Jennifer Doudna

Three UC’s Join Forces to Launch CRISPR Clinical Trial Targeting Sickle Cell Disease

/ Kevin McCormack / Leave a comment
Sickle shaped red blood cells

The University of California, San Francisco (UCSF), in collaboration with UC Berkeley (UCB) and UC Los Angeles (UCLA), have been given permission by the US Food and Drug Administration (FDA) to launch a first-in-human clinical trial using CRISPR technology as a gene-editing technique to cure Sickle Cell Disease.

This research has been funded by CIRM from the early stages and, in a co-funding partnership with theNational Heart, Lung, and Blood Institute under the Cure Sickle Cell initiatve, CIRM supported the work that allowed this program to gain FDA permission to proceed into clinical trials.    

Sickle Cell Disease is a blood disorder that affects around 100,000 people, mostly Black and Latinx people in the US. It is caused by a single genetic mutation that results in the production of “sickle” shaped red blood cells. Normal red blood cells are round and smooth and flow easily through blood vessels. But the sickle-shaped ones are rigid and brittle and clump together, clogging vessels and causing painful crisis episodes, recurrent hospitalization, multi-organ damage and mini-strokes.    

The three UC’s have combined their respective expertise to bring this program forward.

The CRISPR-Cas9 technology was developed by UC Berkeley’s Nobel laureate Jennifer Doudna, PhD. UCLA is a collaborating site, with expertise in genetic analysis and cell manufacturing and UCSF Benioff Children’s Hospital Oakland is the lead clinical center, leveraging its renowned expertise in cord blood and marrow transplantation and in gene therapy for sickle cell disease.

The approach involves retrieving blood stem cells from the patient and, using a technique involving electrical pulses, these cells are treated to correct the mutation using CRISPR technology. The corrected cells will then be transplanted back into the patient.

Dr. Mark Walters

In a news release, UCSF’s Dr. Mark Walters, the principal investigator of the project, says using this new gene-editing approach could be a game-changer. “This therapy has the potential to transform sickle cell disease care by producing an accessible, curative treatment that is safer than the current therapy of stem cell transplant from a healthy bone marrow donor. If this is successfully applied in young patients, it has the potential to prevent irreversible complications of the disease. Based on our experience with bone marrow transplants, we predict that correcting 20% of the genes should be sufficient to out-compete the native sickle cells and have a strong clinical benefit.”

Dr. Maria T. Millan, President & CEO of CIRM, said this collaborative approach can be a model for tackling other diseases. “When we entered into our partnership with the NHLBI we hoped that combining our resources and expertise could accelerate the development of cell and gene therapies for SCD. And now to see these three UC institutions collaborating on bringing this therapy to patients is truly exciting and highlights how working together we can achieve far more than just operating individually.”

The 4-year study will include six adults and three adolescents with severe sickle cell disease. It is planned to begin this summer in Oakland and Los Angeles.

The three UCs combined to produce a video to accompany news about the trial. Here it is:

Women who have changed, and are changing, the world

/ Kevin McCormack / Leave a comment

The problem with trying to write about something like Women’s History Month is where do you start? Even if you narrow it down to women in science the list is vast.

Marie Curie

I suppose you could always start with Maria Salomea Skłodowska who is better known as Marie Curie. She not only discovered radium and polonium, but she was also the first woman to win a Nobel Prize (in Physics). When she later won another Nobel (in Chemistry) she became the first person ever to win two Nobels and is still the only person ever to win in two different fields. Not a bad place to start.

Agnes Pockels

Or how about Agnes Pockels (1862–1935). Even as a child Agnes was fascinated by science but, in Germany at the time, women were not allowed to attend university. So, she depended on her younger brother to send her his physics textbooks when he was finished with them. Agnes studied at home while taking care of her elderly parents. Doing the dishes  Agnes noticed how oils and soaps could impact the surface tension of water. So, she invented a method of measuring that surface tension. She wrote a paper about her findings that was published in Nature, and went on to become a highly respected and honored pioneer in the field.

Jennifer Doudna (left) and Emmanuelle Charpentier: Photo courtesy Nature

Fast forward to today we could certainly do worse than profile the two women who won the 2020 Nobel Prize in Chemistry for their work with the gene-editing tool CRISPR-Cas9; Jennifer Doudna at the University of California, Berkeley, and Emmanuelle Charpentier at the Max Planck Unit for the Science of Pathogens in Berlin. Their pioneering work showed how you could use CRISPR  to make precise edits in genes, creating the possibility of using it to edit human genes to eliminate or cure diseases. In fact, some CIRM-funded research is already using this approach to try and cure sickle cell disease.

In awarding the Nobel to Charpentier and Doudna, Pernilla Wittung Stafshede, a biophysical chemist and member of the Nobel chemistry committee, said: “The ability to cut DNA where you want has revolutionized the life sciences. The ‘genetic scissors’ were discovered just eight years ago but have already benefited humankind greatly.”

Barbara McClintock: Photo courtesy Brittanica

Appropriately enough none of that work would have been possible without the pioneering work of another woman, Barbara McClintock. She dedicated her career to studying the genetics of corn and developed a technique that enabled her to identify individual chromosomes in different strains of corn.

