Charpentier, notes this,

Prize amount: 10 million Swedish kronor, to be shared equally between the Laureates.

In Canadian money that amount is $1,492,115.03 (as of Oct. 9, 2020 12:40 PDT when I checked a currency converter).

Ordinarily there’d be a mildly caustic comment from me about business opportunities and medical research but this is a time for congratulations to both Dr. Emanuelle Charpentier and Dr. Jennifer Doudna.

Immune to CRISPR?

I guess if you’re going to use bacteria as part of your gene editing technology (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9) then, you might half expect the body’s immune system may have developed some defenses. A Jan. 9, 2018 article by Sarah Zhang for The Atlantic provides some insight into what the new research suggests (Note: Links have been removed),

2018 is supposed to be the year of CRISPR in humans. The first U.S. and European clinical trials that test the gene-editing tool’s ability to treat diseases—such as sickle-cell anemia, beta thalassemia, and a type of inherited blindness—are slated to begin this year.

But the year has begun on a cautionary note. On Friday [January 5, 2018], Stanford researchers posted a preprint (which has not been peer reviewed) to the website biorXiv highlighting a potential obstacle to using CRISPR in humans: Many of us may already be immune to it. That’s because CRISPR actually comes from bacteria that often live on or infect humans, and we have built up immunity to the proteins from these bacteria over our lives.

Not all CRISPR therapies in humans will be doomed. “We don’t think this is the end of the story. This is the start of the story,” says Porteus [Matthew Porteus, a pediatrician and stem-cell researcher at Stanford]. There are likely ways around the problem of immunity to CRISPR proteins, and many of the early clinical trials appear to be designed around this problem.

Porteus and his colleagues focused on two versions of Cas9, the bacterial protein mostly commonly used in CRISPR gene editing. One comes from Staphylococcus aureus, which often harmlessly lives on skin but can sometimes causes staph infections, and another from Streptococcus pyogenes, which causes strep throat but can also become “flesh-eating bacteria” when it spreads to other parts of the body. So yeah, you want your immune system to be on guard against these bacteria.

The human immune system has a couple different ways of recognizing foreign proteins, and the team tested for both. First, they looked to see if people have molecules in their blood called antibodies that can specifically bind to Cas9. Among 34 people they tested, 79 percent had antibodies against the staph Cas9 and 65 percent against the strep Cas9.

The Stanford team only tested for preexisting immunity against Cas9, but anytime you inject a large bacterial protein into the human body, it can provoke an immune response. After all, that’s how the immune system learns to fight off bacteria it’s never seen before. (Preexisting immunity can make the response faster and more robust, though.)

The danger of the immune system turning on a patient’s body hangs over a lot of research into correcting genes. In the late 1990s and 2000s, research into gene therapy was derailed by the death of 18-year-old Jesse Gelsinger, who died from an immune reaction to the virus used to deliver the corrected gene. This is the worst-case scenario that the CRISPR world hopes to avoid.

Here’s a link to and a citation for the preprint,

Identification of Pre-Existing Adaptive Immunity to Cas9 Proteins in Humans by Carsten Trevor Charlesworth, Priyanka S Deshpande, Daniel P Dever, Beruh Dejene, Natalia Gomez-Ospina, Sruthi Mantri, Mara Pavel-Dinu, Joab Camarena, Kenneth I Weinberg, Matthew H Porteus. bioRxiv posted January 5, 2018 doi: https://doi.org/10.1101/243345

This article is a preprint and has not been peer-reviewed …

This preprint (not yet published paper) is open access and open for feedback.

Meanwhile, the year of CRISPR takes off (from a January 10, 2018 American Chemical Society news release on EurekAlert),

This year could be a defining one for CRISPR, the gene editing technique, which has been hailed as an important breakthrough in laboratory research. That’s because the first company-sponsored clinical studies will be conducted to see if it can help treat diseases in humans, according to an article in Chemical & Engineering News (C&EN), the weekly newsmagazine of the American Chemical Society.

C&EN Assistant Editor Ryan Cross reports that a big push is coming from industry, specifically from three companies that are each partly founded by one of the three inventors of the method. They are zeroing in on the blood diseases called sickle-cell anemia and β-thalassemia, mostly because their precise cause is known. In these diseases, hemoglobin doesn’t function properly, leading to severe health issues in some people. Crispr Therapeutics and Intellia Therapeutics plan to test the technique to boost levels of an alternative version of healthy hemoglobin. Editas Medicine, however, will also use CRISPR to correct mutations in the faulty hemoglobin gene. Labs led by university researchers are also joining the mix, starting or continuing clinical trials with the approach in 2018.

Because CRISPR is being used to cut a cell’s DNA and insert a new sequence, concerns have been raised about the potential for accidents. A cut in the wrong place could mean introducing a new mutation that could be benign — or cancerous. But according to proponents of the method, researchers are conducting extensive computer predictions and in vitro tests to help avoid this outcome.

The January 8, 2018 Chemical and Engineering News (C&EN) open access article by Ryan Cross is here.

Finally, if you are interested in how this affects research as it’s being developed, there’s University of British Columbia researcher Rosie Redfield’s January 16, 2018 posting on RRResearch blog,

Thursday’s [January 11, 2018] post described the hypothesis that bacteria might use gene transfer agent particles to inoculate other cells in the population with fragments of phage DNA, and outlined an experiment to test this.  Now I’m realizing that I need to know a lot more about the kind of immunity I should expect to see if this GTA-as-vaccine hypothesis is correct.

That should give you some idea of what I meant by “research as it’s being developed.” Redfield’s blog is not for the mildly interested.

Redfield is well-known internationally as being one of the first to refute research which suggested the existence of an ‘arsenic bacterium’ (see my Dec. 8, 2010 posting: My apologies for arsenic blooper. She’s first mentioned in the second excerpt, second paragraph.) The affair was known online as #arseniclife. There’s a May 27, 2011 essay by Carl Zimmer on Slate titled: The Discovery of Arsenic-Based Twitter: How #arseniclife changed science.