Disease, denial, and support: the many kinds of family

Huntington’s disease, a cruel and fatal illness with no treatment or cure, triggers the best and worst in people’s ways of facing adversity.

In my own extended family the different reactions to HD have brought me both the deepest emotional pain and the warmest feelings of human solidarity.

Something’s wrong with Mom

In the late 1980s my mother started having strange emotional outbursts. When I visited home during the holidays in 1989, I heard my mother crying as she told a friend on the phone that she couldn’t handle having me home, even though I hadn’t seen her in more than a year. My father complained that they would dress for church or an evening out, only to have my mother insist at the last minute that they stay home. By 1992 her legs sometimes starting shaking uncontrollably at night. My father would hold them down in the bed for a while, but the shaking would not stop. At the time I did not know about these incidents, and my parents, probably thinking the shaking was not a serious problem, did not seek medical assistance.

I was living in another time zone, so I could not observe my mother’s daily behavior. My sister, who lived around the corner from my parents, did not take any action, and, for a combination of reasons that included lack of knowledge about medical matters, she never commented to me about the changes in my mother.

Then, in early 1995, my parents came to spend two months with my wife and me. We immediately saw that something was wrong with Mom. She was depressed and would pout like an angry child. I took her to a bedroom and, with my father watching, gave her a neck and back massage to calm her down. I suspected (wrongly) that my mother’s anti-depressant was causing a negative reaction or was at the wrong dosage.

I urged my father to take my mother to a specialist, and he finally did. They made the rounds to different doctors and heard diagnoses such as dystonia and chorea (but not specifically Huntington’s chorea, as HD used to be called). Then a neurologist suspected Huntington’s disease. In mid-1995, without my knowledge, my mother tested positive.

Ignoring the problem

Although my parents had learned that HD was a genetic disease and that my sister and I each had a 50-50 chance of inheriting it, they did not call or write with the diagnosis. (They never explained why. I can only speculate that at the time my parents didn’t fully understand the disease, and, like lots of other members of my extended family, believed that ignoring the problem would make it disappear.) The day after Christmas I opened a holiday letter from my sister stating that she was relieved to finally learn the cause of my mother’s problems.

I immediately called her and for the first time heard the phrase “Huntington’s disease.” In the space of a few minutes, the seemingly distant and certainly resolvable problems of my mother had become something very different. Not only did she face a monstrous future; so too, possibly, did my sister, her husband and three sons, my wife, and I.

Reacting to the trauma

I quickly became involved in the local support group of the Huntington’s Disease Society of America (HDSA). But I did not react calmly. In a few months I went into a period of denial and irresponsible decision-making. I did not right myself until the spring of 1998, when I became an activist with the local chapter.

With each year my activism has grown exponentially, as I have recounted in so many entries in this blog. As my wife puts it, not a day passes that we don’t think about Huntington’s disease.

As I learned about the disease, I passed information along to my father and sister in the hopes that they would do everything possible to keep my mother as healthy as possible as we waited for a treatment or cure. My father cared for my mother until she went into a nursing home in August 2005. I deeply admired his love and devotion, but I became increasingly frustrated at his and my sister’s inability and unwillingness to obtain therapies that might slow my mother’s decline.

Unbearable possibilities

I was the family problem-solver and, whenever I went home, I mobilized the family to take necessary steps. However, living so far away, I was limited. And I could not force my father and sister to take my advice.

Aside from concerns about specific aspects of my mother’s health, I had few conversations about HD with my father and practically none with my sister. I sent them publications and told them about dietary supplements and experimental drugs. Once, at the beginning of my HDSA advocacy, I convinced them to donate $300 each to a fundraiser. My father followed my suggestion to serve my mother blueberries and have her take a fish oil supplement. But we had no serious, sustained engagement about Huntington’s.

Whereas I took the HD test in mid-1999 and have rigorously taken the supplements recommended by Huntington’s Disease Drug Works (HDDW), my sister decided against testing. Because there is no effective treatment or cure, she would rather live without the devastation caused by a positive test and the long-term worry of wondering when symptoms would start. Many, many at-risk individuals take this path. For her, I believe, it’s unbearable to consider the possibility of having inherited HD from my mother and perhaps having passed it on to her three sons.

My father and especially my sister have preferred total denial. Before a visit back home in 2001 my sister had agreed to allow me stay at her house so that I could save hotel money and would not have to see our deteriorating mother every minute of my time there. At the last minute she went back on her word. Distraught, I cancelled the trip.

During another trip home I called my sister to discuss the need for communication and family solidarity. She hung up on me. We did not see each other that visit.

Around that time my wife and I offered to buy her eldest son, a high-school student, a round-trip plane ticket to come visit us. My sister never responded.

My gene-positive status is a constant reminder to my sister and her family of the threat of HD. Our daughter, who tested negative in the womb, is a symbol of the peace of mind my sister must wish she could have for her own children.

No sympathy

After I revealed my positive test result to my sister and father, they did not respond: no sympathy card, no phone calls, no offers of help or solidarity. Not once did I hear the phrase: “I’m sorry that you tested positive.”

Only when my mother’s death became imminent did my sister express any sympathy. After I visited my mother in the nursing home in January 2006 and contemplated my possible future by looking into the genetic mirror, my sister said: “That must have been hard for you.”

Only about a year after my mother’s death did my father, watching me take HDDW supplements, recognize for the first time that I could be struck with HD.

Now that my mother is gone, my sister and I have had to focus on finding an assisted living facility for my father, who is going downhill rapidly. During July 4 week I took my eight-year-old daughter back home to visit her grandfather for what could be the last time. I hoped the trip would create a sense of family for my daughter and build family solidarity.

But the attempt at solidarity backfired. My brother-in-law refused to shake my hand and to greet my daughter, and my sister was visibly nervous throughout the visit.

In recent weeks I left my sister messages to call me about our father. She called me back once and, with her family egging her on in the background, she began an angry tirade, then hung up. When I tried to call back to calm her down and reason with her, my brother-in-law and oldest nephew angrily answered the phone and swore at me. When I started to raise the issue of HD, my brother-in-law laughed and hung up.

With no hope of effectively communicating with my sister and her family, I have turned over my part in the matter of my father’s care to a lawyer and asked him to serve as an intermediary between me and my sister.

HD all over again?