At the time it was thought that genes were stable and were arranged in a linear fashion on chromosomes, like beads on a string. McClintock’s work showed that genes could be mobile, changing position and altering the work of other genes. It took a long time before the scientific world caught up with her and realized she was right. But in 1983 she was awarded the Nobel Prize in Medicine for her work.

Katherine Johnson at her desk at Langley Research Center: Photo courtesy NASA /AFP

Katherine Johnson is another brilliant mind whose recognition came later in life. But when it did, it made her a movie star. Kind of. Johnson was a mathematician, a “computer” in the parlance of the time. She did calculations by hand, enabling NASA to safely launch and recover astronauts in the early years of the space race.

Johnson and the other Black “computers” were segregated from their white colleagues until the last 1950’s, when signs dictating which restrooms and drinking fountains they could use were removed. She was so highly regarded that when John Glenn was preparing for the flight that would make him the first American to orbit the earth he asked for her to manually check the calculations a computer had made. He trusted her far more than any machine.

Johnson and her co-workers were overlooked until the 2016 movie “Hidden Figures” brought their story to life. She was also awarded the Presidential Medal of Freedom, America’s highest civilian honor, by President Obama.

There are so many extraordinary women scientists we could talk about who have made history. But we should also remind ourselves that we are surrounded by remarkable women right now, women who are making history in their own way, even if we don’t recognized it at the moment. Researchers that CIRM funds, Dr. Catriona Jamieson at UC San Diego, Dr. Jan Nolta at UC Davis, Dr. Jane Lebkowski with Regenerative Patch technologies and so many others. They’re all helping to change the world. We just don’t know it yet.

If you would like to learn about other women who have made extraordinary contributions to science you can read about them here and here and here.

Brave new world or dark threatening future: a clear-eyed look at genome editing and what it means for humanity

/ Kevin McCormack / Leave a comment

Frankenstein

   Is this the face of the future?

“Have you ever wished that there were something different about yourself? Maybe you imagined yourself taller, thinner or stronger? Smarter? More attractive? Healthier?”

That’s the question posed by UC Davis stem cell researcher (and CIRM grantee) Paul Knoepfler at the start of his intriguing new book ‘GMO Sapiens: The Life-Changing Science of Designer Babies’.

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You can find GMO Sapiens on Amazon.com

The book is a fascinating, and highly readable, and takes a unique look at the dramatic advances in technology that allow us to edit the human genome in ways that could allow us to do more than just create “designer babies”, it could ultimately help us change the definition of what it means to be human.

Paul begins by looking at the temptation to use technologies like CRISPR (we have blogged about this here), to genetically edit or alter human embryos so that the resulting child is enhanced in some ways. It could be that the editing is used to remove a genetic mutation that could cause a deadly disease (such as the BRCA1 gene that puts women at increased risk of breast and ovarian cancer) or it could be that the technique is used to give a baby blue eyes, to make it taller, more athletic, or to simply eliminate male pattern baldness later in life.

Paul says those latter examples are not as ridiculous as they sound:

Paul Knoepfler

Paul Knoepfler

“If you think these ideas sound far-fetched, consider that Americans alone spend tens of billions of dollars each year on plastic surgery procedures and creams to try to achieve these kinds of goals. Some of the time elective cosmetic surgery is done on children. In the future, we might have “cosmetic genetic surgeons” who do “surgery” on our family’s genes for cosmetic reasons. In other countries the sensibilities and cultural expectations could lead to other kinds of genetic modifications of humans for “enhancements”.

While the technology that enables us to do this is new, the ideas behind why we would want to do this are far from new. Paul delves into those ideas including a look at the growth of the eugenics movement in the late 19th and early 20th century advocating the improvement of human genetic traits through higher reproductive rates for people considered “superior”. And there was a darker side to the movement:

“Indiana had instituted the first law for sterilization of “inferior” people in the world in 1907. Astonishingly this state law and then similar laws (the original was revoked, but a new law was passed later) stayed on the books in that state until 1974.

This led to approximately 2,500 governmentally forced sterilizations. The poor, uneducated, people of color, Native Americans, and people with disabilities were disproportionately targeted.”

Paul explores the ethical and moral implications of changing our genetic code, changes that can then be passed on to future generations. While he understands the desire to use these technologies to create positive changes, he is also very clear in his concerns that we don’t yet have enough knowledge to be able to use them in a safe manner.

“CRISPR can literally re-write the genomic book inside of us. However, it remains unknown how often it might go to the wrong page or paragraph, so to speak, or stay on the right page, but make an undesired edit there.”

Tiny errors in editing the genome, particularly at such an early stage in an embryo’s development, could have profound and unintended consequences years down the road, resulting in physical or developmental problems we can’t anticipate or predict. For example, you might remove the susceptibility to one disease only to create an even larger problem, one that is now embedded in that person’s DNA and ready to be passed on to subsequent generations.

