Fixing the Code: Genetically Engineering Your DNA to Cure Disease

ARCHIVAL (ABC NEWS, GOOD MORNING AMERICA, 8-3-17):
DIANE MACEDO: This is a milestone that could one day erase hereditary conditions.

MATTHEW PORTEUS: Just like you can change a single letter in a Word document, now we can change single letters in the DNA.

ARCHIVAL (CBS, 12-1-15):
JERICKA DUNCAN: It’s called CRISPR.

ARCHIVAL (CBS NEWS, 11-30-15):
JENNIFER DOUDNA: Clustered regularly interspaced short palindromic repeats.

NARRATION: The new gene editing platform, CRISPR, is generating a lot of excitement. But this isn’t the first time scientists have tried to fix the genes that make us sick. It started over 30 years ago.

ARCHIVAL (CBS NEWS, EVENING NEWS, 4-1-94):
CONNIE CHUNG: Gene Therapy.

ARCHIVAL (NBC, NIGHTLY NEWS, 9-4-85):
TOM BROKAW: Medicine’s new frontier.

ASHANTHI DESILVA: It was the first time they were going to be altering a human’s DNA.

JAMES WILSON: The expectations were crazy.

TEXT ON SCREEN: RETRO REPORT & STAT PRESENT:

FIXING THE CODE
WITH SPECIAL CORRESPONDENT CARL ZIMMER

PIERCETON CHARLES: I like reading as well as playing chess, and I like to go to different places. I want to make people more aware about sickle-cell.

NARRATION: Pierceton Charles has sickle-cell anemia. It’s a painful genetic disease that distorts his red blood cells so that they can’t deliver oxygen to his organs.

TAMMY SALAMI 9PIERCETON CHARLES’S MOTHER): His first blood transfusion was seven months old. He had a stroke. He lost his spleen, and shortly thereafter the gallbladder. He’s had a total of 48 hospitalizations.

NARRATION: He’s one of about 100,000 people in the United States with sickle-cell. Most are African American, and on average live to their mid-40s.

ARCHIVAL (ASSOCIATED PRESS, MAY 1972):
YANCY YANK DURHAM: There is no definite treatment for sickle-cell.

NARRATION: Sickle-cell was one of the first hereditary diseases to have its gene mutation, or sequence change, identified.

MATTHEW PORTEUS (STANFORD UNIVERSITY): Ever since I met my first patient with sickle cell disease that’s been really my challenge to say, let’s find a cure that is based on the cause. We’ve known the sequence change since the early 1970s. But I’ll point out, that’s over 40 years ago and we don’t have any therapy based on knowing that sequence change.

NARRATION: So, in his lab at Stanford University, Matthew Porteus is trying to repair the gene that causes sickle-cell.

MATTHEW PORTEUS (IN LAB): So what we have to do is edit some blood stem cells.

NARRATION: He’s using a new gene editing technology called CRISPR CAS-9.

MATTHEW PORTEUS (IN LAB): Ready to electroporate.

NARRATION: It works like a genetic scissors—cutting out and replacing a gene’s mis-spelled bits ofDNA.

MATTHEW PORTEUS: We can change single letters in the DNA and convert the disease-causing variant to a non-disease causing variant.

MATTHEW PORTEUS (IN LAB): The cells that have been edited are these bright green cells.

NARRATION: Pierceton needs monthly treatments to replace his sickle shaped red blood cells with normal cells. He donates the old blood for Porteus’s research…Which he hopes could someday help him.

PIERCETON CHARLES: They’re attempting to modify the genes so they can cure sickle-cell. I think that it’s pretty amazing.

NARRATION: Porteus has applied for approval for a clinical trial.

MATTHEW PORTEUS: We think these cells represent cures for patients. They do everything that they’re supposed to do. So that gives us confidence that it’s worth trying in a human patient.

TAMMY SALAMI: We have our fingers crossed. We’re excited.

NARRATION: But along with CRISPR’s promise come fears about its accuracy…

MATTHEW PORTEUS: A DNA break could be dangerous. It could cause other mutations.

NARRATION:…and its potential use editing genes not just in patients, but in embryos, which would impact future generations.

ARCHIVAL (CBS NEWS, 11-30-14):
JENNIFER DOUDNA: We’re talking about something that would affect human evolution.

ARCHIVAL (NBC):
NEWS REPORT: Critics worry CRISPR could be used to create designer babies.

ARCHIVAL (CBS NEWS, THIS MORNING, 8-3- 17):
DAVID AGUS: You may want to make a baby taller, faster, smarter.

MATTHEW PORTEUS: The power of this new CRISPR technology has resurfaced questions that people have been thinking about for 40 years. If we had a tool that would allow you to change the DNA that would then be passed along to next generations, is that something we should or shouldn’t do?