My sister’s strong reaction eerily reminded me of our mother’s outbursts at the start of her disease. My sister is 46, and it was in her late 40s that my mother perhaps began to show the first psychiatric symptoms. My wife and I wondered: could my sister be showing the first signs of HD?

In a farewell e-mail to one of my nephews, I asked whether my sister had ever sat down with him and his brothers, now adults, to discuss the possibility that they and their potential children could inherit HD. They know that their grandmother died of Huntington’s, but, following in the footsteps of their mother’s denial, they seem oblivious to its implications.

“Mental problems”

For all their denial and aggressive behavior, at least my sister and her family know what HD is. An uncle and aunt have displayed an even stranger, more perverse form of denial.

Ever since they learned about my mother’s illness, my mother’s older brother and his wife have completely hidden the fact of HD from their two children, their son-in-law and daughter-in-law, and, by extension, their five grandchildren. According to my aunt and uncle, my mother had “mental problems.” My aunt has always alleged that she needed to protect her family from having to worry about HD.

I have heard rumors over the years that my uncle would get tested, but I don’t know if he ever went through with it. He’s now in his mid-70s and probably does not have the disease.

My uncle is a successful small businessman. He lives in a fine home and always drives the latest cars. Whenever I tried to call him to ask for a donation to fight HD, he complained about all of the solicitations he was getting from HDSA and other causes. One time he gave $100. I later wrote a long letter explaining how the family had to rally together around my mother. I hinted that, as a successful businessman with many contacts, he could make a substantial donation and also play a leadership role in fundraising. I never heard back.

Over the years I became weary of hearing my aunt talk of the need to shield her children. She and my uncle rarely visited my mother throughout her illness. Only when she came close to death in the nursing home did they come to visit more frequently. Even then, my aunt could not get much beyond her concerns about protecting her immediate family.

However, when my mother died, my aunt and uncle had no choice but to reveal the truth. But they told only my cousins – not their spouses – about HD. Somehow they arranged for only my cousins, and not their families, to attend my mother’s funeral. I can only imagine what strange logic was used.

I never pressured my aunt and uncle to change their views or to reveal anything to their children. The fear and stigma of HD in this branch of the family seem like a page out of Alice Wexler’s new book on Huntington’s disease, which I recently reviewed (click here to read the review). HD had become such a huge taboo that I decided simply to live and let live.

A polar opposite

Another branch of the family has acted in a completely different way. From the start, my father’s brother and his family have demonstrated complete solidarity.

I hadn’t seen my cousin—my uncle and aunt’s eldest son—in some fifteen years. When I called him out of the blue in 1999 to seek a donation for my first HDSA fundraising event, he demonstrated that he had been completely informed of my mother’s illness. When I sheepishly asked if he could donate $300, he shot back: “How about $1,000?”

I opened up immediately to my cousin about my gene-positive status and got advice from him on insurance questions. Later, when HDSA sought to improve its advocacy program, my cousin used his connections in the legal profession to help out. When The Washington Post published an article about HD and my story in 2005, my cousin immediately ran out to buy extra copies of the newspaper for me (click here to read the article).

During my July 4 trip back home I visited my cousin’s home along with my daughter and my father. We talked about HD, my sister, and my father’s decline, but we also enjoyed many stories from the past. I don’t drink hard liquor, but my cousin showed me his collection of Scotch whiskeys and got me to try a few. It’s been decades since I’ve felt such family togetherness. I was thrilled that my daughter could experience such a warm reception from relatives. My cousin is a true leader in the family. I know I can count on him.

Building a new family

After my sister and her family yelled and swore at me on the phone, a feeling of deep gloom about humanity came over me. I wanted to write this entry immediately, but for several days I became emotionally paralyzed.

Sadly, it is the inability to overcome denial and the lack of solidarity that sometimes make HD families their own worst enemies. Rather than reaching out, these families hide.

How wonderful it would be if my sister and maternal uncle and their families could join our cause. But they operate with the belief that information is harmful. I operate with the hope that it can ultimately be liberating.

I cannot change their way of thinking. And although it confounds me, I do not judge them. Because they have never opened up about HD, it’s impossible to fully understand their motives. I have to accept that each person deals with adversity uniquely. And as adversity goes, HD is extremely difficult. The bigger life’s challenges, the greater the potential for rising to the occasion – or hiding in the sand. I truly hope that they do not have to face the scourge of a positive test result for Huntington’s disease and all that it implies.

The good news is that I can focus on the positive side of the family in the person of my cousin and those around him. And I can be a force for greater openness by writing in this blog and continuing my work with HDSA.

And the gloom begins to dissipate even further when I think of all of the HDSA support group members, fellow activists, scientists, physicians, generous attendees at our fundraisers, and the virtual community of HD people and at-risk individuals with whom I communicate from around the world. They do care. Together we have built our own family.

The roots of our stigma

Huntington’s disease carries a huge stigma. Many families with HD cover it up, and many face discrimination. Surrounded by fear and ignorance, in many ways Huntington’s is stuck in the Dark Ages.

Why is this so?

Most people have not heard of Huntington’s or have only a very vague idea about it. It’s a devastating disease that people, once they see it, would rather not think about because it makes them confront an ugly version of mortality. HD destroys people’s humanity, frequently reducing patients to shaking, emaciated, wheelchair-ridden bodies unable to communicate with others. It’s like looking at death in slow motion.

Indeed, in remembering loved ones lost to HD, family members often refer not to the date of death, but the time of the onset of HD symptoms. I know that I lost my own mother, who died of HD in 2006, many years before that.

But the stigma derives not just from HD’s destructiveness. Different people in different times and places have reacted to the disease according to their circumstances and the beliefs of their communities about disability, science, and human nature. The stigma becomes hard to wipe away because it is part of the way people have learned to think and feel about HD, as taught by their families, doctors, schools, and government.

A new book uncovers prejudices

For the first time, a new book explores the roots of HD’s stigma. Written by historian Alice Wexler, it is titled The Woman Who Walked into the Sea: Huntington’s and the Making of a Genetic Disease (Yale University Press).

Many will recall Alice as the author of Mapping Fate: A Memoir of Family, Risk, and Genetic Research (1995), in which she chronicled her mother’s demise because of HD and her dynamic family’s quest for a cure. Starting in the late 1960s her father, the late Milton Wexler, became a national champion of HD research, and her sister Nancy Wexler, a top scientist, helped pioneer the Genome Project and the discovery of the HD gene in 1993.

