Category Archives: Transhuman News

May 29, 2017 CRISPR-associated protein Cas9 (white) from Staphylococcus aureus based on Protein Database ID 5AXW. Credit: Thomas Splettstoesser (Wikipedia, CC BY-SA 4.0)

As CRISPR-Cas9 starts to move into clinical trials, a new study published in Nature Methods has found that the gene-editing technology can introduce hundreds of unintended mutations into the genome.

"We feel it's critical that the scientific community consider the potential hazards of all off-target mutations caused by CRISPR, including single nucleotide mutations and mutations in non-coding regions of the genome," says co-author Stephen Tsang, MD, PhD, the Laszlo T. Bito Associate Professor of Ophthalmology and associate professor of pathology and cell biology at Columbia University Medical Center and in Columbia's Institute of Genomic Medicine and the Institute of Human Nutrition.

CRISPR-Cas9 editing technologyby virtue of its speed and unprecedented precisionhas been a boon for scientists trying to understand the role of genes in disease. The technique has also raised hope for more powerful gene therapies that can delete or repair flawed genes, not just add new genes.

The first clinical trial to deploy CRISPR is now underway in China, and a U.S. trial is slated to start next year. But even though CRISPR can precisely target specific stretches of DNA, it sometimes hits other parts of the genome. Most studies that search for these off-target mutations use computer algorithms to identify areas most likely to be affected and then examine those areas for deletions and insertions.

"These predictive algorithms seem to do a good job when CRISPR is performed in cells or tissues in a dish, but whole genome sequencing has not been employed to look for all off-target effects in living animals," says co-author Alexander Bassuk, MD, PhD, professor of pediatrics at the University of Iowa.

In the new study, the researchers sequenced the entire genome of mice that had undergone CRISPR gene editing in the team's previous study and looked for all mutations, including those that only altered a single nucleotide.

The researchers determined that CRISPR had successfully corrected a gene that causes blindness, but Kellie Schaefer, a PhD student in the lab of Vinit Mahajan, MD, PhD, associate professor of ophthalmology at Stanford University, and co-author of the study, found that the genomes of two independent gene therapy recipients had sustained more than 1,500 single-nucleotide mutations and more than 100 larger deletions and insertions. None of these DNA mutations were predicted by computer algorithms that are widely used by researchers to look for off-target effects.

"Researchers who aren't using whole genome sequencing to find off-target effects may be missing potentially important mutations," Dr. Tsang says. "Even a single nucleotide change can have a huge impact."

Dr. Bassuk says the researchers didn't notice anything obviously wrong with their animals. "We're still upbeat about CRISPR," says Dr. Mahajan. "We're physicians, and we know that every new therapy has some potential side effectsbut we need to be aware of what they are."

Researchers are currently working to improve the components of the CRISPR systemits gene-cutting enzyme and the RNA that guides the enzyme to the right geneto increase the efficiency of editing.

"We hope our findings will encourage others to use whole-genome sequencing as a method to determine all the off-target effects of their CRISPR techniques and study different versions for the safest, most accurate editing," Dr. Tsang says.

The paper is titled, "Unexpected mutations after CRISPR-Cas9 editing in vivo." Additional authors are Kellie A. Schafer (Stanford University), Wen-Hsuan Wu (Columbia University Medical Center), and Diana G. Colgan (Iowa).

Explore further: Accurate DNA misspelling correction method

More information: Unexpected mutations after CRISPR-Cas9 editing in vivo, Nature Methods (2017).

Researchers at the Institute of Basic Science (IBS) proved the accuracy of a recently developed gene editing method. This works as "DNA scissors" designed to identify and substitute just one nucleotide among the 3 billion. ...

A team from the Center for Genome Engineering, within the Institute for Basic Research (IBS), succeeded in editing two genes that contribute to the fat contents of soybean oil using the new CRISPR-Cpf1 technology: an alternative ...

Researchers from Memorial Sloan Kettering Cancer Center (MSK) have harnessed the power of CRISPR/Cas9 to create more-potent chimeric antigen receptor (CAR) T cells that enhance tumor rejection in mice. The unexpected findings, ...

The IBS research team (Center for Genome Engineering) has successfully confirmed that CRISPR-Cas9 has accurate on-target effects in human cells, through joint research with the Seoul National University College of Medicine ...

A team of researchers at Western University is playing with molecular-Lego by adding an engineered enzyme to the revolutionary new gene-editing tool, CRISPR/Cas9. Their study, published today in the Proceedings of the National ...

Using the new gene-editing enzyme CRISPR-Cpf1, researchers at UT Southwestern Medical Center have successfully corrected Duchenne muscular dystrophy in human cells and mice in the lab.

Princeton researchers have developed a way to place onto surfaces special coatings that chemically "communicate" with bacteria, telling them what to do. The coatings, which could be useful in inhibiting or promoting bacterial ...

A research group at the University of Helsinki discovered the fastest event of speciation in any marine vertebrate when studying flounders in an international research collaboration project. This finding has an important ...

(Phys.org)A team of researchers affiliated with several institutions in China has dated rice material excavated from a dig site in South China's Zhejiang province back to approximately 9,400 years ago. In their paper published ...