NARRATION: Many of the questions, and the controversy, remind Ashanti DeSilva of her own experience with a different kind of genetic engineering, called gene therapy, nearly 30 years ago.

ARCHIVAL (NOVA, CHILDREN BY DESIGN, 2-9-93):
ADULT: Ashanti, Ashanti, come baby.

ASHANTHI DESILVA (GENE THERAPY PATIENT): When I was born, the umbilical cord was infected and I would turn blue a lot.

NARRATION: She was born with ADA Deficiency, a rare genetic disorder that crippled her immune system. Although there was no cure, her doctor had an idea…. Though it could take a lifetime.

ASHANTHI DESILVA: He said, there’s this potential trial going on at the National Institutes of Health. Let me send her blood.

ARCHIVAL (NOVA, CHILDREN BY DESIGN 2-9-93):
VAN DESILVA: And he told me, Mrs. DeSilva, this is for possible gene therapy when your daughter is 60 years old. And I thought, oh, how wonderful!

NARRATION: Unlike CRISPR, which repairs genes, gene therapy would send in an extra healthy gene to do the work of the defective one. But before Ashanti could be treated, there were scientific – and ethical –hurdles to overcome.

ASHANTHI DESILVA: They had told my parents there would be risks of leukemia, death. It was the first time they were going to be altering a human’s, you know, DNA. We all went to the NIH. And they actually didn’t have FDA approval yet. It was really up until that day, they were waiting for the phone call.

ARCHIVAL (EXHIBITION VIDEO):
VAN DESILVA (READING OUT LOUD): This is the 14th of September. “A great day for the world, a great day for medicine. Gene therapy has been approved.”
ASHANTHI DESILVA (CONTINUING READING): “Our daughter is the first patient in the world to receive gene therapy.”

ASHANTHI DESILVA: They had taken my cells and injected the vector with the corrected gene into my cells. They transferred those cells back to me to see if they would give me a new immune system….My parents did receive death threats, because there was this idea that altering someone’s DNA is playing God.

ARCHIVAL (CBS, EVENING NEWS, 9-14-90):
DAN RATHER: There was a historic medical first today…

ARCHIVAL (ABC, WORLD NEWS TONIGHT, 9-14-90):
PETER JENNINGS: Genetic engineering as a potential way to cure an illness in a human being.

NARRATION: The gene therapy revolution seemed to come almost instantly, fueled in part by discoveries from the Human Genome Project, the national effort to find and sequence all human genes.

ARCHIVAL (NBC NEWS, 1-1-97):
FRANCIS COLLINS: Payoff has already begun by the discovery of a long list of genes.

NARRATION: As researchers found more and more of the genes that cause hereditary diseases….

ARCHIVAL (ABC, 8-24-89):
CAROLE SIMPSON: It is only a step toward eventual treatment, but it is a significant one.

NARRATION: …news stories regularly touted gene therapy as the potential cure.

ARCHIVAL (CBS, EVENING NEWS, 4-1-94):
CONNIE CHUNG: Gene therapy to improve a potentially deadly condition.

ARCHIVAL (NBC, NIGHTLY NEWS, 8-29-90)
TOM BROKAW: Such as muscular dystrophy, sickle-cell anemia.

ARCHIVAL (CBS, 5-16-93):
BILL WHITAKER: And possibly even AIDS.

JAMES WILSON: We presumed as a society that if we had the gene we’d be able to then quickly move to a treatment. The expectations were crazy.

NARRATION: James Wilson was one of gene therapy’s pioneers.

ARCHIVAL (NBC, 9-20-90):
ROBERT BAZELL: In these human cells he was able to replace the defective cystic fibrosis gene with a normal gene.

NARRATION: In 1999, at the University of Pennsylvania, he began testing a gene therapy for a rare, liver disease that mostly affects boys.

JAMES WILSON: Upon their first meal they develop a coma. And there’s fifty percent mortality as a result of that.

NARRATION: To deliver the healthy gene into the patient’s body, Wilson used a specially prepared virus, called a vector.

JAMES WILSON: A young man by the name of Jesse Gelsinger received the vector. Things went terribly wrong. He mounted this enormous immune response that led to his death.

JAMES WILSON: I had spent almost ten years trying to make it safe. That’s probably irrelevant. What is relevant is the young man died.

NARRATION: After hundreds of gene therapy experiments, Gelsinger’s death came as an enormous shock.

ARCHIVAL (CBS NEWS, 11-11-99):
WYATT ANDREWS: Every researcher in America was reminded this is messing with the code of life.

ARCHIVAL (CONGRESSIONAL SUBCOMMITTEE ON PUBLIC HEALTH, 2-2-00):
SENATOR BILL FRIST: Why aren’t they reporting these?