The book includes interviews with key figures in the field – scientists, bioethicists etc. – and covers a wide range of views of what we should do. For example, the Director of the US National Institutes of Health (NIH), Francis Collins, said that designer babies “make good Hollywood — and bad science,” while the Center for Genetics and Society has advocated for a moratorium on human genetic modification in the US.

In contrast, scientists such as Harvard professor George Church and CRISPR pioneer Jennifer Doudna of UC Berkeley, say we need to carefully explore how to harness the potential for these technologies.

For Church it is a matter of choice:

“The new technology enables parents to make choices about their children just as they might with Ritalin or cleft palate surgery to ‘improve’ behavior or appearance.”

For Doudna it’s acknowledging the fact that you can’t put the genie back in the bottle:

“There’s no way to unlearn what is learned. We can’t put this technology to bed. If a person has basic knowledge of molecular biology they can do it. It’s not realistic to think we can block it…We want to put out there the information that people would need to make an informed decision, to encourage appropriate research and discourage forging ahead with clinical applications that could be dangerous or raise ethical issues.”

The power of Paul’s book is that while it does not offer any easy answers, it does raise many important questions.

It’s a wonderfully well-written book that anyone can read, even someone like me who doesn’t have a science background. He does a good job of leading the reader through the development of these technologies (from the basic idea of genetically altering plants to make them disease resistant) to the portrayal of these concepts in literature (Frankenstein and Brave New World) to movies (Gattaca – 4 stars on Rotten Tomatoes  a great film if you haven’t already seen it).

It’s clear where Paul stands on the issue; he believes there should be a moratorium on human genetic modification until we have a much deeper understanding of the science behind it, and the ethics and morality underpinning it:

“This is a very exciting time to be alive and we should be open to embracing change, but not blindly or in a rush. Armed with information and passion, we can have a major, positive impact on how this biotech revolution unfolds and impacts humanity.”

By the way, Paul also has one of the most widely read blogs about stem cells, where you can read more about his thoughts on CRISPR and other topics.

 

CRISPR cluster: How the media spotlight is focusing on gene editing tool

/ Kevin McCormack / Leave a comment

Illustration by Ashley Mackenzie: from New York Times Sunday Magazine

Illustration by Ashley Mackenzie: from New York Times Sunday Magazine

Getting in-depth stories about science in general, and regenerative medicine in particular, into the mainstream media is becoming increasingly hard these days. So when you get one major media outlet doing a really long, thoughtful piece about a potential game-changing gene-editing technology it’s good news. But when you get three major media outlets, all reporting on the same technology, all in the space of less than one week, and all devoting lots of words to the pieces, then it’s really a cause for celebration.

That’s what happened in the last few days with features on the gene editing technology CRISPR in the New York Times Sunday Magazine,  the New Yorker Magazine,  and STAT, a new online health and life-sciences publication produced by the Boston Globe.

Making the story personal

Feng Zhang: photo courtesy of the Broad Institute

Feng Zhang: photo courtesy of the Broad Institute

Each takes a similar approach, focusing on the individuals behind the new approach – Feng Zhang at Harvard/MIT and Jennifer Doudna at the University of California, Berkeley. The fact that the two are involved in a fight over patent rights for the process adds an extra element of friction to a story that already has more than its share of drama.

In the New Yorker, Michael Specter neatly summarizes why so many people are excited about this technology:

“With CRISPR, scientists can change, delete, and replace genes in any animal, including us. Working mostly with mice, researchers have already deployed the tool to correct the genetic errors responsible for sickle-cell anemia, muscular dystrophy, and the fundamental defect associated with cystic fibrosis. One group has replaced a mutation that causes cataracts; another has destroyed receptors that H.I.V. uses to infiltrate our immune system.”

Jennifer Doudna: Photo courtesy of iPSCell.com

Jennifer Doudna: Photo courtesy of iPSCell.com

Sharon Begley in STAT, writes that this discovery could bring cures to some of the deadliest health problems we face, from cancer to Alzheimer’s, but that it also comes with big ethical questions hanging over it:

“He (Zhang) has touched off a global furor over the possibility that a genetics tool he developed could usher in a dystopian age of designer babies.”

Jennifer Kahn in the New York Times Sunday Magazine follows up on that thought, writing about Doudna:

“But she also notes that the prospect of editing embryos so that they don’t carry disease-causing genes goes to the heart of CRISPR’s potential. She has received email from young women with the BRCA breast-cancer mutation, asking whether CRISPR could keep them from passing that mutation on to their children — not by selecting embryos in vitro, but by removing the mutation from the child’s genetic code altogether. ‘‘So at some point, you have to ask: What if we could rid a person’s germ line, and all their future generations, of that risk?’’ Doudna observed. ‘‘When does one risk outweigh another?’’

Each article makes for fascinating reading. Collectively they highlight why CRISPR is such a hot topic, on so many different levels, in science right now.

The topic is going to be the focus of a conference, featuring scientists from the US, Europe and China, being held at the National Academy of Sciences in Washington DC the first week of December.

CIRM is also getting involved in the debate and is holding a science-policy workshop on February 4th, 2016 in Los Angeles to consider the future use of genome editing technologies in studies sponsored by CIRM.