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Gene Therapy and the Genetic Study of Disease: @Berkeley and @UCSF – New DNA-editing technology spawns bold UC initiative as Crispr Goes Global

Reporter: Aviva Lev-Ari, PhD, RN

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New DNA-editing technology spawns bold UC initiative

UC Berkeley and UC San Francisco are launching the Innovative Genomics Initiative to lead a revolution in genetic engineering based on a new technology already generating novel strategies for gene therapy and the genetic study of disease.

The Li Ka Shing Foundation has provided a $10 million gift to support the initiative, establishing the Li Ka Shing Center for Genomic Engineering and an affiliated faculty chair at UC Berkeley. The two universities also will provide $2 million in start-up funds.

At the core of the initiative is a revolutionary technology discovered two years ago at UC Berkeley by Jennifer A. Doudna, executive director of the initiative and the new faculty chair.

In April 2013 were create the following report on Prof. Doudna

Ribozymes and RNA Machines – Work of Jennifer A. Doudna

http://pharmaceuticalintelligence.com/2013/04/15/ribozymes-and-rna-machines-work-of-jennifer-a-doudna/

Now, it is an article in the following forthcoming e-Book

Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics. Volume Three in Series A: e-Books on Cardiovascular Diseases

http://pharmaceuticalintelligence.com/biomed-e-books/series-a-e-books-on-cardiovascular-diseases/volume-three-etiologies-of-cardiovascular-diseases-epigenetics-genetics-genomics/

 

New DNA-editing technology spawns bold UC initiative

By Robert Sanders, Media Relations | March 18, 2014

BERKELEY —

The University of California, Berkeley, and UC San Francisco are launching the Innovative Genomics Initiative (IGI) to lead a revolution in genetic engineering based on a new technology already generating novel strategies for gene therapy and the genetic study of disease.

The Li Ka Shing Foundation has provided a $10 million gift to support the initiative, establishing the Li Ka Shing Center for Genomic Engineering and an affiliated faculty chair at UC Berkeley. The two universities also will provide $2 million in start-up funds.

Jennifer Doudna, executive director of the new Innovative Genomics Initiative and the new Li Ka Shing Chancellor’s Chair in Biomedical and Health Sciences.
At the core of the initiative is a revolutionary technology discovered two years ago at UC Berkeley by Jennifer A. Doudna, executive director of the initiative and the new faculty chair. The technology, precision “DNA scissors” referred to as CRISPR/Cas9, has exploded in popularity since it was first published in June 2012 and is at the heart of at least three start-ups and several heavily-attended international meetings. Scientists have referred to it as the “holy grail” of genetic engineering and a “jaw-dropping” breakthrough in the fight against genetic disease. In honor of her discovery and earlier work on RNA, Doudna received last month the Lurie Prize of the Foundation for the National Institutes of Health.

“Professor Doudna’s breakthrough discovery in genomic editing is leading us into a new era of possibilities that we could have never before imagined,” said Li Ka-shing, chairman of the Li Ka Shing Foundation. “It is a great privilege for my foundation to engage with two world-class public institutions to launch the Innovative Genomics Initiative in this quest for the holy grail to fight genetic diseases.”

In the 18 months since the discovery of this technology was announced, more than 125 papers have been published based on the technique. Worldwide, researchers are using Cas9 to investigate the genetic roots of problems as diverse as sickle cell anemia, diabetes, cystic fibrosis, AIDS and depression in hopes of finding new drug targets. Others are adapting the technology to reengineer yeast to produce biofuels and wheat to resist pests and drought.

“We now have a very easy, very fast and very efficient technique for rewriting the genome, which allows us to do experiments that have been impossible before,” said Doudna, a professor of molecular and cell biology in the California Institute for Quantitative Biosciences (QB3) and an investigator in the Howard Hughes Medical Institute at UC Berkeley. “We are grateful to Mr. Li Ka-shing for his support of our initiative, which will propel ground-breaking advances in genomic engineering.”

Transforming genetic research

The new genomic engineering technology significantly cuts down the time it takes researchers to test new therapies. CRISPR/Cas 9 allows the creation in weeks rather than years of animal strains that mimic a human disease, allowing researchers to test new therapies. The technique also makes it quick and easy to knock out genes in human cells or in animals to determine their function, which will speed the identification of new drug targets for diseases.

“The CRISPR/Cas9 technology is a complete game changer,” said Jonathan Weissman, codirector of the initiative and professor of cellular and molecular pharmacology in the UCSF School of Medicine. “With CRISPR, we can now turn genes off or on at will. I am particularly interested in using CRISPR to understand the normal functions of genes as well as how disease-causing mutations alter these functions.”

“The main goal of the initiative is to develop the CRISPR/Cas9 technology for applications in human health, and create a library of research resources that will make it available broadly,” Doudna added. “This is an exciting time in science right now, when the cost of sequencing a genome is going way down, to around $1,000 for a complete human genome sequence. Cas9 technology will take genomics to the next level, to enable editing of the genome.”