NARRATION: Congress held hearings and federal agencies investigated.

ARCHIVAL (CBS NEWS, 2-2-00):
JERRY BOWEN: The FDA says Penn researchers failed to report previous toxic reactions in humans, and the death of test animals in similar experiments.

ARCHIVAL (CBS NEWS, 2-2-00):
PAUL GELSINGER (JESSE GELSINGER’S FATHER): I wasn’t given all the information. And some of the information I was given was not true.

NARRATION: Penn’s program was shut down, and Wilson banned from clinical trials for five years. Then, investigators began uncovering problems at other institutions around the country.

ARCHIVAL (CBS NEWS, 2-2-00):
DAN RATHER: Several others died, hundreds more had side effects, but researchers didn’t tell federal health officials.

NARRATION: Gene therapy also faced scientific setbacks.

ARCHIVAL (ABC NEWS, 12-8-99):
JOHN MCKENZIE: A cystic fibrosis treatment, a muscular dystrophy treatment, a brain cancer treatment: all failed. To this date, gene therapy has yet to cure anyone.

NARRATION: Including Ashanti DeSilva. The benefits from her gene therapy diminished with time, so she still needed regular enzyme injections to support her immune system.

ASHANTI DESILVA: Gene therapy, at least initially, did give me that that I needed. But it wasn’t what they could call a cure.

JAMES WILSON: The tragic death of Jesse Gelsinger was one of several events that led to a precipitous decline in the support for this field. Support just evaporated after that.

NARRATION: It seemed that gene therapy’s prospects were over, but a small group of researchers continued on.

JAMES WILSON: Our first responsibility to everyone including Jesse Gelsinger was to try to figure out what happened and why. We learned that the problem was immune response not to the gene, but to the delivery vehicle itself.

NARRATION: Wilson returned to the lab, hoping to make safer vectors.

JAMES WILSON: And the vectors that we generated seem not only really safe but were much more efficient. I knew that they would be a game changer. We just distributed these to my colleagues. And I hoped that there would get traction. It
didn’t take long to discover them. It took a lot longer for there to get traction.

NARRATION: Almost 20 years later, gene therapy has been experiencing a revival and is showing promise for conditions ranging from hemophilia to Parkinson’s disease.

Peter McConnell has a genetic eye disease called choroideremia.

PETER MCCONNELL: It leads to tunnel vision, and in some cases blindness.

NARRATION: He’s the father of two young children, and hoping to see them grow up, joined a clinical trial at the University of Pennsylvania.

PETER MCCONNELL (GENE THERAPY PATIENT): When I initially was approved, I didn’t think twice about it. I was just going to do it. They take a genetically mutated virus and they inject it in the back of your retina. The goal isn’t to miraculously restore our eyesight. What they would consider successful was stopping the eye from progressing and getting worse. I’d be more than happy if that was the case.

ARCHIVAL (NBC, NIGHTLY NEWS, 8-30-17):
LESTER HOLT: For the first time ever, the FDA has just approved a gene therapy treatment.

NARRATION: The first gene therapy was recently approved in the United States for a form of childhood leukemia. But because gene therapy doesn’t actually fix broken genes, no one knows how long it’s benefits will last.

JAMES WILSON: What we’re asking to do here is to cure diseases and whether we can ultimately achieve a permanent genetic graft that reverses their disease forever, we’ll see.

NARRATION: That hope– for a permanent cure —is why so many are excited about CRISPR.

ARCHIVAL (CBS, 8-3-17):
DAVID AGUS: Wow. Human genetic engineering yesterday was science fiction, and today it’s reality.

ARCHIVAL (ABC7):_
JESSICA CASTRO: Get this… it could eliminate chemotherapy!

ARCHIVAL (CBS, THIS MORNING, 11-30-15):
NORAH O`DONNELL: It’s fast, cheap and can cut and paste genetic code with great precision.

MATTHEW PORTEUS: All the results say that it is working. The ultimate test is going to be those first few patients, they’re the ones taking all the risks.

NARRATION: Patients who take risks like Ashanthi DeSilva did with gene therapy. She’s grateful for the treatment she got, but regrets gene therapy’s long hiatus.

ASHANTHI DESILVA: When you’re doing something like altering someone’s DNA, there are risks. But it gave me life. I was able to complete my masters, get married, you know have a nice home life, so, I’ve been very lucky.

NARRATION: As for James Wilson, he is now working with CRISPR, but remains mindful of the lessons from gene therapy’s early days.

JAMES WILSON: That period of exuberance early on in the development of a new novel cutting edge technology, it’s very easy to get caught up into that. The reality is, is this is still science. And these are still experiments and we are still learning.

(END)