Altered States

# The strange malady of Alessandro’s uncle

BMJ 2007; 335 (Published 20 December 2007) Cite this as: BMJ 2007;335:1306
1. Neil A (Tony) Holtzman, professor emeritus pediatrics
1. 1McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA
1. nholtzma{at}jhsph.edu
• Accepted 27 April 2007

A tale of overhyped genetic discovery, by Neil A (Tony) Holtzman

Had it not been for Alessandro, Professor Johnson’s talk would have received little attention. Had it not been for his uncle’s malady, Alessandro would not have paid much attention either. Shortly before Alessandro covered the scientific meeting as a reporter for L’Unione Sarda, he had learnt that his uncle was being treated for the disorder that Johnson spoke about. At the end of the session, Alessandro picked up the press release in the congress media room.

It read: “Under the leadership of Professor Henry Johnson, a team of scientists from universities in Europe and the United States announced the discovery of a major gene for schizophrenia at the Fifteenth International Congress of Genetic Psychiatry in Cagliari, Sardinia, today. They studied the genes from an international collection of patients with schizophrenia, their normal parents, and their siblings. Patients with schizophrenia were five times more likely to possess a genetic variant (allele) of a gene than their unaffected relatives. The scientists have named this gene Schizo-12. Professor Johnson said that a test to detect the presence of the variant would be on the market within a year, and a drug that would prevent or effectively treat schizophrenia in patients who tested positive would be developed within five years. The work was supported by Psychotropics-R-Us, an American drug company.”

A month before the congress, Alessandro had driven to the mountainous region of Barbagia, northeast of Cagliari, to visit his uncle who was a goatherd. After he had parked on the side of a dirt road, he hiked the mile to his uncle’s stone hut, arriving at midday. He found his uncle seated on a stool on one side of a rough hewn table. On each of the other three sides a goat sipped milk from its bowl, forefeet firmly planted on the table, hind legs on the earthen floor. While he waited for his uncle to finish eating, Alessandro inspected the hut. He noticed a crumpled paper on the otherwise empty shelf above his uncle’s cot. He took it to the table where he smoothed it out. “Who gave this to you?” he asked his uncle.

“A doctor.”

“Were you sick?” His uncle shook his head. “What were you doing when the doctor came?”

“Having lunch.”

“Was anyone else here?”

“A nurse—and my pet goats.”

Alessandro took the prescription back to Cagliari. He did a Google search on olanzapine, the prescribed drug, and learnt that the drug was used to treat schizophrenia.

Surprised, Alessandro made an appointment to see the doctor who had signed the prescription. The doctor confirmed that his uncle had schizophrenia. After more inquiries, Alessandro pieced together the sequence of events that had led to the diagnosis.

The previous spring—after the winter snows had melted off the Gennargentu—a public health nurse from Cagliari was making her calls through the Barbagia. She arrived by foot at the goatherd’s hut, knocked, and entered when he grumbled, “Avanti.” After her eyes became accustomed to the darkness she saw three of his goats standing around the table, exactly as Alessandro saw several months later. Sitting on a stool, the goatherd occupied the fourth side, his elbows on the table, watching the goats as they sipped their milk. Occasionally, the old man uttered a few words. The nurse thought he was speaking gibberish.

In early autumn, the nurse returned with the doctor while the goatherd was having lunch. After introducing the doctor, the nurse urged the goatherd to continue his meal as she and the doctor retreated to the shadows in the one room hut. The doctor thought the goatherd was speaking logudorese (an ancient Sardinian dialect) to his four legged companions. Stepping from the shadows, the doctor asked the old man a few questions, had him stick out his tongue, and then wrote the prescription, which Alessandro found on his visit a few weeks later.

After Alessandro read the press release, he wanted to question Professor Johnson about his uncle—did the professor think he had schizophrenia? Could he get the Schizo-12 test and what was the best treatment? But the professor was nowhere to be seen. Alessandro returned to the offices of L’Unione Sarda in Cagliari, where he wrote his story. It appeared in the next printed edition and on the paper’s website. The story was quickly picked up by Corriere della Sera, which published an English translation.

The next morning, congress participants were surprised by the newspaper headlines. The International Herald Tribune proclaimed, “Gene for schizophrenia found.” Other papers bore similar captions. By email, a few of the participants from the United States ordered their stockbrokers to buy shares in Psychotropics-R-Us. The time was then only 3 am in New York.

A few hours later the story was on US National Public Radio’s weekday morning news show. ABC television had awakened a well known American psychiatrist and brought him to the nearest studio where his comments on the report were viewed by millions on Good Morning, America. “If the results are confirmed,” he said, “the findings are very exciting.”

Psychotropics-R-Us stock opened on the New York stock exchange that morning at $4 (£2; €2.7) a share. It closed at$26.