Like so many of us, Alice, too, is at risk.

In The Woman Who Walked into the Sea, Alice explores how Americans over the past two centuries dealt with and interpreted HD. Although people in the early 1800s did not know what caused St. Vitus’s dance – as HD was then known – they understood that it ran in families. Some people with HD faced prejudice, but others were tolerated in their communities. Contrary to popular images of the disease, a number of HD-affected individuals achieved local prominence and great respect, as Alice explains.

However, today’s HD-affected families also will be all too familiar with the portraits and struggles depicted. For example, on a summer night in 1806, Phebe Hedges, a 40-year-old woman from East Hampton, New York, walked into the sea in an act of suicide. Remembering doctors’ failure to understand my mother’s condition, I found it painful to read about past families’ experiences with clinicians who were unfamiliar with HD’s symptoms or who refused care and instead urged affected families to avoid marriage and having children.

Instead of following the standard line about heroic researchers, Alice spends much of the book focusing on the challenges faced by the families.

The ambiguous Dr. Huntington

Thus the American physician Dr. George Huntington (1850-1916) appears in the book as a very ambiguous figure. On the one hand, he was the first scientific observer to note that HD involved what would eventually be called “dominant inheritance” – in other words, that a child of an affected parent had a 50-50 chance of inheriting the genetic defect and that the disease disappeared in the branch of a family where a particular parent did not have it. As a result, after the publication of Dr. Huntington’s findings in 1872, St. Vitus’s dance quickly became known as Huntington’s chorea – “chorea,” of course, meaning the shaking produced by the disease. (“Chorea” later gave way to the word “disease” when it became clear that HD also involved cognitive and other problems.)

On the other hand, Dr. Huntington used the concept of “insanity” to describe the depression and difficulties in judgment resulting from HD. That emphasis, Alice asserts, “introduced a term with powerful negative associations” and “may have heightened social fears surrounding the disease.” Scientists classified Huntington’s as a “degenerative disease,” reflecting not only its neurological reality but beliefs in social Darwinism, survival of the fittest, and the concept of a superior race.

Despite the importance of his discovery, Dr. Huntington showed no interest in carrying out further research. The Woman Who Walked into the Sea teaches us that, in the late 1800s and early 1900s, many other scientists were involved in discussions about HD, both positive and negative. Understanding the disease was a collective, international effort.

As the field of medicine modernized in the late 1800s and created the new specialty of neurology, Huntington’s was transformed from a “medical curiosity” into an “interesting” disease, Alice observes. Because of HD’s genetic cause and consistent symptoms, many neurologists came to see it as the “neurological disorder par excellence.” Research on HD broke new ground in the history of medicine. It helped to disprove the widely held belief that acquired – not genetic – influences could be passed on to the next generation. Understanding that a disease could have a specific genetic cause invalidated the belief that a person’s “weakness” or generalized tendency to illness could degenerate into any number of diseases.

Eugenics and sterilization

However, scientific progress, combined with an exaggerated emphasis on survival of the fittest, fostered extreme measures against people with disabilities. Long before Nazi Germany, the United States embraced eugenics, the idea that society should improve its genetic stock by preventing the unfit from having children. In 1907, Indiana passed the first legislation legalizing sterilization of inmates in public institutions. Over the next three decades, our country produced the harshest eugenics laws in the world outside those implemented by the Nazis.

Families with HD bore the brunt of eugenics. Alice describes the work of Dr. Elizabeth Muncey, a federal Eugenics Record Office researcher who compiled information on more than 4,000 people, past and present, who were linked to Huntington’s.

“Muncey was doing science, but also surveillance,” Alice writes. “She was scrutinizing certain families, diagnosing and labeling them, and in this manner, setting them apart from their neighbors. In this environment, her questioning, not only of the affected families but of their neighbors, ministers, and physicians, as well as town officials, inevitably put the families on display in a way that they had never experienced before.”

Alice Wexler

Charles Davenport, a scientist who worked with Muncey and analyzed her data, concluded that “it would be a work of far-seeing philanthropy to sterilize all those in which chronic chorea has already developed.” It was the government’s job “to investigate every case of Huntington’s chorea that appears and to concern itself with all of the progeny of such.” A government that failed to prevent the spread of Huntington’s was “impotent, stupid” and invited “disaster.” And immigrants with Huntington’s should not be allowed into the country. Davenport called for developing a predictive test for Huntington’s for eugenic purposes.

In the 1930s the Nazis may have forcibly sterilized as many as 3,500 people affected by HD. Tens of thousands of Americans were also involuntarily sterilized between the 1920s and 1960s, some of them perhaps affected by Huntington’s.

A long life for historical fictions

Alice illustrates how the scientific theories of the early 1900s, although eventually rejected, endured in our culture as beliefs held by everyday people. This deepened the stigma of HD. For decades, doctors continued to recommend against marriage for families affected by HD. Sadly, rather than researching ways to alleviate the disease, the scientific and medical communities advocated control of the families.

Fear about Huntington’s reached a crescendo in the 1930s and 1940s. New theories emerged, claiming that the original sufferers of the disease had been accused of witchcraft and had even played a part in the famous Salem witch trials of 1692. Both respected scientific journals and the popular magazine Literary Digest published articles on the alleged witchcraft connection; the Digest referred to HD as “the witchcraft disease.”

Not until 1969 did others debunk these “historical fictions,” as Alice calls them, adding that one perpetrator still clung to them as recently as the 1980s. Alice states unequivocally: “I have found no credible examples of an individual accused of witchcraft who behaved in ways evocative of this disease.” Even some people in the HD community still subscribe to the witchcraft theory as a way of highlighting the status of affected individuals as victims of oppression.

Time for indignation and action

The long history of prejudice and misunderstanding about HD reconstructed in The Woman Who Walked into the Sea will make you indignant, no matter what your relationship to HD. Alice’s book provides important information for scientists, activists, and families involved in the search for treatments and better care for people with neurological diseases. She shows us that disease is not just a question of science and medicine, but also of history and the cultural codes that we all live by.

As a gene-positive individual and activist, I will use The Woman Who Walked into the Sea to explain to our community and to others why the disease has so long been stigmatized and shrouded in mystery.

It also will help combat the stigma today. As Alice so expertly illustrates, substituting “fact” for “superstition” does not always lessen stigma and prejudice: at first, modern science actually increased prejudice via the practice of eugenics.

