To our Trustees and Supporters:
VIEW FROM THE CHAIR
The news exploded all over the world in every form of media - television, radio, newspapers, magazines, even the Internet. The Human Genome has been sequenced and every step of the three billion steps that make up the blueprint for creating a human being is now known. This is the entire alphabet contained in human DNA, which guides the development of each and every one of us.
To announce this achievement, the President of the United States invited Dr. Francis Collins, head of the public Human Genome Project, and Dr. Craig Venter, who sequenced the genome under the auspices of Celera Genomics, a commercial company. The President had also invited Dr. Nancy Wexler, our Foundation President, to come to the White House. Unfortunately, the invitation was misdirected and arrived too late for her to get to Washington. But the invitation itself was an acknowledgment of the contribution made by the Hereditary Disease Foundation in helping to energize and contribute to the start and the conduct of that great project.
If the President was full of enthusiasm for the potential importance of the Genome Project, some scientists were even more extravagant in their praise. For several days I heard scientists liken the achievement to the mastery of fire by human beings or to the discovery of the wheel. One scientist went so far as to say that the completion of the Genome Project was perhaps the most important scientific achievement in the course of human history! Hyperbole or not, all of this made me think that our trustees and the many contributors who supported the Hereditary Disease Foundation should be mighty proud that they have an association with a scientific development that brought forth such accolades.
Many of you will recall that Dr. Francis Collins was for years a member of our Scientific Advisory Board and was a very important member of the collaborative team which identified the gene for Huntington's disease. At one time, for a brief spell, Dr. Venter was also associated with that collaborative team. The presence of these investigators in the White House to announce the completion of the Genome Project suggests the part our Foundation has played in this major biological accomplishment.
I sometimes reminisce with amusement that many years ago, before there was any Genome Project, Dr. Lee Hood and Dr. Bill Dreyer called me to Cal Tech and suggested that I raise three billion dollars so that they could do a Human Genome Project. This was long before any such idea was being discussed. At least it was the first I had heard of it. I had to laugh at the grandiose notion that I was able to raise three billion dollars but in retrospect I am filled with admiration for their early understanding that this was the right way to go. Already we are seeing the tremendous benefits in the laboratory - and even in the clinic - of the insights coming out of this phenomenal achievement.
- Milton Wexler
SCIENCE BRIEFS
The mouse brain can cure itself of HD - if you give it a chance!! So found Columbia University researchers Ai Yamamoto, Jose Lucas and RenŽ Hen, supported entirely by Hereditary Disease Foundation funding. The Columbia scientists wanted to learn if an animal - or better yet a person - can cure itself of Huntington's symptoms, once the disease has started. Is it possible to turn the gene off - and stop the HD gene protein from being made? Can a mouse - and hopefully a person - cure itself - even after symptoms have started?
In order to answer the question "is Huntington's disease reversible, once it begins?" they designed an extremely clever experiment. The scientists "genetically engineered" a piece of the human HD gene with a kind of "genetic switch." This "switch" enabled them to turn the HD gene on and off at will. We know that mice, and probably humans as well, need the protein made by the HD gene - called "huntingtin" - to survive. The investigators left the mouse's own huntingtin protein intact. But in addition to the mouse huntingtin protein, the scientists placed into the mouse embryo the human HD gene, connected to their "switch." At first they left the human HD gene on to make its "toxic protein." This protein began to make the mice sick, just as it makes humans sick. The mice have abnormal motor coordination and, even more significantly, they have changes of important chemicals in the brain and the development of sticky clumps or "aggregates" that seem to clog up the works in the brains of people and mice with HD.
After five months, Ai and RenŽ "flipped the switch." They turned the human HD gene off so that no abnormal human HD protein was made! They continued to watch the mice for another four months and to compare these mice to their litter mates in whom they had not flipped the switch. In other words, half of the mice stopped making the HD protein, while half of the mice continued to make it.
Much to their amazement, the mice that were no longer producing the abnormal protein began to recover their functionality! Before the eyes of the shocked investigators, the mice seemed to get well!!! Even more dramatic were the changes in the mouse's brain. Where clumps had appeared in the brain cells of the sick mice - suddenly these clumps had disappeared!!!!!! And even more surprising, some of the biochemical abnormalities had even recovered!! Who knows what would have happened if the investigators had continued to let the animals improve for longer than four months.