Doudna noted that UC Berkeley and UCSF have made fundamental discoveries about human disease through studies in organisms as diverse as yeast, fruit flies, zebrafish and rodents. The new technology will help these researchers make the leap from fundamental research in animal models to tests in human cells and tissue and eventually to the clinic, where CRISPR/Cas9 would make human gene therapy simpler.

“We now have a technique to reprogram the software of a cell by editing the genome, which will allow us to conduct genetic manipulations in human cells that we couldn’t do before,” Doudna said.

Applications in human health and beyond

In the past, for example, making a strain of mice with a specific and heritable genetic mutation took at least a year of costly experiments. Using the Cas9 technique, UC Berkeley immunologist Russell Vance disabled a gene in mice that regulates fur color and in just six weeks had a strain of mice with white coats instead of brown. Similar research in animal models ranging from rodents to primates is being done in labs around the world using the CRISPR/Cas9 technology.
Human cardiac myocytes (muscle cells) stained green for proteins encoded by edited genes using the new CRISPR/Cas9 technology.
Other researchers have already adapted the technology to reprogram stem cells to regenerate damaged organs, such as the liver, and made attempts to reprogram immune cells to cure AIDS in HIV-positive patients.

Doudna and her colleagues also are building resources and infrastructure for an incubator to assist researchers, postdoctoral fellows and students to spin off companies. This Entrepreneurial Fellows program will coordinate with the QB3 Startup-in-a-Box program to help launch new companies that address important societal challenges and create new jobs in California.

The Cas9 technology adapts a DNA-snipping system used by bacteria to cut up and destroy the DNA of invading viruses. Doudna and colleagues Martin Jinek of the Howard Hughes Medical Institute at UC Berkeley and Emmanuelle Charpentier of the Helmholtz Centre for Infection Research (and formerly of the Laboratory for Molecular Infection Medicine-Sweden) discovered how the enzyme Cas9 works with small RNA molecules to target and cut specific areas of DNA. Jinek and Doudna also showed that the RNA-programmable CRISPR/Cas9 system works in human cells, and is much faster and easier than other genome editing methods.

Initiative codirector Michael Botchan, UC Berkeley professor of molecular and cell biology, is most excited about the potential to explore the 95 percent of the human genome once called “junk DNA” that is now known to contain most of the regulators that turn genes on and off, and may harbor defective genes responsible for many diseases.

“What makes humans different from monkeys is not the 6-7 percent of the genome that codes for proteins, but the regulatory genes in the rest of the genome,” he said. “But we don’t know what most of these regulatory genes do. It’s likely they are involved in diseases like schizophrenia, diabetes and many others.”

The CRISPR/Cas9 technology also allows researchers to disrupt multiple genes or regulatory sequences at once to determine their function and interactions. This kind of research is likely to uncover new targets for drugs, Botchan said.

“The Innovative Genomics Initiative is important not only for discovering new science and new therapeutics, but also for developing new tools for manipulating DNA,” Botchan said. “There are thousands of bacteria and Archaea out there with similar genome-editing systems, and we want to explore them too to find additional tools for genome engineering.”

Li Ka-shing, a Hong Kong-based, self-made businessman and philanthropist, has been a UC Berkeley benefactor in multiple areas. He provided a cornerstone gift of $40 million to establish the Li Ka Shing Center for Biomedical and Health Sciences, which opened its doors in 2012. To date, the Li Ka Shing Foundation has contributed more than $1.86 billion to healthcare and educational initiatives around the world.

RELATED INFORMATION

Innovative Genomics Initiative website
Jennifer Doudna’s website
Li Ka Shing Foundation website
A Powerful New Way to Edit DNA (3/4/14 New York Times)
Crispr Goes Global

Categories: Health & medicine, News, Press Release, Research, Science
Tags: genetic engineering, genetics, innovation

SOURCE

http://newscenter.berkeley.edu/2014/03/18/new-dna-editing-technology-spawns-bold-uc-initiative/

 

 

Crispr Goes Global

March 18, 2014
By:
Wallace Ravven

 

The New York Times calls it “a scientific frenzy.” Science magazine dubbed it “red hot” — “The CRISPR Craze.”

It’s been less than two years since Berkeley biochemist Jennifer Doudna reported in Science a startlingly versatile strategy to precisely target and snip out DNA at multiple sites in the cells of microbes, plants and animals.

But since her landmark paper, more than 100 labs have already taken up the new genomic engineering technique to delete, add or suppress genes in fruit flies, mice, zebrafish and other animals widely used to model genetic function in human disease.

Jennifer Doudna in her lab. Photo: Roy Kaltschmidt
Last year, Doudna and her colleagues showed that this “molecular scissors” approach, known as CRISPR/Cas9, can be used with great precision to selectively disable or add several genes at once in human cells, offering a potent new tool to understand and treat complex genetic diseases.

Journal articles now appear almost weekly as researchers around the word apply the technique in basic and clinical research. Patents have been filed and licensed, and companies founded last year in Cambridge, London and Berkeley have begun zeroing in on agricultural, industrial and biomedical applications.

“I’ve never experienced anything like the pace of discovery before in my life,” Doudna says of the flurry of experimentation flowing from her 2012 paper co-authored with Emmanuelle Charpentier, now at the Helmholtz Centre for Infection Research in Germany.