Recently I read a reader’s comment on a newspaper website asserting that it was wrong for a couple facing HD to have children. It angered and saddened me. Today we have genetic testing for HD, but, thankfully, the decision to go through with it lies solely with the at-risk individual. The information is confidential. We also have pre-implantation genetic diagnosis (PGD), which permits a couple to select a non-HD-carrying embryo for in vitro fertilization.

My wife and I tested our own daughter, conceived before PGD was available, while still in the womb. She is negative for HD. We wanted a child, even though we knew that my own gene-positive status meant I could soon become disabled. The history of HD as recounted in The Woman Who Walked into the Sea warns us of the need of HD families to assert their rights to have children and to guard against discrimination.

We know that we can shape a better future for ourselves by advocating for better understanding of HD and, as Alice urges, demanding that the medical and scientific communities use new biomedical knowledge to benefit families. This means getting involved in advocacy and politics. Many people may find this distasteful or difficult, but unless we do so, we run the risk of facing new versions of the HD stigma.

Huntington's disease, destroyer of families

When my mother died of Huntington’s disease 28 months ago, she became but the first victim of the disease in our family.

The stark truth of HD’s reach into our lives came down like an anvil on my head when I received a surprise phone from a social worker, who told me that my 80-year-old father might have to be admitted to the geriatric psychiatric ward of the hospital back in my hometown. Someone at the Veterans Administration, where my father has occasional medical appointments and picks up his discounted medicines, had filed a complaint with Adult Protective Services, the agency that looks after adults who are neglected or unable to take care of themselves.

When the social worker looked in on my dad, she saw him talking to my mother’s wedding picture, turning on the television for it, and checking frequently to make sure that “she” was okay.

My father started caring for the picture around the first anniversary of my mother’s death, about 16 months ago. He sometimes takes it with him in the car and to my sister’s and friends’ homes, and he hangs a decoration on it.

“You know that it’s just a picture, don’t you?” my relatives and I always ask him. He readily responds yes.

HD wiped out the ‘golden years’

After 48 years of marriage and 15 years of caring for my mom after her HD became full-blown, it’s understandable that my dad would develop an attachment to her photo. He’s especially lonely because I live thousands of miles away and because he has relatively little contact with my sister, her husband, and their three sons. According to my sister, he became alienated from them in part because he had dedicated himself fully to caring for my mother and had no time for them. He has nobody to help him with the grieving process.

My father had remained quite alert while my mother was alive, but he has declined physically, mentally, and emotionally since her death. He does not eat properly, has lost weight, and has several serious health problems. In addition, his short-term memory has severely deteriorated, and he often becomes disoriented. He refuses to even discuss an assisted living facility, so as a stopgap measure late last year we arranged for caregivers to come into the home for a couple hours three times a week. Early this year he fired them, claiming they were too expensive. He is stubborn, proud – and unaware of his changing circumstances. When I continue to press upon him the need for assistance, he becomes angry and defensive and says, “I don’t need any help!”

My mother was only 68 when she died. I had always assumed that she would be his caregiver someday, and that he would die first. Huntington’s disease reversed their roles and robbed them both of their “golden years.” Instead of trips and time with the grandchildren and friends, they struggled together with her decreasing ability to walk, talk, and eat. Slowly my mother became but a faint shadow of her once vital self.

Avoiding the lock-down

The social worker arranged for counselors to come to my father’s house to evaluate him. It was a Friday afternoon, and they would arrive at 10 a.m. on Monday. Because I was preparing to hire a geriatric care manager to keep watch on my dad and his health, I tried to negotiate with her to postpone the meeting for at least a few days. But she was adamant: she was concerned about my father’s safety. A lawyer urged us to “play along” with Adult Protective Services, because it has lots of “authority and clout.” I finally convinced her to hold the meeting at 3 p.m., when my sister and others could be present.

I learned that my dad could be in the hospital for as long as ten days. Worse yet, the geriatric psych ward was a so-called “lock-down” facility: he would not be allowed to leave. If they found him incompetent, he would go immediately to a nursing home or similar facility. Depending on the availability of beds, we might not even have a choice of location.

I feared a devastating shock to my father’s fragile emotional state. The first night of the crisis I stayed up until 2 a.m. on the computer researching the law and potential solutions to my dad’s plight.

That night I had a vivid dream in which my father – the man who had guided me through so many of life’s challenges – led me through a desert filled with vipers, a white bobcat, and other threatening animals. I in turn helped him navigate the same dangers.

Rallying the family

I considered flying home but, given the precious little time before the meeting, decided it was best to work the phones to rally family members (including a cousin who’s an attorney) and discuss the predicament with a geriatric care manager, who was already familiar with my dad’s situation.

My sister and five other people representing our family attended the evaluation. I believe that the show of solidarity with my father convinced the counselors that he did not need immediate hospitalization.

But there is no doubt that my father needs immediate help in many other ways. The counseling agency will arrange to spend several hours with him three times a week, and he will start getting Meals on Wheels. We need to stop him from driving and start making plans for an eventual move to an assisted living facility.

HD’s many victims

Like my dad, my sister and I are stoic about life and really good at denial, too. But we’re forced once again to stare Huntington’s disease in the eye. Instead of enjoying our father’s final years, we’re constantly reminded of my mother’s illness and his loving, heroic, and tragic attempts to deal with it. We see how sad and run-down he has become after the long fight against HD.

So we are victims too. My father’s episode reminds me of my own gene-positive status and the likelihood that I will follow in my mother’s footsteps. My sister, who is 46, is untested, and she and her husband wonder about the status of their sons. My wife stands by helplessly as she worries about me and what her own life will be like when my inevitable symptoms start and I can no longer be the dedicated father I have been to our daughter, now eight years old.

HD is more than a disease. It is a destroyer of families. And that is all the more reason why we must stop it.

Building a ‘laser-guided missile’ to attack Huntington’s disease

Isis Pharmaceuticals, Inc., a world leader in developing technology to attack the genetic causes of diseases, is now engaged in the fight to stop Huntington’s disease.

In previous entries in this blog I outlined the basics of the project (click here to read more) and expressed my enthusiasm for its potential to control HD (click here to read more). Isis aims to block HD at its genetic root, and, if all goes as planned, the company will be ready to test a drug in humans by late 2010.

