An extended family in Colombia struck by hereditary and very early onset Alzheimer's is taking part in a new drugs trial that doctors hope will lead to a cure for sufferers worldwide.
Johnhaider sits in a wheelchair, rubbing one leg compulsively. His eyes are empty. He can no longer talk. He doesn't know where he is. He doesn't know his sister Patricia.
Johnhaider is in the final stages of Alzheimer's disease - the most common form of dementia.
This is remarkable for two reasons. He is only 53, when most patients at the same stage of this terminal illness are in their mid-60s at least.
He is also a member of an extended Colombian family, half of whom will contract Alzheimer's at an early age, according to medical researchers who have been monitoring the occurrence of the disease in the clan.
"
I saw we had three generations affected, and in each generation half of the children were affected - this was hereditary”
Dr Francisco Lopera University of Antioquia
There is now hope that research involving this family - who are described by one scientist as a "natural laboratory" - will help speed the discovery of a cure for this devastating condition.
The clan is currently about 5,000-strong and scattered across remote villages in the Andes mountains that surround the northerly city of Medellin - the second largest in Colombia. All are descendants of one couple of Basque origin, who settled here in the early 1700s.
The man responsible for uncovering this family's cruel medical history is Dr Francisco Lopera, a behavioural neurologist at Medellin's University of Antioquia.
Dr Lopera first stumbled on the phenomenon in the early 1980s.
"I saw a man of 47 with dementia that was very similar to Alzheimer's disease. That was curious because he was very young."
Then Dr Lopera learned that the man's father, grandfather and several brothers had also suffered from dementia.
Scientists from around the world are working with the family to test theories about potential cures
"I saw we had three generations affected, and in each generation half of the children were affected. This was hereditary."
Dr Lopera and a small team from his university scoured the region, despite the risks from drug traffickers and rebels of the Revolutionary Armed Forces of Colombia (Farc).
By the end of the 1980s, he had assembled a family tree stretching back nearly 300 years, big enough to cover the wall of an auditorium.
It took another decade to isolate the cause - a gene thought to trigger early onset of the disease.
If one parent has the gene, there is a 50% chance their child will have it too. Half the Colombian family members carry the gene, called the paisa mutation - "paisa" refers to the people of the region.
This rare mutation in an isolated population has attracted scientists from the Banner Institute in Phoenix, Arizona - a world leader in dementia research.
~~~~~~~~ What causes Alzheimer's?
* No single factor has been identified, but it may be a combination of... * Age * Genetic inheritance * Environmental factors * Lifestyle and general health ~~~~~~~~
Dr Adam Fleisher, a geriatric neurologist at the institute, says Alzheimer's is like "an approaching pandemic". With life expectancy increasing, and the number of dementia suffers growing exponentially, the disease has the potential to devastate public healthcare systems in developed countries, he says.
"The truth is it's going to affect you, and your ability to get healthcare, whether you get Alzheimer's or not. We need to find a cure."
The Banner Institute scientists will test drugs on the family which are designed to attack a neural plaque that builds up on the brains of all Alzheimer's sufferers. The sticky, chewing gum-like plaque is caused by a malfunction which causes the misproduction of a starch-like protein called amyloid.
The hope is that by using experimental drugs, growth of this amyloid plaque will be inhibited before the illness strikes. Continue reading the main story
“ I want to participate - it's for me, it's for my family, it's for the rest of the world”
Patricia, Johnhaider sister
The Colombian family present researchers with the chance to work with healthy people before they develop dementia.
Using lumbar punctures, brain scans and other techniques, they will monitor and measure those on the drugs and those receiving a placebo.
The hope is that with funding in place, the trials can begin in late 2012.
If in the extended family the onset of Alzheimer's is delayed, or stopped, then the researchers will have hit the mother lode - a potential cure for sufferers worldwide. That remains a big if.
No-one yet knows if amyloid plaque is the cause or an effect of Alzheimer's. As Joseph Arboleda, a Harvard-based researcher working with Dr Lopera says, the trial puts this hypothesis to the test.
It is possible that drugs will inhibit the brain plaque and yet the family will still get dementia. Such results would prove devastating for current research.
Doctors recruiting volunteers for research Doctors recruit members of the family for research
"It would be a huge setback for everybody," says Arboleda. "The patients, the scientists - this is the best we've got. If it falls down everyone is in trouble."
