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A Gene for Fish Odor

  • By Ari Daniel Shapiro
  • Posted 03.22.12
  • NOVA

British scientists have developed a genetic test for a disorder that causes people to emit an unusual body odor: The gene causes sufferers to smell like rotten fish. For those who have been ostracized—shunned by friends and unable to hold jobs because they are perceived as unhygienic—the test offers some solace. But one patient says the genetic discovery has not changed his life as much as he had hoped for.

Listen to the story.

The discovery of a gene that explains an embarrassing body odor offers a little comfort to those who suffer.

Genetic tests allow doctors to diagnose disease and patients to glimpse their medical future, but the knowledge of what's in your DNA doesn't always help in the way one might hope. This is the story of one man and his unusual gene.

In a corner of his home in Carlisle, England, Grahame Lancaster keeps a box of framed photographs. He pulls one out. It shows 50 police officers arranged into rows. "That's me in the back row," he says. "The big lump. Bigger than everyone else there, I think."

They said he smelled like rotting fish.

He was only 22, but he was formidable—six-foot-four, 250 pounds, and confident. He served with the Greater Manchester Police. "My favorite times were nights," he says. "Catching criminals. I always used to pride myself on being able to catch most people."

Grahame Lancaster, center back row, with the Greater Manchester Police Enlarge Photo credit: Courtesy Greater Manchester Police

Aside from the paperwork, he loved the job. But a few years after that photograph was taken, he started getting odd remarks from his fellow officers.

They said he smelled like rotting fish.

Following His Nose

"I just thought it was maybe something I'd eaten, even though I was never a great fish-eating fan," he says. "So I couldn't really understand where it was coming from." One officer suggested the odor came from Lancaster's hair gel, but that didn't explain it.

The comments grew more frequent. Suspects told Lancaster that the interrogation room reeked of fish. Defense attorneys made comments too. So Lancaster went to see his doctor. "He basically said it was all in my head," Lancaster recalls. The doctor suggested he bathe with strong soap.

Lancaster began showering up to four times a day. He caked on the deodorant. But within 15 minutes of showering the comments would start again. The remarks became harder and harder to stomach.

"Because people make the comments, you then think that people who aren't making comments can still smell it, but they're not saying anything," he says. "So you then start to become paranoid."

A Genetic Discovery

Around that same time—in the late 1990s—British scientists discovered a gene that causes a rare condition called trimethylaminurea, or TMAU.

"TMAU is a disorder in which people are unable to complete the metabolism of a small molecule called trimethylamine," says one of the scientists, Elizabeth Shephard of University College London. "That small molecule is derived from the ordinary foodstuffs that we eat such as eggs, soya, meat."

Co-discovers of the TMAU gene, Elizabeth Shephard and Ian Phillips. Enlarge Photo credit: Courtesy Ari Daniel Shapiro

In most people, an enzyme breaks down trimethylamine in the liver, but people with TMAU excrete the molecule in their urine, breath, and sweat. And that molecule – trimethylamine – is what gives rotting fish its distinctive odor. In fact, TMAU is sometimes called fish odor syndrome.

"It's not your fault. It's not the fact that you're unhygienic."

TMAU can be triggered by liver or kidney disease, but it can also be hereditary – caused by FMO3, the gene Shephard discovered – although the symptoms may not appear until adulthood. The genetic form of the condition is rare, affecting perhaps one in 40,000 people.

In the case of Grahame Lancaster, a medical researcher recommended that he take a urine test to see if he had TMAU. It came back positive. Lancaster was relieved. "It's a definitive medical diagnosis that you've got something wrong with you," he says. "It's not your fault. It's not the fact that you're unhygienic."

Hope and Disappointment

Once Lancaster knew what was wrong with him, he set about trying to fix it. Doctors recommended he keep a diary to track what foods made the odor better or worse. It didn't help. Changes in what he ate didn't reduce the smell. He grew even more embarrassed and self-conscious. It "ruined the enjoyment of the job," he says. "It kind of destroyed it all for me."

The test that had given him the diagnosis had given him hope that things would change. When they didn't change, he spiraled into a severe depression. Lisa Claire Uren was Lancaster's girlfriend at the time. "He was quite hard to get along with, he just wasn't himself," she says. "And I just didn't know what to do—couldn't do anything, couldn't say the right thing. I couldn't see us ever coming through it, really."

Things fell apart for Lancaster at work, too. He lost focus. He went on medical leave for a year and then was discharged from the force. His career as a police officer was over—not because he smelled like fish, but because of the resulting depression.

Lancaster says part of what made things so difficult emotionally was that he assumed the discovery of the TMAU gene meant that a cure was right around the corner.

