Friday, May 29, 2015

Overcoming the Fear of the Lion: A Courageous Film About Genetic Testing and Huntington's Disease

A new documentary, The Lion’s Mouth Opens, poignantly captures the precarious journey into genetic self-knowledge by Marianna Palka, a 33-year-old filmmaker-actress. She has decided to test for Huntington's disease (HD), which has been referred to as the "devil of all diseases."

The film premieres on HBO on June 1 at 9 p.m. ET.

Read my preview of the film in The Huffington Post.

Wednesday, May 20, 2015

The search for Huntington's disease treatments is indeed ‘rocket science’ – and we can all help build the rocket

For people facing Huntington’s disease and other devastating, untreatable conditions, the powerful wish for a cure can conjure up the image of an elated scientist bursting from a laboratory and declaring “Eureka!”

However, it is unlikely a treatment for HD will emerge in this way.

We often misunderstand scientific progress, as explained in an essay in the May 16, 2015, edition of The New York Times by prominent physicist Leonard Mlodinow, Ph.D.

“Why do we reduce great discoveries to epiphany myths?” asked the sub-headline for Dr. Mlodinow’s online article, which was titled “It Is, in Fact, Rocket Science.”

“The mythical stories we tell about our heroes are always more romantic and often more palatable than the truth,” Dr. Mlodinow writes. “But in science, at least, they are destructive, in that they promote false conceptions of the evolution of scientific thought.”

From Isaac Newton to Charles Darwin to Stephen Hawking, we have oversimplified the process of discovery, Dr. Mlodinow explains. Rather than the eureka moments popularized in books and the media – like the apple falling on Newton’s head – these scientists’ discoveries involved years of hard work and questioning of assumptions, including their own.

Thus, Dr. Mlodinow reminds us that breakthroughs result from the cumulative build-up of many moments of discovery by scientists past and present.

He thus underscores a crucial point for the Huntington’s disease community: finding treatments will necessarily involve a collective effort by scientists and volunteers in research studies and clinical trials.

“Even if we are not scientists, every day we are challenged to make judgments and decisions about technical matters like vaccinations, financial investments, diet supplements and, of course, global warming,” Dr. Mlodinow points out. “The myths can seduce one into believing there is an easier path, one that doesn’t require such hard work.”

We in the HD community must all play our part in the quest for treatments.

A eureka moment deflated

As a carrier of the deadly HD mutation who watched his mother succumb to the disease, I have sometimes fallen prey to the seductive scenario described by Dr. Mlodinow, and even done so in this blog.

Four years ago this month, I was so excited about Alnylam Pharmaceuticals’ progress towards a remedy that I posted a picture of myself holding an Alnylam compound designed to attack HD at its genetic roots. I wrote that the compound, “the potential cure in my hand,” seemed magical.

I later made the image my Facebook profile photo.

(See the photo below and click here to read more.)

Gene Veritas holding the Alnylam compound in 2011 (photo by Dr. Matthias Kretschmer, Alnylam)

I had perhaps become overconfident about the Alnylam project.

In collaboration with its partners Medtronic and CHDI Foundation, Inc., the nonprofit virtual biotech focused on HD treatments, Alnylam was planning to apply in 2012 for permission to start a clinical trial.

In early 2012, however, Alnylam cut a third of its work force in order to reduce costs. In May of that year, less than a year after my 2011 visit, the company shifted its business strategy. It downgraded the HD project and fired the scientific director in charge

Alnylam chose instead to concentrate on less complex – and perhaps more profitable – projects to find drugs for other conditions. Alnylam passed on the responsibility for testing the compound in a human clinical trial to Medtronic.

To date, Medtronic has announced no plans for a human clinical trial of the Alnylam compound.

“Medtronic believes the siRNA [gene-silencing] drug-device program continues to represent an exciting opportunity to combine an innovative therapeutic strategy with state-of-the-art drug device delivery technology for Huntington’s disease,” Jack Lemmon, Ph.D., a Medtronic program manager, responded in an e-mail to my request for an update on the project. “Pre-clinical work has generated promising results; however the therapy research program has been paused since 2013 until partnerships can be established allowing us to sustain the research. At this time, it is premature to discuss timeframes, but we hope to continue work to find a treatment for this devastating neurodegenerative disease.”