For the family, though, the burden of care, the terrible knowledge that for half of them the disease is inevitable, and that the paisa mutation will be passed on to half of their children far outweighs the risk of trialling unproven drugs.
Johnhaider was in his mid-40s when the symptoms first struck, and by that time his mother had already died from the disease. She too had begun to exhibit symptoms in her mid-40s.
Johnhaider's sister, Patricia, does not know if she carries the gene. At 49, and with no signs yet, she is hopeful but worried, and that is why she is prepared to take part in the trial.
"I have no options," she says, gently adjusting a worn blanket that covers her brother's thin legs.
"I am a little bit worried," says Patricia. "But I want to participate: it's for me, it's for my family, and it's for the rest of the world."
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But as he worked through the slides, it became clear to the audience on that day in July 2008 that the drug was not delivering and that its makers, Elan and Wyeth, could lose out on blockbuster profits. Along with other Wall Street analysts in the front rows, David Moskowitz zapped messages to clients to dump shares of the companies. “I can remember gasping” at the results, Mr. Moskowitz said.
Little did anyone in the room know that 12 days earlier, Dr. Gilman had e-mailed a draft of the presentation to a trader at an affiliate of one of the nation’s most prominent hedge funds, according to prosecutors, allowing the fund, SAC Capital [ http://topics.nytimes.com/top/news/business/companies/sac_capital_advisors/index.html ], and its affiliate to sell over $700 million of Elan and Wyeth stock before Dr. Gilman’s public talk.
While he appeared a grandfatherly academic, Dr. Gilman, 80, was living a parallel life, one in which he regularly advised a wide network of Wall Street traders through a professional matchmaking system. Those relationships afforded him payments of $100,000 or more a year — on top of his $258,000 pay from the University of Michigan — and travels with limousines, luxury hotels and private jets.
The riddle for Dr. Gilman’s longtime friends and colleagues is why a nationally respected neurologist was pulled into the high-rolling life of a consultant to financiers and how he, by his own admission, crossed the line into criminal behavior.
“My first reaction was, ‘That can’t possibly be right,’ ” said Dawn Kleindorfer, a former student of Dr. Gilman’s at Michigan.
What is clear is that Dr. Gilman made a sharp shift in his late 60s, from a life dedicated to academic research to one in which he accumulated a growing list of financial firms willing to pay him $1,000 an hour for his medical expertise, while he was overseeing drug trials for various pharmaceutical makers. Among the firms he was advising was another hedge fund that was also buying and selling Wyeth and Elan stock, though the authorities have given no sign they have questioned those trades.
His conversion to Wall Street consultant was not readily apparent in his lifestyle in Michigan and was a well-kept secret from colleagues. Public records show no second home, and no indication of financial distress. Nevertheless, he was willing to share a glimpse of his lifestyle with a 17-year-old student whom he sat next to on a flight from New York to Michigan a few months ago, telling her how his Alzheimer’s research allowed him to enjoy fine hotels in New York and limousine rides to the airport.
“I wouldn’t say he was egotistical because he didn’t come across as obnoxious, but he definitely mentioned the kind of lifestyle that he had,” said the student, Anya Parampil, who had been upgraded to first class.
Dr. Gilman’s role in the case involving SAC Capital has largely been overshadowed by the possibility that investigators may be narrowing in on the firm’s billionaire founder, Steven A. Cohen. Mr. Cohen and his firm have not been accused of wrongdoing in acting on the insider information.
Colleagues now say Dr. Gilman’s story is a reminder of the corrupting influence of money. The University of Michigan, where he was a professor for decades, has erased any trace of him on its Web sites, and is now reviewing its consulting policy for employees, a spokesman said.
The case also turns the spotlight back onto the finance world’s expert networks, which match sources in academia and at publicly traded companies — like Dr. Gilman — with traders at hedge funds and financial firms.
The networks have been a central target of prosecutors in the sprawling insider trading investigations that have resulted in dozens of convictions in recent years.
Some networks have closed, and many are shifting their focus outside the financial world, hoping to make up revenue by consulting for corporate America.
Days after the charges were filed, Dr. Gilman retired and has gone into seclusion at his home on a wooded lot overlooking the Huron River on the outskirts of Ann Arbor, which is listed in public records as worth $400,000. He declined to open the door to a reporter last week, directing questions to his lawyer. “I can’t discuss it,” he said. “I’m sorry.”