Yet with many inherited conditions, including TMAU, the discovery of the faulty gene has not led to a treatment or cure. The science has proved more complicated than many expected at the beginning of the genomics revolution.

"My main concern was whether I'd passed on the defect to Emma."

And there are additional obstacles for rare and non-life-threatening conditions like TMAU. Ian Phillips of Queen Mary, University of London—co-discoverer of the TMAU gene—says he can't convince funding agencies to invest in the research needed to develop a cure. "It's frustrating because, having identified the genetic basis of the disease, we are no longer able to follow that up in any meaningful way that would be of use for the patients," he says.

New Test, New Questions

Even without a cure, things improved for Grahame Lancaster. He gradually came to terms with his condition. He took up a more suitable career in information technology. (His new job has less stress and no physical demands, so he is less likely to sweat and produce the fish odor.) His relationship with Lisa improved, and they got married.

By this time, there was another test for TMAU—a genetic test that could identify the specific mutations that caused the disorder. The test could tell family members if they're likely to develop the condition, even if they don't currently show symptoms.

Lancaster now had a daughter, Emma, and was faced with a new decision about testing. "My main concern was whether I'd passed on the defect to Emma," he says. "If she's going to get it, I'd rather be pre-warned and pre-armed."

Grahame Lancaster with wife Lisa and daughter Emma. Enlarge Photo credit: Courtesy Ari Daniel Shapiro

Grahame and Lisa Lancaster decided to test Emma when she was a year old. It came back positive. Sort of. Emma had inherited a faulty copy of the gene from her father, and a somewhat faulty version from her mother. That means Emma may develop a mild form of TMAU later in life.

The test result caused Grahame and Lisa to confront a new set of questions. Should they tell Emma, even though she may never exhibit the condition? What good would the information do her?

It's similar to the dilemma many people face who've been tested for genes linked to diseases—like Alzheimer's—for which there is no good treatment or cure. If you find out you're at high risk, what do you do?

Grahame Lancaster realizes there's a big difference between dementia and the condition afflicting him, but he says TMAU is nothing to laugh at. "One of the most evocative things is your [sense of] smell," he says. "Sometimes you smell things and it brings back pleasant memories. I read in some article that the smell of rotten fish is one of the worst things you could ever smell. So it's just unfortunate that TMAU doesn't smell of roses."

Visit our friends at PRI's "The World" for a behind-the-scenes interview with reporter Ari Daniel Shapiro, and to find other stories about personal genetic testing. For more information on trimethylaminuria, visit tmau.org.uk.

Transcript

A Gene for Fish Odor

Posted: March 22, 2012

Ari: Grahame Lancaster kneels in front of a box of framed photographs.

(rummaging)

Lancaster: Ah, here's some.

Ari: It sits in a corner of his home in Carlisle, in the north of England.

Lancaster: There's a couple from the, from the police. That was one 1992.

Ari: Lancaster holds up a picture. 50 police officers are arranged into rows.

Lancaster: That's me on the, on the back row, the big lump. Bigger than everyone else there, I think.

Ari: He was only 22, but he was formidable—6-foot-4, 250 pound—and confident. He served with the Greater Manchester Police.

Lancaster: My favorite times were nights, you know, chasing after stolen cars. Catching criminals, really. I always used to pride myself on being able to catch most people.

Ari: Aside from the paperwork, he loved the job. But a few years after that photograph was taken, he started getting odd remarks from his fellow officers. They said he smelled like rotting fish.

Lancaster: I just thought it was maybe something I'd eaten even though I was never a great fish-eating fan so I couldn't really understand where it was coming from.

Ari: How would you respond to them when they would say these things to you?

Lancaster: I kinda just used to ignore the comments. There was one guy, I remember him sniffing my hair. And he said, "Oh, it's your hair gel." So then I kind of used to blame it on that for a while. But then, I realized it obviously wasn't the hair gel. And then the comments started getting more frequent.

Ari: It wasn't just police officers who smelled the peculiar odor. Suspects told Lancaster that the interrogation room reeked of fish. Defense attorneys made comments too. So Lancaster went to see his doctor.

Lancaster: And he basically said it was all in my head, it was nothing to worry about. Try some strong soap, and that should sort it out.

Ari: Lancaster began showering three times a day, sometimes four. He caked on the deodorant. But within 15 minutes of showering, the comments would start again. The remarks became harder and harder to stomach.

Lancaster: Because people make the comments, you then think that people who aren't making comments can still smell it. But they're not saying anything. So you then start to become paranoid about it as well.

Ari: Now, around that same time—in the late 1990s—a molecular biologist named Elizabeth Shephard at University College London co-discovered the gene that causes a rare condition called trimethylaminurea, or TMAU.