On April 9 I visited Isis in Carlsbad, California, to meet the people who are seeking to relieve the suffering of tens of thousands of Huntington’s families and prevent the disease from destroying the brains of people like myself who have tested positive for the defect but not yet shown its most obvious symptoms of shaking limbs and dementia.

A new technology

“We have a technology that prevents the huntingtin protein from being expressed. We showed in cells and animals that we could inhibit mutant huntingtin,” said C. Frank Bennett, Ph.D., senior vice president of research at Isis. “If you don’t express the mutant form of huntingtin, you can abrogate or delay the onset of the disease.”

Isis developed that technology in a feasibility study carried out two years ago for Cure Huntington’s Disease Initiative, Inc. (CHDI), a Los Angeles-based non-profit foundation dedicated exclusively to finding a treatment or cure for HD. Isis demonstrated that it could block the action of the huntingtin gene in mouse and human cells and in actual mouse brains. All humans have two copies of the huntingtin gene, the recipe from which they make huntingtin protein, but in some people one copy of the gene has a mutation that makes a faulty protein, which causes Huntington’s disease. HD is a genetic disease. Children of affected people have a 50 percent chance of inheriting the mutation, and everybody who tests positive for the defect will eventually develop HD.

In October 2007 Isis and CHDI announced the current project, which seeks to control the mutant form of huntingtin in humans. CHDI will provide Isis up to $9.9 million to carry out the various stages of the project over the next three years. CHDI receives support primarily from an anonymous donor (the High Q Foundation) and is also supported by the Huntington’s Disease Society of America and the Hereditary Disease Foundation.

The weapon: big molecules called ‘oligos’

Scientists refer to this approach as “antisense technology.” DNA, the building block of all life, runs our cells by telling them which proteins to make. It does so by sending messages via another molecule called messenger RNA. As encoded by DNA, RNA has a very specific template, somewhat akin to a unique electrical outlet into which only a unique plug can fit. RNA is known as a sense molecule, and Isis manufactures the antisense plugs to control them. These antisense molecules are called oligonucleotides, or oligos.

“Our technology allows one to basically, with a laser-guided missile, target that specific messenger RNA that causes a particular disease and kill it or take it out of the body so that you don’t produce that messenger RNA,” Dr. Bennett explained about the project’s goals. “The result is that you prevent the bad protein from being expressed…. We’re designing oligonucleotides that will bind to the huntingtin messenger RNA, and upon binding to the messenger RNA, prevent it from being translated into a protein product.”

Frank Bennett, Senior Vice President of Research, Isis Pharmaceuticals

Dr. Bennett, who has published more than 90 papers in the field of antisense research and development and has more than 100 issued U.S. patents, likened the manufacture of oligos to playing with Tinkertoys.

Remember that Tinkertoys have circular pieces of wood with holes into which a child puts pencil-like sticks and thus builds a small structure. Isis does the same thing using a complex piece of machinery and produces extremely long molecules. “We do that with chemistry on a machine called an oligonucleotide synthesizer,” he said. Isis can make just a few milligrams of oligos for initial testing and then much larger amounts using much larger machines in order to prepare the oligos for commercial application in partnership with a larger pharmaceutical company.

Fine-tuning the approach

Many researchers are looking at antisense technology for a variety of scientific and medical applications. However, in a field that once had other competitors, Isis is now the only company in the world working with its particular kind of antisense technology, and it has a number of patents for its oligo designs.

Isis’s strength lies in its ability to “measure RNAs in cells,” Dr. Bennett continued. Isis has a room with “rows and rows” of instruments for studying the RNA, “as well as robots that extract the RNAs from cells and put them on machines. We have really industrialized that part of the process.” According to Janet Leeds, Ph.D., CHDI’s director of pre-clinical development, the point person for the Isis project, and a former eight-year employee of Isis, the company has decreased the cost of producing oligos tenfold.

Isis is currently working on fine-tuning the oligo it developed in the feasibility study and has already tested over 200 compounds, said Dr. Leeds. Once the best match is found, it will test the oligo in transgenic mice provided by CHDI. Developed by Dr. William Yang of the University of California, Los Angeles, those mice are engineered so that they have both a normal mouse huntingtin gene and a mutant copy of the human gene. They develop Huntington’s-like symptoms. Isis employs a special clamp known as a stereotactic device to inject drugs into mice at exactly the same spot each time, and it uses other devices to measure the mice’s behavior, muscle strength and coordination, and brain function – all crucial factors in Huntington’s disease.

If mouse tests are successful, Isis will repeat the experiment in monkeys to better assess the safety of the oligo for testing in humans.

“We’re breaking ice in learning how to modulate huntingtin,” Dr. Bennett continued. “Nobody’s had a technology that would allow you to address what is the function of huntingtin in a developed organism. It clearly plays a role in normal physiology. It’s not well understand what that role is, but it seems to be important for some aspects of normal function of neurons as well as other cells in the body. It’s expressed everywhere in the body, not just in the brain.”

Making a safe drug

Now that Isis is close to an oligo, it faces two other huge challenges. First, because the oligo would regulate both normal and mutant huntingtin, Isis and CHDI must determine how much huntingtin should be controlled in order to reduce the effects of the disease, avoid adverse effects, and lessen the chances that gene-positive people start having symptoms. For now the plan is to reduce or “knock down” huntingtin’s action by about 50 percent, said Dr. Leeds.

“That’s no different than any other drug that we use today,” Dr. Bennett said. “Say if you take a drug that lowers your blood pressure. If you’re hypertensive, and are at risk for cardiac dysfunction, because you have high blood pressure, lowering your blood pressure is good. But you don’t want to lower it to zero! All drugs will produce toxicity if you overdose. The animal models will be very instructive for giving us that guidance, because we will be able to lower the normal level of huntingtin as well as mutant huntingtin and cover whatever are the potential adverse effects of that.”

Dr. Leeds added that the Isis scientists could end up discovering that each individual needs a particular molecule to regulate his or her level of huntingtin. But this “personal medicine” approach is not yet feasible.

Getting the remedy into the brain

Secondly, Isis must get the oligo into the brain.

CHDI is banking on Isis’s success in developing the world’s first antisense drug clinical use, Vitravene, which is used to treat an eye disease associated with AIDS. Vitravene is injected directly into the eye. With current technology an oligo for Huntington’s disease cannot be delivered via a pill or injection into the brain, and any medication will have to cross the blood-brain barrier.