In a one-paragraph statement, his lawyer, Marc Mukasey, said: “Dr. Gilman’s accomplishments in medicine, research and education speak for themselves. He moved the ball way down the field in helping to find a cure for those who suffer from Alzheimer’s disease.”
The University of Michigan has severed its ties to Dr. Gilman and a spokesman, Pete Barkey, said the case was “caused by a faculty member’s unethical and illegal behavior during the conduct of external activities.”
Dr. Gilman graduated with top honors from the University of California, Los Angeles, trained at Harvard Medical School and moved into a life of teaching. He married Carol Barbour, a psychoanalyst, in 1984. People who know him almost invariably mention his fatherly demeanor, and his gift for teaching.
Brett Kissela, a resident under Dr. Gilman in the late 1990s, remembered him as “a little bit formal” but warm and generous. When faculty members had to sign up for an undesirable task, Dr. Gilman would start by signing up himself, Dr. Kissela remembered.
He was well-known for shaping trials for Alzheimer’s drugs and served on Food and Drug Administration drug advisory panels. J. Timothy Greenamyre, who has known Dr. Gilman for about 30 years, remembered turning to him for help with ethical issues after succeeding him at a top industry journal, Neurobiology of Disease.
“He always gave me rock-solid advice and counseled me to maintain transparency so as to avoid even the appearance of a conflict of interest,” Dr. Greenamyre said.
For most of his career, almost the only work Dr. Gilman did outside Michigan was in national advisory positions and academic journals that provided almost no compensation, according to his 43-page résumé. But in 2000, as he scaled back his academic and editing duties, colleagues said, Dr. Gilman’s desire for recognition remained and he began consulting for two pharmaceutical companies.
He was soon contacted by one of the first expert network firms, Gerson Lehrman, which began in 1998 by enlisting academics in health care and connecting them with financial firms. Experts on drug development, and especially those involved in drug trials, are sought by investors because the fortunes of a pharmaceutical company can rise or fall with the fate of a single treatment.
Dr. Gilman quickly became a popular consultant, working with more than 40 clients and participating in 50 to 100 meetings a year, people with knowledge of his work said. Each meeting paid around $1,000.
In 2006, the SAC Capital trader, Mathew Martoma, asked Gerson Lehrman to find an expert who knew about an Alzheimer’s drug under development, bapineuzumab, according to the affidavit filed by the F.B.I. agent in the case. Dr. Gilman was chairman of the board monitoring trials of the drug. Gerson Lehrman connected the men, but told Dr. Gilman not to discuss the drug, according to the criminal complaint in the case.
Within weeks, Dr. Gilman was speaking with Mr. Martoma shortly after confidential meetings about the drug trials, the complaint said.
To avoid arousing suspicion at Gerson Lehrman, Dr. Gilman began asking Mr. Martoma to falsely request meetings on other topics, the complaint said. Ultimately the men had 42 meetings. Gerson Lehrman declined to comment on the relationship.
At first, Mr. Martoma’s fund, CR Intrinsic, bought shares of the firms developing the Alzheimer’s drug, Wyeth and Elan, and encouraged SAC’s founder, Mr. Cohen, to do the same, prosecutors say. When Dr. Gilman told Mr. Martoma that the trial results were not as good as expected, the funds sold all their shares, netting gains and avoiding losses totaling $276 million, the complaint said.
Kenneth Fischbeck, a neurologist who has known Dr. Gilman for years, said that it might have been the same urge that led him to be such a good teacher — a desire to share information — that also led him into trouble.
“It’s a cautionary lesson for all of us in academic medicine,” Dr. Fischbeck said. “I think it could happen to anybody if they’re not careful.” The complaint said that Dr. Gilman eventually came to view Mr. Martoma “as a friend and a pupil.”
Besides contracting with expert networks, Dr. Gilman was hired to serve on scientific advisory boards of financial firms including Pequot Capital. His connection to Pequot has rarely been mentioned, but that fund built up its own $25 million position in Wyeth stock and a stake of around $20 million in Elan, according to Pequot’s public filings, at the same time Dr. Gilman was overseeing drug trials for the two companies.
While the records don’t reveal the exact dates of trades, Pequot sold its Wyeth position in the quarter before both drug companies’ shares fell in 2007, and it sold its Elan position at some point during the quarter when it dropped, the filings show. Pequot went out of business in 2010 after admitting its own insider trading scandal involving Microsoft stock.