This discovery is very good news - for mice, men and women! It means that the brain has restorative powers of which we little dreamed! If we can figure out a way to stop the abnormal HD protein from being made, we will have a cure for Huntington's! But even more gratifying is the knowledge that if we can stop the protein from being made - even in people who have been affected for some time - they should anticipate at least some degree of recovery. This elegant, imaginative and even brilliant research is enormously encouraging to all of us.
The paper was accepted in the journal Cell - one of the most prestigious science journals in the world. It rated a "Commentary," an honor afforded to only a few articles in the journal. Science Advisory Board member Huda Zoghbi, along with fellow researcher Harry Orr, wrote in the Commentary "that the brain has abilities of which biologists know little."
Our heartfelt congratulations and gratitude go to these dynamic and dedicated investigators. RenŽ Hen, a superb scientist, is an Associate Professor of Pharmacology at Columbia University. Jose Lucas began the work when he was a postdoctoral student in RenŽ's lab and then returned to Spain and is continuing to work on some aspects of it. Amazingly enough, Ai Yamamoto took over this extremely challenging research as her graduate thesis work. Needless to say, Ai will graduate with flying colors, but right now she is hard at work - talking to the mice every day trying to learn their secrets for curing themselves of HD. As soon as she learns the secret, she will certainly pass it onto us and we will pass it onto you and the world will rejoice!
Dr. Robert Friedlander, author of the exciting work last year on those multifaceted enzymes- caspases - which cause cells to commit suicide, has come up with yet another promising advance, also funded by the Hereditary Disease Foundation. Caspases serve useful functions in many instances by helping to get rid of excessive or abnormal cells. But sometimes they run amok, targeting essential cells, such as healthy neurons. Friedlander started this new experiment from the realization that after people have suffered a stroke, the common antibiotic minocycline can help reduce damage to the brain, since minocycline evidently limits production of the deadly caspases. He decided to see if minocycline might have a similar effect in Huntington's disease, at least in the mouse version. He already knew that a certain type of caspase (caspase-1) played a role in the advance of Huntington's disease, so it seemed logical that interfering with caspases might help slow down the disease. Friedlander treated Gill Bates' famous HD mice with minocycline.
The results were definitely encouraging. Friedlander and his group found that minocycline indeed blocked the production of two different caspases, caspase-1 and caspase-3. It also interfered with production of another substance, inducible nitric oxide synthase or iNOS, which also seems to be among the culprits in Huntington's.
As a result, the disease slowed down in Friedlander's mice, so that they remained relatively healthy longer. Though very preliminary, these results suggest possible new directions for human therapy. Minocycline has already been used therapeutically in people for lengthy periods of time with relatively few side effects. This new work suggests that minocycline may represent a new potential drug for the treatment of HD, though much additional work must be done to confirm if the promise will become a reality.
Our own Science Board member Dr. Leslie Thompson, University California Irvine, has come up with some provocative insights about possible interactions between the HD gene and the famous cancer-suppressing p53 gene, a relationship which was the subject of a lively workshop at Rockefeller University in New York in June. P53 is a master regulator of many fundamental cellular processes, and many cancers are the result of p53 mutations. Thompson's group noticed similarities between the structures of huntingtin and p53, a relationship that no one had previously suspected. They then carried out a series of experiments suggesting that these two proteins might be functionally related as well. The results are not yet complete: huntingtin might perhaps be mimicking some of the activities of p53 within the cell.
Alternatively, huntingtin might be blocking some of the cell's crucial activities. In either case, it will take more work to understand what's going on. But because no one had previously imagined that these two proteins might have some sort of relationship - possibly even engaging in a sort of cellular rendezvous - Thompson's insight opens up a whole new line of research that could prove important. At the Rockefeller University workshop, participants proposed many experiments to advance this fascinating hypothesis, and we look forward to upcoming reports.
Finally, researchers at Oxford University in England have shown that a "stimulating, enriched environment may also help slow down the onset of Huntington's disease!" Using mice models as their research subjects, a group of researchers compared the lives of a group of mice in a "normal" environment to another group in an "environmentally enriched" setting. For mice, such an enriched setting means additional cardboard, paper and plastic objects which the researchers changed every two days! How about books, music, movies, games, gardens, pianos and paintings - for people!
What the investigators found was intriguing. Not only did the lucky mice in the "enriched" setting show normal behavior for a longer period of time, they also showed greater brain volume and fewer seizures. Again, enrichment did not prevent the disease, but it definitely slowed down the damage. The authors conclude that occupational therapy based on the principle of environmental enrichment may delay the onset of Huntington's disease in people as well.