The president of the congress and Henry Johnson were deluged with phone calls and email messages. The president decided to convene a special public session the next day at which Johnson would summarise the findings and then invite questions. One of Johnson’s English collaborators and the scientific director of Psychotropics-R-Us flew to Cagliari to participate in the session.

Unlike the previous sessions, the special one was packed. Johnson summarised his group’s findings and concluded with the prediction that a test for Schizo-12 would be available within a year and a treatment within five years. The first questions concerned the DNA analyses and the association studies. Johnson and his colleagues answered them with ease.

Then, a reporter at the back of the auditorium asked, “You call this gene Schizo-12. Are there 11 others?”

Johnson replied, “Yes there are, but the claims for an association with schizophrenia were not based on as large a number of patients. Some of the claims have been retracted, but the gene names stick.”

The reporter then asked, “What was the basis for the retractions?”

Johnson’s British colleague answered, “A few relatives who had neither any symptoms of schizophrenia nor the predisposing allele were classified as normal. After the study was published, they were diagnosed with schizophrenia. The same problem has been reported for bipolar affective disorder.”1

Alessandro asked, “Professor, would you say that a man who heard his pet goats talking had schizophrenia?”

Surprised, Johnson thought for a moment and said, “Well, I’m not a psychiatrist, you know,” he paused, gazing at the ceiling, “but keeping goats for pets is unusual to begin with. I would say he probably does.”

Alessandro wanted to add that the man in question was a goatherd, but the president called on a woman who had been standing by one of the floor microphones. She asked, “Dr Johnson, do you own stock in Psychotropics-R-Us?”

“Yes, I do.”

“Doesn’t that pose a conflict of interest?”

“If you are insinuating that I or my colleagues fabricated results I find that highly insulting.”

She clung to the microphone and responded before the president pointed to the next person. She replied, “No, professor, I am only suggesting that it is in your financial interest to develop the test and get the drug to the market as soon as possible.”

As Johnson hesitated, the president called on the next questioner, a distinguished congress participant from the London School of Hygiene and Tropical Medicine. “Your slides,” he began, “showed the frequency of the predisposing Schizo-12 allele to be 10 times higher than the frequency of schizophrenia. Under those conditions, most people who have the allele will never develop schizophrenia.”

The scientific director of Psychotropics-R-Us shot back, “But they have five times the risk of people without Schizo-12.”

Not to be fazed, the distinguished participant replied calmly, “That may be, but if you are going to prescribe drugs for healthy people who test positive for the predisposing allele, most will never benefit from the drug.” A murmur went through the audience. “From your data, I might add, this allele will account for less than one third of cases of schizophrenia.”2 He turned and walked away from the microphone. Abruptly, the president thanked Johnson, his colleagues, and the audience for their interest, and adjourned the session.

Psychotropics-R-Us shares hovered around $25 for the next two years. Then the company offered a test for Schizo-12 in its own laboratory, thereby circumventing the tight control the US Food and Drug Administration (FDA) has over genetic tests sold as kits to other laboratories.3 Once the test was on the market, the company’s shares rose to$40 each.

Several people who were tested for the Schizo-12 variant committed suicide shortly after learning their results were positive. Some families of people in whom the test was negative sued Psychotropics-R-Us when they were diagnosed with schizophrenia. When the company abandoned its test for Schizo-12, the media did not report it.

Three years after the Sardinia meeting, the FDA refused to allow Psychotropics-R-Usto begin phase III trials of its “anti-Schizo-12” drug because of safety concerns. A report of this denial was buried on the back page of the business section of the major papers. The price fell to \$5 a share.

Together with an expanded group of collaborators who provided many more patients with schizophrenia and controls, Henry Johnson submitted an abstract to the 17th International Congress of Genetic Psychiatry in Bangkok, Thailand, four years after the Sardinia meeting. They reported that the risk of schizophrenia in people with the Schizo-12 allele was only 1.5 times that of relatives without the allele (95% confidence intervals 0.8 to 1.9). The abstract was not accepted for presentation. As expected, no newspaper published this non-event.

Alessandro had his uncle’s prescription for olanzapine filled and brought the medicine to the goatherd. Whether his uncle or his pet goats took the medicine is unclear, but the pills disappeared. When the nurse returned to the mountains the next spring she found the old man still discussing matters with his pet goats over lunch.

## Footnotes

• Competing interests: NAH was reimbursed for attending the symposium at which the paper was presented by the organisers.

• Provenance and peer review: Not commissioned; not externally peer reviewed.

• A slightly different version of this story was presented by invitation at the Fourteenth World Congress on Psychiatric Genetics, Sardinia, Italy, October, 2006, under the title “Genetic tests, commercialization, and conflict of interest.” Any resemblance to persons living or dead is purely coincidental.

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