Shots on goal

I am concerned that the project runs the risk of entering a not uncommon limbo, which one former director of the National Institutes of Health calls the “valley of death,” the increasingly difficult transition between laboratories and clinical trials.

Devising the Alnylam compound involved a significant investment of time, money, and expertise. In my extensive interviews with Alnylam scientists in 2011, and even in a conference call with some of those same researchers after the announcement of the 2012 cutback, they expressed enthusiasm about the promise of the compound.

The Alnylam compound may – or may not – ultimately play a role in the search for treatments.

Without the Alnylam compound, the HD community would have one less shot on goal in the critical gene-silencing field.

I am disappointed at the lack of action – much less progress – regarding the Alnylam compound.

Fortunately for the HD community, one of those shots is scheduled to take place this year: Isis Pharmaceuticals, Inc., and Roche will start a historic gene-silencing clinical trial using a different type of drug technology. Other companies and labs are also focusing on the development of gene-silencing approaches for HD.

The Alnylam project didn’t meet the expectations of many in the community. However, it has still provided valuable data from which other researchers can benefit. I am grateful for Alnylam’s contributions to the quest for treatments, and I’m crossing my fingers that Medtronic can resume the project.

I indeed recognize that the path to treatments is not easy. Nor is it straight.

One example of a potentially fortuitous outcome of the Alnylam decision: the dismissed HD project director, Dinah Sah, Ph.D., now works as the senior vice president of neuroscience for Voyager Therapeutics, one of the new companies exploring gene-silencing for HD.

Dinah Sah, Ph.D., of Voyager Therapeutics (photo by Gene Veritas)

A road paved with cooperation

Enthusiasm is essential, but it must be tempered with the recognition that scientists need time – and money – to test hypotheses.

It took some two decades to discover the huntingtin gene. At the time of this breakthrough in 1993, people in the HD community celebrated.

Rightfully so, hope for treatments increased significantly.

Since then, hundreds of researchers from around the globe have published thousands of scientific papers on HD. Along the way they have identified hundreds of potential HD drug targets (biological pathways).

From the 1970s until today, thousands of individuals from HD-affected families have participated in research studies and, more recently, a growing number of clinical trials.

While many of us are disappointed that successful treatments have not emerged, we must recognize that the enormous amount of scientific work regarding HD should contribute – perhaps in ways no one yet knows – to future progress.

The road to treatments is paved with cooperation, and with the recognition that multiple drugs may be needed to manage this complex genetic disorder. (Thus, scientists don’t say “cure” when referring to HD.)

Cooperation: the HD community out in force at an HDSA Team Hope Walk (photo by Gene Veritas)

Something larger than ourselves

Our society worships individual “heroes.

However, in the fight to defeat HD, each participant contributes with his or her talents and resources: financial donations, scientific expertise, caregiving, and daily dedication to the cause.

In this long-term commitment, we strive for the well-being of those beyond ourselves: the children who have yet to develop symptoms, the future generations of HD families, and other disease communities such as Alzheimer’s, Parkinson’s, and many conditions even rarer than HD like dentatorubral-pallidoluysian atrophy, known as DRPLA.

For now, I’ll keep my Facebook profile photo as a symbol of hope governed by caution.

Yes, defeating HD is rocket science. When, collectively, we have completed that rocket, we can all ride it together.

(Please remember during HD Awareness Month to donate generously to the Huntington’s Disease Society of America or the HD cause of your choice!)

Sunday, May 10, 2015

Deciphering signals from Huntington’s disease brains in the search for treatments

From coast to coast and around the world, scientists like Andrew F. Leuchter, M.D., and Michael Levine, Ph.D., are engaged in the quest for Huntington’s disease treatments.

During May, Huntington’s Disease Awareness Month, I want to call attention to the critical work of Drs. Leuchter and Levine on the West Coast. They exemplify the partnership of scientists and physicians with the HD community, aiming to advance potential remedies into crucial clinical trials.

Drs. Leuchter and Levine, faculty researchers at the renowned Semel Institute for Neuroscience and Behavior at the University of California, Los Angeles (UCLA), are collaborating on a project that could ultimately lead to new drugs. In the near term, they aim to understand more fully the electrical signals that naturally but abnormally emanate from the brains of HD patients and presymptomatic carriers of the HD gene mutation like me.