Neither Dr. Gilman’s lawyer, Mr. Mukasey, nor prosecutors would say whether investigators are questioning Dr. Gilman about his other relationships. In exchange for prosecutors’ not charging Dr. Gilman, he has agreed to share information about “any matters” they want to ask him about. Dr. Gilman stopped meeting with Mr. Martoma in 2008, the complaint said, but continued to consult for Gerson Lehrman until this year, people familiar with his work said.
Dr. Gilman’s life changed starkly on Nov. 20, when Mr. Martoma was arrested. Dr. Gilman agreed to pay federal authorities $234,000 of the money he had earned from Wyeth and Gerson Lehrman. He has been ostracized by the university, and the consequences are broader still as a debate over the propriety of professors’ receiving payments from financial firms has been rekindled.
“What is the argument for sanctioning your full-time faculty, using your brand name, to advise the financial sector?” said Dr. Garret A. FitzGerald, a cardiovascular researcher at the University of Pennsylvania, who has been outspoken about conflicts of interest. “What’s the public good there?”
Her death was announced by Mayor Gianni Alemanno of Rome.
“I don’t use these words easily, but her work revolutionized the study of neural development, from how we think about it to how we intervene,” said Dr. Gerald D. Fishbach, a neuroscientist and professor emeritus at Columbia.
In the years after the discovery, Dr. Levi-Montalcini, Dr. Cohen and others described a large family of such growth-promoting agents, each of which worked to regulate the growth of specific cells. One, called epidermal growth factor and discovered by Dr. Cohen, plays a central role in breast cancer .. http://health.nytimes.com/health/guides/disease/breast-cancer/overview.html?inline=nyt-classifier ; in part by studying its behavior, scientists developed drugs to combat the abnormal growth.
Dr. Cohen, now an emeritus professor at Vanderbilt University, said Dr. Levi-Montalcini possessed a rare combination of intuition and passion, as well as biological knowledge. “She had this feeling for what was happening biologically,” he said. “She was an intuitive observer, and she saw that something was making these nerve connections grow and was determined to find out what it was.”
One of four children, Rita Levi-Montalcini was born in Turin on April 22, 1909, to Adamo Levi, an engineer, and Adele Montalcini, a painter, both Italian Jews who traced their roots to the Roman Empire. In keeping with the Victorian customs of the time, Mr. Levi discouraged his three daughters from entering college, fearing that it would interfere with their lives as wives and mothers.
It was not a future that Rita wanted. She had decided to become a doctor and told her father so. “He listened, looking at me with that serious and penetrating gaze of his that caused me such trepidation,” she wrote in her autobiography, “In Praise of Imperfection” .. http://www.nytimes.com/1988/05/01/books/a-self-made-scientist.html .. (1988). He also agreed to support her.
She graduated summa cum laude from the University of Turin medical school in 1936. Two years later, Mussolini issued a manifesto barring non-Aryan Italians from having professional careers. She began her research anyway, setting up a small laboratory in her home to study chick embryos, inspired by the work of Dr. Hamburger, a prominent researcher in St. Louis who also worked with the embryos.
During World War II, the family fled Turin for the countryside, and in 1943 the invasion by Germany forced them to Florence. The family returned at the close of the war, in 1945, and Dr. Hamburger soon invited Dr. Levi-Montalcini to work for a year in his lab at Washington University.
She stayed on, becoming an associate professor in 1956 and a full professor in 1958. In 1962, she helped establish the Institute of Cell Biology in Rome and became its first director. She retired from Washington University in 1977, becoming a guest professor and splitting her time between Rome and St. Louis.
Italy honored her in 2001 by making her a senator for life.
An elegant presence, confident and passionate, she was a sought-after speaker until late in life. “At 100, I have a mind that is superior — thanks to experience — than when I was 20,” she said in 2009.
She never married and had no children. In addition to her autobiography, she was the author or co-author of dozens of research studies and received numerous professional awards, including the National Medal of Science .. http://www.nsf.gov/od/nms/recip_details.cfm?recip_id=216 .
“It is imperfection — not perfection — that is the end result of the program written into that formidably complex engine that is the human brain,” Dr. Levi-Montalcini wrote in her autobiography, “and of the influences exerted upon us by the environment and whoever takes care of us during the long years of our physical, psychological and intellectual development.”
This article has been revised to reflect the following correction:
Correction: December 30, 2012
An earlier version of this obituary misstated the year Mussolini issued a manifesto barring non-Aryan Italians from having professional careers. It was 1938, not 1936.
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