The technology combines RNA molecules with an enzyme known as Cas9 to target specific DNA sequences. The enzyme cuts the DNA in a precise location, so that researchers can either knock out the gene’s activity or patch in a healthy gene.

Since every gene’s DNA has an RNA counterpart, virtually any gene can be targeted by using a specific RNA sequence. And since only one type of enzyme is needed, many genes can be edited at the same time. Last year, one researcher successfully modified five genes in experiments with mouse embryonic stem cells. If advanced to human cells, this could greatly boost the promise of therapy for diseases involving multiple genes.

“The CRISPR/Cas9 technology is a complete game changer,” said Jonathan Weissman, professor of cellular and molecular pharmacology at UCSF. “With CRISPR, we can now turn genes off or on at will” to study normal gene function and understand how genetic defects do their damage at the molecular level.

The new approach lies at the heart of the Innovative Genomics Institute (IGI), just announced by UC Berkeley and UCSF to develop genomic analysis to explore disease processes and generate new treatments. Doudna is the executive director and UCSF’s Jonathan Weissman is co-director of the new Institute.

A time to toast

On her office bookcase, flanked by molecular biology and biochemistry texts, stands a handsome bottle of Veuve Cliquot Brut champagne wrapped in golden ribbon.

“It’s for the Lurie Prize,” she says simply — the prestigious Lurie Prize in the Biomedical Sciences, awarded last month by the Foundation for the National Institutes of Health in recognition of her discovery and the research leading up to it.

“It’s an honor to be recognized by my colleagues,” she says. “The prize really recognizes so many people who have worked in my lab. An award like this honors a body of work contributed by many researchers.” Doudna is a professor of biophysics, biochemistry and structural biology at Berkeley.

Molecular scissors: A new DNA-editing strategy aims to disable harmful genes and restore normal function. (Video and voiceover: Janet Iwasa.)
Doudna, Charpentier and their colleagues devised the editing strategy by manipulating an immune defense system used by bacteria against viral attack. The surprisingly sophisticated microbial defense was identified less than ten years ago. Researchers discovered that when a bacterium is invaded by a virus, it “saves” a snippet of the viral DNA – called a spacer — and inserts it into its own DNA.

If the microbe encounters the same virus again, it can convert the original viral spacer DNA into RNA. The RNA then essentially guides the Cas9 enzyme to snip the matching stretch of DNA in the new invader, disabling the virus.

Ultimately, the bacterial genome becomes studded with the spacers from different viruses the microbe has encountered — a virtual “mug shot” of invaders, as one observer called it.

Doudna began studying the bacteria’s capacity to edit viral genes in 2006, and eventually realized that its specificity might be exploited to cut and paste defective human genes. In 2012, she and Charpentier teased apart some of the key molecular mechanics of the microbial defense process.

Just a few months later, along with postdoc Martin Jinek, they reported their success developing a streamlined version of the bacterial editing process. It now allows a “single-guide RNA” to escort the Cas9 enzyme to the target gene, where it can be cut to disable it or to insert a healthy gene.

“Here we have a single protein that can be reprogrammed to work with any RNA sequence to edit selected genes,” Doudna explains. “I think that’s why we’re seeing such an explosion. It’s so accessible, inexpensive and it works very efficiently.”

CRISPR/Cas9 is simpler, quicker, more precise and versatile than current genomic engineering techniques — a kind of one-stop genomic editing shop.

Doudna calls her team’s discovery “a triumph of basic science.”

“A reporter for 60 Minutes was interviewing me last week and was asking me if I set out to discover a better genomics technology. We were actually studying the bacterial immune system to find out how it works. It was only through the process of discovery – of basic research — that we found something very useful for genomic engineering.”

Her lab continues to probe the molecular mechanics underlying the bacterial system and to refine the innovations derived from it. She and Berkeley’s Eva Nogales, professor of molecular biology and biochemistry, recently used x-ray crystallography and electron microscopy to determine key structures of the RNA and enzyme that team up in the bacterial gene editing system.

As recently as March 6, in the cover article in Nature, Doudna further clarified how the RNA-enzyme complex recognizes its gene target, providing more detail to help expand the CRISPR technique or improve its efficiency.

Doudna thinks advanced genomic engineering techniques like the one she developed will first aid research and treatment “ex vivo” — withdrawing diseased cells in human blood, restoring genetic defects and then introducing them back into the patient. Other genomic strategies are already being tested in this way in clinical trials to treat sickle cell anemia and HIV.

She expects the CRISPR/Cas9 approach to quickly accelerate progress toward treatments.

“I wouldn’t have said this even six months ago, but I think we will see clinical applications with this technology. I’d be honored and excited if our work leads to new treatments to help people’s lives.”

Maybe then she’ll open that bottle of champagne.

 

RELATED INFORMATION – See links ABOVE

New DNA-editing technology spawns bold UC initiative (3/18/14 UC Berkeley News Center)
Innovative Genomics Initiative website
Jennifer Doudna’s website
A Powerful New Way to Edit DNA (3/4/14 New York Times)

SOURCE

http://vcresearch.berkeley.edu/news/profile/doudna_jennifer