It has now been shown for the first time that non-avian reptiles are able to adjust their calls in relation to environmental noise as is known for the complex vocal communication systems of birds and mammals. In Tokays, night ...

Climate change is a threat to all species, but which species will be under the greatest threat?

A study by scientists from the University of Cambridge has revealed how cooperative behaviour between insect family members changes how rapidly body size evolves with the speed of evolution increasing when individual ...

Adjust slider to filter visible comments by rank

Display comments: newest first

If a person has 3 months to live and they use crispr/cas9 to cure the cancer, and it works, what is the worst than can happen to him?

I'm not a biologist, so no idea how conceivable or absurd that idea might be. But then there's the whole thing with the Tasmanian devils. Anyway, you asked about worst cases, and that is one possible thing that people who are against this might be thinking.

Open a door, find 12 new doors. Like the knowledge that carbon nanos caused cancer but the powers-that-be decided we should use it any way because it was so convenient.

We are so screwed! This is worse than the advent of nuclear weapons.

this might cause regulated interests to think twice before deploying this for profit. It will not help us at all against weaponized CRISPR, though...

Crispr is the only way the human race will survive. Without it the machines rule. With crispr the human race increases everyone's IQ 10 fold. The vary smartest of us say "be very afraid of AI". Musk likened AI to a devil in a bottle. It's the 2nd level of our most brilliant people that can't see the danger AI poses. Raise everyone's IQ by 10X and we will make much better decisions and solve the current world's problems overnight.

Meatbrains are passe which is why we are so intent on replacing them.

Watch Forbidden Planet to see what happens when you mix intelligence with the need to survive to procreate.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Excerpt from:
CRISPR gene editing can cause hundreds of unintended mutations - Phys.Org

Xconomy Boulder/Denver

The randomized controlled trial has long been held up as the gold standard for testing new drugs. But the nations top drug evaluator, Janet Woodcock, believes they arent necessary for all new experimental treatments. Randomized trials are long, expensive to run, and ultimately produce limited answers, she said at a medical conference last week.

The ability to use genetic information to classify patients and match them to potential therapies opens up new possibilities for evaluating drugs. As these capabilities increase, Woodcock says, the FDA should adjust its approach to reviewing drugs.

People have been very happy with the use of the traditional standard randomized controlled trial, Woodcock said last Thursday at the Precision Medicine World Conference at Duke University. People know how to interpret that evidence. Yet that may not be appropriate for some of these diseases.

The FDA has shown such flexibility with two recent approvals based on better genetic insights. Last week, the FDA approved Mercks (NYSE: MRK) cancer drug pembrolizumab (Keytruda) for all solid tumors with a specific genetic signature, regardless of where in the body the cancer started. That decision came days after the regulator expanded use of Vertex Pharmaceuticals (NASDAQ: VRTX) cystic fibrosis drug, ivacaftor (Kalydeco), so more patients with a particular genetic mutations could get treatment. The additional approvals for both drugs did not require the companies to conduct more randomized controlled trials. Woodcock described the approvals as landmarks for precision medicine.

Pembrolizumab was already approved to treat cancers of the skin, lung, and bladder, among others. The data supporting the latest approval for the Kenilworth, NJ-based companys drug came from open-label basket trials that simultaneously tested pembrolizumab on a variety of tumors that all share a specific genetic alteration. Patients were selected for the studies based on genetic tests that identified that signature, a predictor of whether they would respond to the Merck therapy. The FDAs ruling was an accelerated approval, meaning Merck must gather additional evidence to confirm the earlier studies. Woodcock said that this type of flexible approach is particularly important for diseases that have no treatment alternatives.

Genetic information has also played a role in the development and approval of Vertexs cystic fibrosis drug, ivacaftor. The drug was initially approved to treat patients who have specific mutations that indicate they would respond to the drug. On May 17, the FDA expanded the approval from 10 mutations to 33. Woodcock said the FDA based this decision on several factors, but the main evidence was a laboratory test that showed the drug could also help CF patients with more gene mutations. Woodcock said that this decision opens a pathway for drugs in cystic fibrosis and other diseases that have similar signs and symptoms. After a drug is first approved, a drugmaker could get additional approvals for additional patient subsets by using the lab test, rather than conducting a randomized clinical trial for each group.

The FDA and drug companies have been talking about adding new approaches to clinical trials for years, and that effort is now getting a nudge forward under federal law. Among the provisions of the wide-ranging 21st Century Cures Act, signed into law last year, are requirements that the FDA hold public hearings and issue guidance to help drug companies use new clinical trial designs to test their drugs. The law also calls on the FDA to use real-world evidence to support applications for new uses of already approved drugs. (Regulatory Affairs has a good breakdown of what the new federal law means for the FDA.)

Woodcock didnt reference the Cures Act in her remarks. But she said that for some drugs, different trial designs are warranted. Platform trials might be useful to evaluate multiple drugs and drug combinations simultaneously, with the ability to adjust the studies on the fly by adding or dropping arms. This flexibility allows Next Page

Frank Vinluan is editor of Xconomy Raleigh-Durham, based in Research Triangle Park. You can reach him at fvinluan [at] xconomy.com

The rest is here:
Woodcock: New Approvals Show FDA is Adapting to Precision Medicine - Xconomy