In the mouse experiment Isis inserted pumps under the animals’ skin and ran a tube into the brain. For humans, they are considering the use of a hockey puck-sized pump placed in the abdomen, which would pump the drug through a tube carefully inserted into the brain. Dr. Bennett pointed out that people with a number of conditions such as chronic back pain or diabetes already use commercially approved pumps. Doctors can use infrared signals to program the pumps and control the flow of medication and can inject a new supply into the pump through a port just under the skin.

“It’s obviously not ideal, but considering the severity of this disease, it’s well worth the inconvenience that these pumps produce,” Dr. Bennett observed. “Once patients acclimatize to them, they’re really not that bothersome.”

Isis is exploring the possibility of pumping the oligo into the spinal fluid. From there it would diffuse into the brain. This method might use a less invasive pump system.

Dr. Leeds pointed out that CHDI and another company are exploring a third method of delivery: a subcutaneous shot (just under the surface of the skin). A person would receive such a shot about once a month. This technology, however, could be at least a decade off. The longest term goal would be to develop a pill.

Regardless of the method, the patient would have to take the medication for life because of the genetic nature of HD, said Dr. Leeds.

Isis Pharmaceuticals’ unique flavor

Scientists began working with the concept of antisense in the 1970s, and in 2002 they discovered that oligos actually exist in nature and provoke RNA interference (RNAi). Other researchers are seeking ways to use RNAi to treat diseases, including Huntington’s. “Antisense is like a fruit,” Dr. Bennett explained. “We have apples, oranges, and pears. There’s well over a dozen different mechanisms by which you can exploit antisense to modulate gene expression.” For the Huntington’s disease project Isis is employing a particular enzyme involved in the cell’s normal RNA processing, called RNase H.

“We as a company are broadly exploiting all types of antisense,” Dr. Bennett said. “We have a little bit different flavor that we are using for this project, because in our opinion it’s working more efficiently and it’s ready for testing in man today.” The key to understanding the different “flavors,” he added, is to understand that different enzymes block or degrade the RNA in different ways. Whereas RNAi molecules are twice as large as the Isis oligo and do not enter a cell as easily, the Isis product gets into cells without a special formulation.

If all goes as planned, after the monkey study Isis will apply for permission from the U.S. Food and Drug Administration to administer a test in a small group of humans. Following that step the company would seek a partnership with a commercial drug company to run a large-scale clinical trial. Isis will count on CHDI for establishing contact with a larger pharmaceutical company and designing an efficient large clinical trial. The Huntington Study Group’s “Predict HD” program, which tracks the health of people over 18 who have tested positive for HD but not yet developed symptoms, will be an important source of assistance in a large clinical trial, Dr. Leeds said.

The company’s potential

Isis, a publicly traded company which has about 300 employees, will have as many as eight people working on its HD project, including chemists, biologists, specialists in pharmacokinetics (measuring the drug in tissues), toxicologists, and specialists in clinical trial development.

In addition to Vitravene, the company is developing Mipomersen, an antisense drug targeted at people with extremely high cholesterol levels (500 and higher). Known as familial hypercholesterolemia, this condition is similar to Huntington’s disease because of its roots in a genetic defect. It is also possible that the drug could also be used for others with high cholesterol. Dr. Bennett is confident that Mipomersen will reach the marketplace.

Isis has also used an antisense drug to reduce the effects of Lou Gehrig’s disease in test rodents. Isis delivered the drug, ISIS 333611, directly into the rodents’ spinal fluid via an implanted pump. The company is also starting a new project on Parkinson’s disease.

Frank Bennett with just a few of Isis's more than 1,500 patents.



Not a ‘cure,’ but a historic step for science and patients

Like all other scientists, Dr. Bennett hesitates to refer to the potential HD antisense drug as a “cure.” “I don’t think we’ll cure the disease,” he said. “But what I think we may do is benefit the patients so that either we stabilize the disease and they don’t get worse, or we slow the decline…. That would be a fantastic outcome.”

If the CHDI-Isis project is successful, it would be the first time that humanity brought a neurological disorder under control. According to Dr. Bennett, such a result would validate the large investment that science has made in recent years to understand how these diseases come about.

Isis, which began in 1989, has yet to turn a profit but has almost a half billion dollars in the bank for its operating expenses. It expects to have a respectable operating loss of only $15 million for 2008.

“We do this for the patients,” Dr. Bennett said. “These are diseases where there really isn’t much to offer those patients. We’re very motivated to provide therapies for those patients. Ultimately if we help the patients we’ll help the company. I’m paraphrasing – the CEO of Merck actually said this 40 years ago: ‘If you focus on the patients, the rest of it will fall in place.’ I truly believe that.”

(Next time: an at-risk person’s inside look at Isis)

Observing the cure in progress

In a couple of hours I will tour the innards of the company that could save me from the ravages of one of the cruelest diseases to afflict humanity, the disease that took my mother’s life two years ago and which will very likely destroy my own brain.

Isis Pharmaceuticals, Inc. of Carlsbad, California is working to develop a drug that will halt Huntington’s disease at its root cause: the genetic process leading to the making of bad proteins that somehow kill brain cells.

By visiting Isis I’m trying to tackle HD head-on by learning yet more about the disease and then hoping to inform the HD community of this potential scientific breakthrough.

Genetic pioneers

I want to walk in the midst of scientists who, whether they think about it or not, have my life and the lives of hundreds of thousands of at-risk and affected HD people around the world in their hands. I want to meet the men and women who could be the heroes for the families who are struggling so valiantly against HD but who are powerless to stop its genetic onslaught. The people at Isis are the genetic pioneers who could introduce us to a whole new vista of hope and health.

I want to witness firsthand the making of what would be a miracle for the HD community – and millions of people affected by numerous other neurological diseases.

I want to observe the cure in progress.

Making sense of antisense

Yesterday I prepared for the visit to Isis by interviewing Dr. Janet Leeds of the Cure Huntington’s Disease Initiative, Inc (CHDI). CHDI is funding the Isis project, and Dr. Leeds is the project’s scientific manager. We discussed the two biggest challenges of the project: first, administering a drug that will not interfere with the normal function of the huntingtin gene (a gene that everybody has but which has gone awry in HD people) and, secondly, delivering the drug to the brain.

I also learned that scientists have been thinking about the technology being studied by Isis – a technology to make an antisense drug – since the 1970s, and not only since 2002, as I wrote in my previous entry here.

