Targeting Genes to Understand Behavior
Dr. Mario Capecchi developed the revolutionary technique of gene targeting. (Courtesy of Eccles Institute of Human Genetics)
Physical attributes like hair color and skin tone can be traced to the expression of certain genes in our DNA. But, what about behavior? As reporter Sheri Quinn finds, researchers at the University of Utah may have discovered a genetic link to obsessive compulsive disorder, based on the work of this year’s Nobel Prize for Medicine winner, Dr. Mario Capecchi.
CURWOOD: It’s Living on Earth. I’m Steve Curwood. Amid the flood of this year’s Nobel Prize announcements, we noticed that Mario Capecchi was honored with the prize in medicine for his work on genetics. Dr. Capecchi was the subject of a piece by Sheri Quinn, which Living on Earth originally broadcast in 2005. We thought we’d bring it to you today to give you insight into the work the Nobel committee has decided to recognize.
The story tells of the technique called gene targeting, developed by Mario Capecchi in the late 1980s. The technique lets scientists find specific genes and change them within living mice. And as reporter Sheri Quinn discovered, this breakthrough has led researchers at the University of Utah to engineer a mouse in a way that may help us understand how genes may be tied directly to certain human behaviors.
QUINN: Christina Pearson is paying close attention to a certain group of genetically engineered mice at the University of Utah. She believes discoveries recently made there might change her life.
PEARSON: When I would pull my hair I would feel for a certain texture, I would feel for a certain sensation, a certain type of hair and then when I found the one that worked, it was if I had found gold and my nervous system would just light up.
QUINN: Pearson has trichotillomania. It's part of a spectrum that includes obsessive compulsive disorder, or OCD. Those afflicted are obsessed with pulling their hair out. But Pearson thinks this behavior is part of her inner core, locked into every cell of her body.
PEARSON: The urge to pull my hair was as strong as the urge to breathe. It felt like if I didn't pull my hair that I was suffocating. It was as if I was in a pool of water drowning, and struggling for air. I tried drinking myself into black outs because I found if I could black out and fall asleep, I wouldn't pull my hair. If we could develop an animal model it might helps us make sense and come up with treatments for human beings so they don't have to go through the 30 years of hell that I went through.
QUINN: Researchers at the University of Utah might just have such a model. But in order to understand why this work is happening here, we have to understand the work of a World War II refugee who became an American scientist. Mario Capecchi was born in Verona, Italy in 1937. When he was four, his mother was sent to the concentration camp Dachau for posting anti-fascist pamphlets. Capecchi survived by begging and stealing. Hunger, he says, helped form him.
CAPECCHI: If you are going to survive, things aren't going to work out every time. I mean, you go after a certain source of food and sometimes things don't work out and you don't get food that time and so then you have to persist and try and try again. You have to set your own inner determination—that is to be able to go after things—and that's sort of a doggedness that is important also for survival.
QUINN: Capecchi's mother was released from Dachau five years later. She searched for her now nine-year old son for over a year and found him ill with typhoid in an orphanage hospital. A few days later she brought him to the United States and Capecchi began to thrive. He grew up on a Quaker commune then went to Harvard where he eventually came to know the famous biologist James Watson, the man who together with Francis Crick had discovered the structure of DNA.
CAPECCHI: If you work in a field where lots and lots of people are working in that particular area then it does not make a big difference whether you do it or you don't do it. That science will be done. And I'd rather work on something that I feel I can uniquely contribute to.
QUINN: Capecchi taught at Harvard Medical School. But in 1973, he moved to the University of Utah. Colleagues thought he was crazy to leave Harvard. But the University of Utah had begun to build a reputation as a goldmine for human geneticists, thanks to the Church of Jesus Christ of Latter Day Saints, or Mormon Church, which keeps detailed genealogical records of its large families. At the University of Utah Capecchi spent a decade developing gene targeting. Scientists already knew how to insert altered DNA into cells. But out of thousands of cells, typically only a few will incorporate that altered DNA. The challenge was to identify which ones.