“Most of the brain’s energy goes to creating electrical gradients – electrical impulses – but we haven’t been very good at using that for diagnosis and treatment,” Dr. Leuchter said during a March 20 interview in his office at the Semel Institute. He and Dr. Levine aim to “decipher the signals that are coming out of the brain.”

The Semel Institute for Neuroscience and Behavior (photo by Gene Veritas)

Measuring brain energy

A psychiatrist specializing in depression and Alzheimer’s disease, Dr. Leuchter (pronounced LUKE-ter) frequently employs quantitative electroencephalography (quantitative EEG) to measure the energy emitting from people’s brains. One example: a group of 27 HD subjects he and others observed for a study published in 2010 and funded by CHDI Foundation, Inc., the nonprofit virtual biotech dedicated exclusively to the discovery of HD treatments.

Allan Tobin, Ph.D., at the time the head of UCLA’s Brain Research Institute and a senior scientific advisor at CHDI, had asked colleague Leuchter for assistance in finding HD biomarkers, signals that reveal the progression of the disease and/or the effectiveness of a medication.

As the number of HD clinical trials expands exponentially, the search for useful biomarkers has become one of the hottest areas in Huntington's disease research. (Click here to read about one new potential biomarker.)

As Dr. Leuchter pointed out, neurological and psychiatric disorders are “much more limited in diagnostic tests for the organ that we are studying than any other branch of medicine.” Cardiologists insert catheters into the heart, and gastroenterologists use scopes to view the stomach and intestines.

“If you’re a psychiatrist, we talk to people, which is great, but we don’t have physiologic tests that guide decision-making,” he added.

Scientists and doctors rarely put electrodes in living human brains or take biopsies of brain tissue. However, they have been measuring brain energy with EEGs for more than a century, Dr. Leuchter explained.

As he demonstrated in his lab (see photo below), today patients undergoing testing wear a cap with 35 separate EEG electrodes, or contacts, that touch the head. The attending researcher stretches the cap over the patient’s head. In contrast with the traditional EEG, which involves one-by-one placement of the electrodes on the head, this method is quick, efficient, and less burdensome to patients, he noted.

Above, Dr. Andrew Leuchter points out the electrodes on the EEG cap worn by research subjects. Below, he explains digitized EEG readings displayed on a computer monitor. (photos by Gene Veritas) 

“We find that this helps to standardize our measurements of brain activity, and that we can place the electrodes in about 15 minutes,” Dr. Leuchter said.

EEG is inexpensive, convenient, and easy to administer. Additionally, it does not expose patients to radiation or require them to lie inside a machine such as an MRI scanner, he noted.

“You can tote it wherever you like,” he said of the EEG device.

The brain’s pacemaker

As they had hoped, Dr. Leuchter and three other UCLA researchers discovered abnormal EEG readings in HD patients with just mild symptoms.

“But the really intriguing thing there was that, even in people who were gene-positive but premanifest, we could see differences in brain function estimated 15, 20 years out from diagnosis,” Dr. Leuchter said, referring to signals of future decline. “So we thought this could be something that could be useful for treatment development.”

As Dr. Leuchter explained, “the brain like the heart has pacemakers.” Healthy brains produce lots of high-frequency waves. Brain illnesses commonly result from changes in the firing of the pacemaker, resulting in a greater quantity of low-frequency waves.

“What we found is that years before people start to show symptoms with Huntington’s, they’re producing more low-wave energy,” Dr. Leuchter said. So it’s a very subtle indicator that the pacemaker of the brain is starting to slow down.”

Scientists cannot predict the actual onset and progression of symptoms from EEG signals. However, as noted below, they did discover a correlation between the severity of genetic mutation and EEG readings.

Clear genetic impact on the brain

Furthermore, the team observed that, in contrast with healthy brains, the distribution of different types of waves across the different regions of the HD brains became more uniform. “The regions of the brain start to look more similar than different,” he explained.

Researchers have not yet discovered what this phenomenon means.