So I spent a part of the evening studying a report from Isis that describes the similarities and differences between antisense technology and a more recent technology, developed after the discovery of RNA interference in 2002. I hope to learn more about these two technologies today.

Wanting to help

The attempt to grasp all of this technical information and the anticipation about my visit to Isis caused me to sleep fitfully last night. I dreamt that I had to make a presentation to Isis scientists that would convince them to hire me to help them market their firm to the world. They were highly skeptical, but then I gave a passionate speech about the need to relate to people on a human level. They began to listen.

I am not a scientist, but I urgently want to help in the effort to cure HD. I depend on the cure, and so do my wife and daughter. I refuse to let this disease ruin my life and prevent me from seeing my daughter grow up.

Time for optimism: a cure for Huntington's could be near

On October 26, 2007 a California pharmaceutical company announced a multi-million-dollar project to develop a drug that would eliminate the root cause of Huntington’s disease.

If it works, the project would not only cure Huntington’s but could revolutionize treatments for other diseases and usher in a new era of medical advances that just a few years ago seemed like science fiction.

Isis Pharmaceuticals, Inc., located in the San Diego suburb of Carlsbad, revealed that it is working on an antisense drug for HD. This class of drugs is designed to block the action of genes that cause disease. In the case of HD Isis aims to stop the huntingtin gene from making proteins that disrupt brain cells and cause the harmful symptoms of HD.

An impressive development

In my opinion this is the most impressive and promising initiative ever developed for finding a treatment or cure for HD. Isis is aiming for results now and in humans, not just in a test tube or in a mouse.

The technology is based on the discovery of RNA interference, or RNAi. RNAi is a natural process in which genes are switched off. Its discovery was considered the top scientific breakthrough of 2002, and scientists have been studying it intensively ever since. So are some drug companies.

Isis has already gotten approval from the U.S. Food and Drug Administration (FDA) for Vitravene, which it calls the “world’s first antisense drug” to go to market. Vitravene is used to treat an eye disease associated with AIDS.

And Isis has used an antisense drug to reduce the effects of Lou Gehrig’s disease in test rodents. Isis delivered the drug, ISIS 333611, directly into the rodents’ spinal fluid via an implantable pump.

A pump in the brain

I have long imagined that this could be the future for me and many hundreds of thousands of other people around the world who are gene-positive for HD: we would have a small pump on or in our heads delivering a life-saving drug to our brains. HD would be totally controlled.

Such pumps now exist because of nano-technology and have actually been used safely in thousands of people. Doctors surgically insert the device into the brain. They inject medication into the brain during a routine visit to the doctor’s office.

It is especially encouraging that Isis has already shown that it could reduce the action of huntingtin in the brain and peripheral tissues of normal mice using an antisense compound.

$9.9 million in funding

The Isis research is backed by the Cure Huntington’s Disease Initiative, Inc. (CHDI), a recently founded drug discovery firm targeted exclusively at HD and funded by a private, anonymous donor. Based in Los Angeles, CHDI will provide Isis up to $9.9 million for the project. This is one of the largest amounts – if not the ­largest – ever spent on an HD research project.

The project will first focus on testing an antisense drug in transgenic HD mice – genetically engineered animals that have the same genetic defect as human HD patients. If successful, Isis will then test the drug in monkeys. CHDI could then approach the FDA for approval for human testing as early as the third year of the project.

“This is very good news because a potent RNA drug will stop Huntington's at its source, and we could let ourselves say the ‘cure’ word,” Dr. LaVonne Goodman, the founder of Huntington’s Disease Drug Works and an expert on HD research, wrote shortly after the Isis announcement. “I confess that just a year ago I didn’t believe I’d see this much progress on RNA therapy in my lifetime, and I’m glad I’m wrong.”

Reversing HD’s devastating effects

If successful, the Isis antisense drug could very well do more than prevent HD: it might also partially reverse the disease. Studies of RNAi treatment in mice have shown that the animals recovered normal motor function because of the ability of brain cells to regain health and take over the job of cells destroyed by HD.

This possibility brings me a mixture of joy, frustration, sadness, and guilt. I am excited to know that if my own symptoms start soon, the potential Isis drug may be able to stop them and keep my brain completely healthy. And I am happy that acquaintances with HD might return to a normal life and save their families from witnessing their horrible decline. But I also wish that such promise had existed two years ago February, when my own mother died of HD.

I learned about my mother’s HD in 1995, and I tested positive in 1999. Living at risk for HD – a 100-percent genetic disease that affects all gene-positive individuals – has impacted every aspect of my and my family’s lives. It has been extremely frustrating to see scores of theoretical advances over the years but no real hope of an effective treatment.

Time for optimism

Now, for perhaps the first time, I am beginning to feel optimistic about my future and that of the HD community. As I wrote recently (click here to read more), in December the state of California moved a step closer to considering a multi-million-dollar project to create a program to seek a treatment for HD using stem cells. Other scientific breakthroughs continue to occur.

I have felt especially moved to express optimism because in the last few days I have felt deeply sad at reading about young people with HD at the new website WeAreHD.org. They are struggling with symptoms and worrying about the fate of their potentially at-risk children.

The HD community needs to support the Isis-CHDI partnership in any way it can. I will visit Isis very soon to learn more about its HD project, so please stay tuned for a new entry on this extremely important topic.

Keeping calm in the face of Huntington's

Living at risk for Huntington’s disease often causes me to try too hard to take care of myself. I’ve always been a bit of a hypochondriac and face the possibility of other health problems, so living with a positive test for HD can greatly magnify my concerns.

Just recently a chain reaction of self-inflicted and misunderstood incidents landed me in the operating room.

Weighing the risks of supplements

About three years ago, I started taking the supplements recommended by the Huntington’s Disease Drug Works program. They are tolerated well by humans and have shown positive results in animal tests, and, significantly, those people with early or mid-stage HD who consistently take them have stabilized or improved. I am hoping that they will delay the onset of my symptoms, which are inevitable because of HD’s 100-percent genetic nature.

As one should do with any supplements, I have carefully followed the instructions. With creatine, for example, I get periodic blood tests to check for possible harm to the kidneys.

Another of the supplements is trehalose, a natural sugar. I take it mixed in water, plain yogurt, or cereal.

Trehalose seemed harmless and I didn’t think it would cause any side effects. In contrast with my concerns about creatine, I took it without thinking about the possible consequences.