CAPECCHI: And so, if that could happen then that would allow us essentially the ability to change any gene we wanted in any way conceivable.
QUINN: Bob Horvitz is a Nobel-winning MIT biologist who is well acquainted with Capecchi's work.
HORVITZ: With Mario there is now a technology that allows the analysis of any gene in the genome. And it is the difference between night and day. No, it is much more than that. It's truly a revolution. It has led to kinds of experimentation that would have been unthinkable not very many years ago.
[SCRATCHY, SCREECHY SOUND]
QUINN: This is the sound of a tiny mouse embryo, the size of a grain of rice. Once scientists see which mouse cells have taken up the new gene, they place them into an embryo that will continue to grow into a mouse. They are called knockout mice because a gene has been knocked out and replaced. With a bit of luck, when they grow up, some of these knock out mice will transmit the new gene to their offspring.
QUINN: Capecchi's 13,000 mice are kept in a facility called the mouse house. They're cared for by a crew of biologists, former veterinary techs and pet store workers. Fred Beasley and Adine Marston often witness strange grooming behavior, and they too wonder what the research could reveal about ourselves.
FRED: Some mice like to groom themselves in interesting ways, make neat little patterns on their fur.
JUNE: Mmm Hmm. I had a cage where 11 other mice had a little rainbow shape above their left eye, every single one of them except for the one that was doing the grooming.
QUINN: Watching mice grooming. It's hard to imagine that a single gene could control such a complex behavior. But geneticist Joy Greer, a former graduate student in Capecchi's lab, replaced a normal copy of a gene called HOXB8 with a defective one. She was expecting to study limb deformities. Instead, she noticed the mice started grooming to the extreme. They stayed awake to do it. It looked to her like a form of OCD, obsessive compulsive disorder.
GREER: Oh, it was totally unexpected. Basically, I noticed that these mice had these huge bald patches and I had to find out why and while I was analyzing the video tapes it became very clear that what was happening was that the mice were removing their hair while they were grooming themselves.
QUINN: HOXB8 is a member of a large family of genes, collectively called the HOX genes, which are mostly known for their role in designing the general body plan—from flies to humans. So finding that a HOX gene could be involved in a behavior was a thrilling discovery.
GREER: And this, as far as I'm aware, is the only HOX gene that has been implicated in behavior.
QUINN: It's one thing to make comparisons between mice and humans when studying disease. But studying mouse genes to understand human behavioral disorders is new.
GREER: I think that these animals could provide a good animal model of repetitive behaviors. Whether or not it will be directly linked to obsessive compulsive disorder still remains to be seen.
QUINN: Since mice and humans have nearly identical genes, Greer and Mario Capecchi are now looking at people with the hair-pulling disorder to see if they can find the same gene defect they found in mice. It's unclear how common trichotillomania is, but it's not rare. It seems to cluster in families. Christina Pearson says most hair pullers aren't aware of it in their family history.
PEARSON: The problem with a disorder like this is that if your great grandmother had trichotillomania you probably wouldn't know it because it's still hard for people to talk about today.
QUINN: In the 1970s, when sufferers dared to seek help, doctors viewed them as psychotic. But now Christina Pearson is proud to be director of the Trichotillomania Learning Center with 32,000 hair-pulling members.
PEARSON: It is amazing the stories that I've heard. One father said to me, he said, ‘you know I was beating my daughter with a belt and she was lying there on the floor and saying, ‘Daddy, it won't help, it won't help.’ I've talked to the mothers of young women who have killed themselves, okay, put guns in their mouths because they could get no help.
QUINN: It's now been several years since Pearson has pulled her hair out. She uses medicine, therapy and group support to fight the urge.
Since the late 1980s, gene targeting has spread to thousands of laboratories throughout the world. Scientists use it to investigate the mechanisms that instruct a gene to make a limb or a wing, a hand or a paw, a behavior, even a memory. For Living on Earth, I'm Sheri Quinn in Salt Lake City, Utah.
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