“We know that the brain has enormous functional reserve and that people call on every cognitive and emotional resource they’ve got to try to keep everything functioning at optimal efficiency,” Dr. Leuchter continued. I don’t think we know what’s compensatory and what’s an early sign of illness.”

Reflecting on another facet of the research, Dr. Leuchter explained that, in general, brain function tests do not correlate with genetic factors.

However, he and his team did find a correlation between the degree of HD genetic mutation and the severity of the changes in the EEG readings.

“Nobody had seen that,” he recalled. “We got excited about that, and that’s what we’ve been trying to follow up on.” These findings will contribute to the search for biomarkers and treatments, as explained below.

Examining brain tissue

A neurophysiologist and veteran basal ganglia researcher, since the late 1960s Dr. Levine has studied these deep, inner parts of the brain that control such actions as voluntary movements. He began to study HD in the 1990s as genetic mouse models with HD-like symptoms became available. His lab has published more than two dozen papers about these mice.

The nuclei of the basal ganglia are significantly compromised in HD, especially in the striatumSpecifically, Dr. Levine has examined how neurons communicate with each other in the cortex and striatum at cellular and molecular levels using tissue from the HD mouse models.

One of the latest techniques for studying the cells in the HD mouse models is optogenetics, in which specific types of brain cells are stimulated with light.

“I can look very closely at mechanisms,” Dr. Levine explained. “I know which types of neurons I am looking at and how they change at a very mechanistic level.”

Michael Levine, Ph.D., veteran HD researcher (photo by Gene Veritas)

Two key goals

Melding approaches, and with the expectation of CHDI support, Drs. Leuchter and Levine now seek to answer two important questions.

The first involves comparing EEG data from both mice and humans to refine the search for biomarkers. Researchers have already made the key discovery of EEG signals common to mice and humans.

“It’s actually pretty uncommon in science that you can see a very similar signal across species, that you can see something very similar in the brains of humans and the brains of animals,” Dr. Leuchter said.

If the Leuchter-Levine project confirms the degree of that similarity, that could mean  potential drugs tested in mice could ultimately be used for human clinical trials, Dr. Leuchter observed.

The second question focuses on the testing in HD mice of a CHDI-developed compound aimed at lowering the amount of mutant huntingtin protein, the major culprit in the disease.

“If we do see a link between lowering of mutant huntingtin and change in the EEG biomarker, this could be used to develop a number of therapeutic agents,” Dr. Leuchter said. “A whole line of research could develop out of this.”

From molecule to the whole brain

Drs. Leuchter and Levine estimated the project will take two years to complete.

As Dr. Levine put it, researchers hope the CHDI-developed compound will restore the EEG signals in HD patients to normal.

Dr. Leuchter reflected on the significance of the project and his collaboration with Dr. Levine: “The fact that in something like Huntington’s disease you’ve got a protein that is affecting how the nerve cells are functioning and altering the way they produce and utilize energy – it’s really a gateway to understanding the connection between what is going on at the deepest molecular level of the cell and what we’re able to see with the brain waves the individual is putting out. We can actually potentially link everything going from the level of the gene all the way to whole-brain function.”

In another potential future project, Dr. Leuchter would like to obtain EEG readings from asymptomatic gene carriers over two to three years to better measure the changes in signals over time.

Drs. Leuchter and Levine (photo by Gene Veritas)

Participation and a positive attitude

Both researchers expressed gratitude to the HD community and fellow HD researchers for their dedication to the cause.

“There are not that many people with this illness, so people get asked a lot to participate in different studies where they’re poked or prodded or scanned,” Dr. Leuchter said. “We are very grateful to those who are so generous with their time, because without their help we could not conduct these research studies.”

Dr. Levine added that he is impressed with the “very positive and sharing attitude of the investigators who do research in HD and who are looking to help the patients.”

While interviewing these two researchers, as an individual racing against the genetic clock of HD, I was once again moved to witness the creativity and enthusiasm of scientists engaged in the quest to save affected families from the devastation of Huntington’s.

(Later this month: from the East Coast a report on Yale School of Medicine researcher Doug Rothman, Ph.D., and the mystery of the mitochondria in Huntington’s disease. Please remember during HD Awareness Month to donate generously to the Huntington’s Disease Society of America or the HD cause of your choice!)