But then early last fall I got a call from a nurse at my health plan stating that I should see my physician because one of my blood tests showed a glucose reading of 109 – nine points above the recommended maximum. I learned pretty quickly that 109 put me in a category known as “pre-diabetic.”

“Diabetes?! I have enough to worry about with HD!” I told my wife. There is no history of diabetes in my family, and I usually keep very close to my recommended weight range.

Dr. LaVonne Goodman, the founder of the Huntington’s Disease Drug Works program, reminded me that the instructions for taking trehalose include reducing my carbohydrate intake. After all, the nine standard-size packets of the sugar were the everyday equivalent of three soft drinks.

Panicking about carbs

For the first time I started paying attention to the carbohydrates in my diet. “Carb counting” is a big new fad in our culture. My wife did it when she took part in a weight reduction program. These days carb stats seem to be on every food label and every restaurant menu.

I did not know the actual cause of my glucose reading. Was it the trehalose? Was it the fact that I had gained twelve pounds over the summer and had gotten out of my exercise routine? Was it a lab mistake or maybe just a fluke reading? Had I crossed some artificial barrier established by a drug company interested in classifying more people as diabetic? Did the reading result from some combination of factors? Both Dr. Goodman and my own physician actually expressed little concern about the number.

Whatever the cause, I panicked. I simply could not accept having another major health threat to worry about. I wanted to cut my carbs and lose weight.

I immediately eliminated practically all carbs from my diet – no bread, no dough, no candy, no corn, no potatoes. I tried to eat just proteins, vegetables, and salads. I had an especially hard time turning down pizza. But I was determined to escape from the “pre-diabetic” range.

From bad to worse

In my worst imagination I could not have imagined the terrible result of this strategy. My stools became rock-hard, and my bowel movements, which have worked excellently throughout my life, turned into an ordeal. Blood started showing up on the toilet paper. I figured the cause was hemorrhoids that occasionally flare up, which I usually treat with some over-the-counter suppositories.

Then one night a large amount of blood came out, leaving a very long streak in the toilet bowl. It must have been close to a tablespoon’s worth. The doctor at the proverbial urgent-care clinic examined me, saw hemorrhoids, and prescribed a medication. It did not work. The bleeding continued, and now I had pain. Several weeks later I returned to the clinic. This time I heard another diagnosis: the doctor said I probably had an anal fissure produced by the hard stools and that it might require surgery.

Anal fissure?! That was a completely new term for me. Surgery?! My fears multiplied. I quickly learned that anal fissure surgery had a high success rate, but in some cases the patient ended up with uncontrollable flatulence or, worse yet, had to wear diapers the rest of his or her life because of anal dripping.

And, I was told, surgery involved general anesthesia. I wanted to avoid this option at all costs, because I had heard stories over the years of people at risk for HD suddenly experiencing their first serious symptoms or seeing their symptoms worsen because of shocks to their bodies such as car accidents.

Staving off surgery

I tried a cream on the fissure with no luck. A surgeon prescribed stool softener, several warm baths per day, and nitroglycerin ointment, used to promote blood circulation and healing in the anal area. He told me to try this treatment for two months.

The pain became excruciating – like a knife cutting into my anus. The doctors I spoke with said it was one of the worst kinds of pain. Every bowel movement caused the fissure to reopen. The pain usually lasted for hours and sometimes as long as half a day. I could not sit comfortably. I did not feel like talking to anybody, and I couldn’t find the energy to blog here except for one important entry in late December (click here to read it). One night I had to eat dinner standing. I became very irritable towards my wife and daughter. Sometimes I felt on the verge of fainting.

The nitroglycerin did not help. I sought a second opinion from another surgeon, who sometimes did Botox injections into a patient's anus as a way of relaxing it and allowing the fissure to heal. But she recommended I have the surgery. And – very important for me – she said I could do it as an outpatient and with local anesthesia.

The procedure, which took place on February 8, immediately relieved the pain, and my recovery went well. Now, for the first time in five months, I am no longer afraid to go to the bathroom.

Valuable lessons

I have learned some valuable lessons from these past few months.

The terrible pain and my subsequent recovery have reminded me once again to savor every moment of life.

It also reminded me that living at risk for or having HD does not exempt people from other health challenges. I know of at least two women who have also had to battle breast cancer.

Just as with standard medications, taking supplements is a serious matter that requires extra vigilance regarding diet and other habits. It actually took me a year to start taking the supplements, and I phased in one after the other.

However, in my case, because I have not revealed my at-risk status to my health plan for fear of genetic discrimination, I do not have a local physician monitoring my body’s reactions as recommended by the Huntington’s Disease Drug Works. If I had, I likely would have avoided the crisis. The crisis, in fact, led me to seek out a naturopath, who has helped me take a more holistic approach to my situation of risk. Thus I am constantly juggling information from Huntington’s Disease Drug Works, my health plan, my psychotherapist, and now the naturopath.

An uncomfortable place in the system

It’s obvious that our health system is failing me. If I could give full disclosure, I could get the proper care locally. Had the system not taken weeks to properly diagnose and treat my anal fissure, I very likely could have avoided the pain and the surgery. Had the system guided me to a dietician after I tested high for glucose, I could have avoided the fissure altogether.

I’m learning not to rush into solutions. Had I not cut my carbs so quickly and drastically, the crisis would not have started. The naturopath put me on a vegetarian diet for a couple of weeks in order to help soften my stools and relieve the pressure on the fissure. That was good short-term advice. But then my wife pointed out to me that, if I stayed on a strict vegetarian diet without further consultation and study, I could be heading for a new crisis.

On a follow-up visit, my naturopath agreed and said, “Listen to your wife.” Health care – especially when one is at risk for a serious disease – is a family matter, not just an individual one.

Managing anxiety

I believe that my crisis provides me and others at risk for Huntington’s disease with one final message: keep anxiety at a manageable level. At the end of my last conversation with the naturopath I concluded that I was trying to “maintain equilibrium.” By equilibrium I mean a balance in activities and diet and proper attention to the mind and soul. Only with that approach can we muster the energy and level-headedness needed in the fight to avoid Huntington’s disease symptoms.

I recently had a new blood test. My glucose is back in the normal range. The months of pain were a high price to pay for my few days of panic. I should have acted more slowly and calmly. But that’s so hard when you face a disease like HD. As I felt relief after my operation, I yearn for a cure for Huntington’s disease so that I and so many others can lead more peaceful lives.