References:
Los Angeles Times, 27 June 2000
Cell, 31 March 2000
Newsday, 5 May 2000
Nature Medicine, July 2000
Proceedings of the National Academy of Sciences, 23 May 2000
- Nancy Wexler and Alice Wexler
NEWS BRIEFS
Welcome back to Dame Julie Andrews Edwards and to Blake Edwards! Once again they have established a home in Los Angeles and will be spending a fair share of their time in this neck of the woods. It tickles me no end when I think of the British queen investing Julie with the title of "Dame." Every time I think of that, I have an echo in my head that says, "There is nothing like a dame!" and there sure ain't, at least not like Dame Julie! I'm sure Blake will be hard at work making movies and thinking up fabulous stories for the stage, and we look forward to the next opening!
Welcome home also to Susan and Peter Feibleman. They have purchased a beautiful house in Beverly Hills and Susan has spent nearly a year putting it into first-class shape. Peter is busy juggling both a novel and a play. His earlier play, "Cakewalk," got a roaring reception when it was read by some very fine actors at the Skirball, here in Los Angeles. Several of us went to hear it and enjoyed it thoroughly. We eagerly anticipate Peter's next productions!
Genetic discrimination continues to receive attention in the Senate. Senator Thomas Daschle, Democrat from South Dakota, is a primary sponsor of the Genetic Non-Discrimination in Health Insurance and Employment Act. He wants to hear from families and individuals who have experienced employment discrimination. If you or someone you know has experienced such discrimination, please write to Senator Daschle and tell your story and encourage others to do so. This information is important in building support for legislative protection against discrimination.
Please address letters to The Honorable Thomas A. Daschle, United States Senate, Washington, D.C. 20510. You can mail or fax letters attention Andrea LaRue at 202-228-4136, in the office of Senator Daschle.
By the way, if you want an exciting read, pick up the new biography of that distinguished scientist Seymour Benzer entitled Time, Love, Memory: A Great Biologist and His Quest for the Origins of Behavior by Jonathan Weiner (available in hardcover or paperback). Seymour, one of the pioneering molecular biologists, was also one of the very first scientists to pitch into our enterprise. It was he, along with his Cal Tech colleague William Dreyer, who first proposed the idea of organizing workshops of young basic scientists, post-docs in particular, and of getting them interested in the problem of Huntington's disease, even if they had never heard of it before. Benzer's prediction that the most creative ideas would come from these young men and women, knowledgeable about new technologies and without established agendas to pursue, has proven accurate. Indeed, Seymour Benzer put us in touch with one of his own post-docs, a talented young researcher named Ron Konopka, a pioneer in Benzer's own area of fruit-fly research and one of those who first identified circadian rhythms in that much-studied Drosophila. Ron served as Science Director in the early days of the Foundation and helped set the pattern for one of the most successful elements of our organization, the Interdisciplinary Workshops.
You can hear beautiful music and support research to find cures for brain diseases such as Huntington's, Alzheimer's, Parkinson's and Lou Gehrig's diseases by visiting http://www.mp3.com/Favorites and listening to the FREE downloads of the great American classical guitarist Michael Lorimer. For every song you play, MP3.com pays HDF money directly towards research! ABSOLUTELY NO PURCHASE NECESSARY AND NO FORMS TO FILL OUT. There has never been a better opportunity to get involved, so please help.
Anne Young teamed up with Michael two years ago to create a new organization website - tigertunes.com - which is devoted to finding a CURE for neurological disorders through the purchase of incredible music. There are currently two CDs available for sale, as well as the free downloads.
If you would like to get further information about specific charities you will be supporting or tigertunes.com, visit http://www.mp3.com/Favorites and click on the Tiger in the upper right hand corner of that page or go directly to the TigerTunes home page (www.tigertunes.com). But please don't forget to return to the download page for your free music!
TIGERTUNES DONATES 100% OF ITS PROFITS TO CHARITIES THAT PROMOTE BRAIN RESEARCH.
Please visit this website and please copy and forward this email to tell your friends about it.
Thank you so much!
- Milton Wexler
REQUIEM
In the midst of tremendously exciting advances on the research front, we mourn the loss of some outstanding friends who have worked with us for many years in the search for cures for Huntington's disease and such related disorders as Alzheimer's, Parkinson's, Tourette's, and even cancer.
Two of our most important trustees died within days of each other in February of this year.
On February 6, our beloved trustee and long-time attorney Michael J. Fasman, died at the age of ninety. It was emblematic of his life dedicated to progressive causes that Mike's death came as he was leaving a benefit dinner for the Venice Family Clinic, a primary health care facility for the poor, which he and his wife Marjorie Lesser Fasman helped found and which they supported for many years. So significant were Mike's contributions to the state of California that the State Assembly observed a moment of silence in his memory.