Shephard: TMAU is a disorder in which people are unable to complete the metabolism of a small molecule called trimethylamine. And that small molecule is derived from the ordinary foodstuffs that we eat such as eggs, soya, meat.

Ari: Most people have an enzyme that breaks down that molecule in their livers. But not if you have TMAU.

Shephard: The trimethylamine then just pervades your whole body and you will excrete it in your urine, in your breath, and all your bodily secretions.

Ari: And that molecule? It's what gives rotting fish its distinctive odor. In fact, TMAU is sometimes called fish odor syndrome.

TMAU can be triggered by liver or kidney disease, but it can also be hereditary – caused by FMO3, the gene Shephard discovered – although the symptoms may not appear until adulthood. The genetic form of the condition is rare, affecting perhaps one in 40,000 people.

In the case of Grahame Lancaster, a medical researcher recommended that he take a urine test to see if he had TMAU. It came back positive. Lancaster was relieved.

Lancaster: Then you can kind of recognize it's not your fault. It's not the fact that you're unhygienic. It's a definitive medical diagnosis that you've got something wrong with you.

Ari: Once Lancaster knew what was wrong, he set about trying to fix it. Doctors recommended he keep a diary to track what foods made the odor better or worse. But it didn't help. Changes in what he ate didn't reduce the smell. He grew even more embarrassed and self-conscious.

Lancaster: Ruined the enjoyment of the job. It kind of destroyed it all for me.

Ari: The test that had given him the diagnosis had given him hope that things would change. But when they didn't, he spiraled into a severe depression.

Lisa Claire Uren was Lancaster's girlfriend at the time.

Lisa: He was quite hard to get along with, he just wasn't himself. And I just didn't know what to do. Couldn't do anything. Couldn't say the right thing. I couldn't see us ever coming through it, really.

Ari: Things fell apart for Lancaster at work too. He lost focus. He went on medical leave for a year, and then was discharged from the force. His career as a police officer was over—not because he smelled like fish, but because of the resulting depression.

Lancaster says part of what made things so difficult was he assumed that when scientists found the gene for TMAU, a cure would be right around the corner. Yet with many inherited conditions, including TMAU, the discovery of the faulty gene hasn't led to treatments or cures. The science has proved more complicated than many expected at the beginning of the genomics revolution. And there are additional obstacles for rare and non-life threatening conditions like TMAU. Ian Phillips, of Queen Mary University of London, co-discovered the TMAU gene. He says he can't convince funding agencies to invest in the research needed to develop a cure.

Phillips: Personally it's frustrating because, having identified the genetic basis of the disease, we are no longer able to follow that up in any meaningful way that would be of use for the patients.

Ari: But even without a cure, things did improve for Grahame Lancaster. He gradually came to terms with his condition. He took up a more suitable career in IT—a job with less stress and no physical demands—so he was less likely to sweat and produce the fish odor. His relationship with Lisa improved, and they got married.

By this time, there was another test for TMAU—a genetic test that could identify the specific mutations that caused the disorder. The test could tell family members, for instance, if they're likely to develop the condition, even if they don't currently have symptoms. And Lancaster was faced with a new decision about testing.

(ambient of Emma playing)

He and Lisa now had a daughter.

Lancaster: My main concern was whether I'd passed on the defect to Emma. If she's gonna get it, I'd rather be pre-warned and pre-armed so you can deal with it.

Ari: They decided to test Emma when she was a year old. It came back positive…sort of. Emma had inherited a faulty copy of the gene from her dad, and a somewhat faulty version from her mom. That means that Emma may develop a mild form of TMAU later in life.

The test result caused Grahame and Lisa to confront a new set of questions. Should they tell Emma, even though she may never exhibit the condition? What good would the information do her?

It's similar to the dilemma many people face who've been tested for genes linked to diseases— like Alzheimer's—for which there's no good treatment or cure. If you find out you're at high risk, what do you do with that information?

Grahame Lancaster realizes there's a big difference between dementia and TMAU. But still, he says it's nothing to laugh at.

Lancaster: One of the most evocative things is, is your smell, you know. Sometimes you smell things—it brings back pleasant memories. I read on some article that the smell of rotten fish is one of the worst things you could ever smell. So it's just unfortunate that TMAU doesn't smell of roses, rather than rotten fish.

Ari: Lancaster says knowing what's in his genes and what he's passed on to Emma has helped him… just not nearly as much as he'd hoped.

For NOVA and The World, I'm Ari Daniel Shapiro, Carlisle, England.

Credits

PRODUCTION CREDITS

Reported by
Ari Daniel Shapiro
Original Footage
©WGBH Education Foundation

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