It is difficult for me to find the appropriate words to honor this most generous and kind man. He and Marjorie were among the first ones I approached for help in 1968 when I heard the dread diagnosis of Huntington's chorea in my wife. Mike and Marjorie were immediately forthcoming in all kinds of ways in the early days of the Foundation, and continued their support unstintingly for over three decades. Michael did all the legal work, charging nothing for his services. Over the past thirty years of the Foundation, he handled endless numbers of estates, gratis, where the Foundation was a beneficiary. He and Marjorie both worked hard to establish a significant and dedicated Board of Trustees. They gave and hosted parties and meetings and recruited many of their own friends for the Foundation. Michael also served thoughtfully and creatively on the Foundation's Executive Committee. Apart from all that practical help was the gentle dignity Michael brought to everyone involved with the Foundation, and the straightforward practicality of his visions. With the loss of Michael Fasman, we have suffered a serious blow. Our sympathies go out to Michael's widow Marjorie and to all their children and grandchildren.
On February 13 of this year, another cherished associate, William L. Dorn, passed away at age fifty-one. Bill Dorn, that quiet, dignified and friendly man, together with his wife Meg, a long-time trustee, lent strength and courage to our enterprise. Living in Denver, they nevertheless attended meetings, dinners and events with a true passion for finding a cure for Huntington's disease. They showed a profound interest in the development of science, and helped recruit many of their friends and relatives to the cause. They also hosted a number of science workshops, parties, and meetings at their place in Colorado. Many of you may not know that Bill was Chairman of the Board of Forest Oil from the summer of 1991 to the time of his death, and also served as President of the company in the early 1990s. A graduate of the Phillips Academy and of the University of Texas at Austin, Bill worked his way up from landman for Forest Oil in Mobile, Alabama, to Rocky Mountain Division Manager in Denver, and subsequently to Vice President, Executive Vice President, President, and finally Chairman of the Board. Throughout his career, he also worked hard in support of research on Huntington's and other neurological diseases. The Julieanne Dorn Chair in Neurology at Harvard University Medical School and Massachusetts General Hospital, which is held by the distinguished Dr. Anne B. Young, is also the gift of Bill and Meg Dorn, and part of Bill's generous legacy.
We extend our deepest sympathies to Bill's widow Meg, to their children David and Courtney Dorn, his sister Lisa and brother Forrest, and to the many other members of his family. We miss you Bill!
We also miss another founding member of the Foundation and longtime trustee, Milton (Mickey) Rudin, who passed away in December of 1999. As one of Hollywood's most colorful entertainment attorneys for over fifty years, Mickey was famous not only for his clients - who included such luminaries as Frank Sinatra, Ronald Reagan and Marilyn Monroe - but also for his great sense of humor. As generous and loyal as he was amusing, Mickey supported the Foundation at every level, financial, legal, and business-wise. It was Mickey who made the critical suggestion some years back of simplifying the Foundation's operations by forming an executive committee. This idea not only proved marvelously efficient but freed most of our trustees from the day-to-day details and allowed them to function at a broader and more creative level. We extend our sympathies to Mickey's widow Mary Carol, and to his children Michael, Lisa, and Pam, and his grandchildren.
Finally, we wish to recognize another longtime trustee who was with us from the beginning, Theodore "Ted" Fritts, who also passed away in 1999. Ted was part of a most unusual family which has owned one newspaper, The Bakersfield Californian, for over a century. With his brothers Bill and Don and his sister Virginia "Ginger" Fritts Moorhouse, Ted participated in running the newspaper, serving as executive editor and as co-publisher from 1978 to 1988. His real love, however, has always been theater. A drama major at Willamette University in Oregon, Ted was active in Bakersfield community theater until his struggle with AIDS took him to San Diego where he lived the last years of his life. Soon after the Foundation was established, I met various members of the Fritts family. Mrs Berenice Fritts Koerber, then a widow, introduced me to her two sons Don, who was acting as publisher, and Ted. Ted was a lively, charismatic and adventurous man who brightened the landscape for all of us. He and Don also brought into the Foundation Michael Fisch, who proved immensely helpful in its affairs. To the end of his life, and despite all kinds of adversity, Ted remained optimistic and cheerful as well as helpful. As a world traveler, Ted would disappear for lengthy periods and then pop up with great vitality and a vast willingness to help the Foundation with all of its endeavors.
