- Medical Education
- Dean for Medical Education
- Financial Aid
- MD Programs
- Combined Degree Programs
- Curriculum Services
- Program Evaluation and Student Assessment
- Student Services
- The Academy at Harvard Medical School
- Class Day 2012
- Teaching Awards
- Contact Us
- Vanderbilt Hall
- Financial Aid
- Office of the Registrar
- Campus Planning and Facilities
- Ombuds Office
- Committee on Microbiological Safety
- Human Resources
- Office for Academic and Clinical Affairs
- Joint Committee on the Status of Women
- The Academy
- Global Health Research Core
- Global Clinical Scholars Research Training Program
- HMA Standing Committee on Animals
- Office of Research Compliance
- Global & Community Health
- Harvard Medical School Event Calendar
- Contact @HMS
- Office of Diversity RIA Program
- Q&A Archive
- The Dean's Perspective
- Harvard Mahoney Neuroscience Institute
- Medical Education
- Human Resources
- Contact us
- Dental Medicine
- Harvard University
Fixing the Brain
July 22, 2012
Of all the health challenges humans face, few are as insidious as those that involve the death or dysfunction of cells in our brains. These illnesses, a category known as neurodegenerative disease, take from us the very things that make us who we are—our thoughts and our memories, our ability to recognize our loved ones, control of our bodies, even our cognitive identity.
For most, diseases such as Alzheimer’s or Parkinson’s attack slowly, leading us down a slope of gradually deteriorating mental or physical function that current scientific methods are able to diagnose only after debilitating symptoms have set in. Even if discovered early, there is no way to prevent their onset, no way to reverse the damage and no cures.
Driven by the immediate need for better understanding and treatments, a coalition of academic researchers, pharmaceutical companies, and state government is now coming together to confront this challenge in a novel way.
In June, Massachusetts Gov. Deval Patrick joined Jeffrey Flier, Dean of the Faculty of Medicine at Harvard, and representatives from major pharmaceutical companies at Bio 2012, the world’s largest biotechnology convention. Together, they announced the formation of the Massachusetts Neuroscience Consortium.
A $1.75 million partnership intended to fundamentally shift how we approach neurological disease research, the consortium aims to establish an environment for the sharing of knowledge and resources between companies in what is often a ferociously competitive industry.
“Neuroscience is profoundly complex,” Flier said. “It is absolutely clear that new, bold approaches involving unprecedented collaborations are vital for our success in treating these devastating conditions.”
Within the consortium, scientists will work to discover interesting genetic or protein targets, which will provide a design framework for pharmaceutical companies’ drug development process. During this initial phase, they will receive input from both academic and industry scientists, pooling their knowledge and expertise. The seven founding members of the consortium—Merck, Pfizer, Abbot, Biogen, Sunovion, Janssen and EMD Serono—have put forth an effort to work with each other and the Massachusetts academic community. Although it is impossible to predict specific outcomes, working together will be to everyone’s advantage, they say, the group uniting scientists, companies and, most importantly, patients and their families.
Though the seed money for the consortium is a relatively small initial investment considering their combined fiscal weights, the collaboration between the state government, academic institutions and biotechnology companies is a potentially groundbreaking moment.
View from the shore
The scope of the problem is immense. Hundreds of thousands of Americans suffer from neurodegenerative diseases, such as Parkinson’s, Huntington’s, multiple sclerosis, and amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), which have an annual combined direct and indirect health care cost in the tens of billions.
Of the major neurodegenerative diseases, Alzheimer’s is, by far, the biggest threat. There are almost 5.5 million Americans living with Alzheimer’s, a number that is expected to triple in the next few decades. It is the sixth leading cause of death in the U.S., and the Alzheimer's Association estimates its economic impact will total roughly $200 billion this year.
That dollar amount is also growing, and rapidly, as lifespans increase and more people enter old age. More than 10 percent of Americans over the age of 65 have Alzheimer’s, and almost half develop it after age 85. If nothing changes, the total economic cost of Alzheimer’s alone will reach a staggering $1.1 trillion annually by 2050, almost 10 percent of the current U.S. GDP.
“This is a tsunami,” said Adrian Ivinson, director of the Harvard NeuroDiscovery Center (HNDC). “We’re all standing around on the beach, looking at this wave and saying, ‘Boy, that wave is big, and that’s going to do a lot of damage.’ We need to move to higher ground. Now.”
The Massachusetts Neuroscience Consortium’s collaborative solution to this challenge does have precedent in neurological research. For more than a decade, the HNDC has provided shared repositories of guidance and technology for researchers across HMS and its affiliated hospitals.
Founders of the community of 900 members recognized that an intensely focused, highly collaborative and coordinated effort must be made to unravel the many complexities of diseases of the brain, a task far too great for any single organization or laboratory.
With the newly formed consortium, the HNDC model of research now has a foothold in industry and academia alike. There is no guarantee of success, but a willingness to share and to collaborate between those with the intent and means to tackle the immense challenge perhaps offers the best hope of more effectively treating the debilitating conditions caused by neurodegenerative disease.
“As complicated as the universe”
For something so devastating to so many, and which has the real potential to bankrupt healthcare, our understanding of neurodegenerative diseases is limited. Scientists today know only a little more about underlying causes than James Parkinson when he wrote “An Essay on the Shaking Palsy” in 1817, or Alois Alzheimer when he noted plaques and tangles in the brain of an elderly woman in 1907. Few modern insights have made any impact in the clinic, as current drugs or treatments can only mitigate symptoms.
The reason for this sluggishness is because the brain is simply the most complex biological system known to humanity. Containing an estimated 100 billion neurons, each with an average of 1,000 connections to other neurons, there are, in effect, 100 trillion connections between cells that scientists must understand in order to reveal how the brain stores memories, processes signals and creates consciousness. That number is roughly three times as many stars as there are in the Milky Way. After that, researchers must figure out what causes the brain’s systems to stop working, and then how to fix them.
“The human brain is the most remarkable feature in the universe. It is as complicated as the universe,” said Joseph Martin, former dean of HMS and a cofounder of the HNDC.
Martin has studied neurological disease for the greater part of four decades. Up until 1980, the neurological research field was limited, according to Martin, and researchers relied heavily on description—for example, correlating dementia with abnormal plaques and tangles found in the brains of Alzheimer’s patients.
Even with correlations, the brain could be studied only after death, limiting the amount of useful data gathered.
“It was all very crude,” said Martin. It took the emergence of modern molecular biology, genetics and imaging technologies for neurodegenerative research to flourish. Martin used the new tools to help identify the first genetic marker for Huntington’s.
Dennis Selkoe, HMS professor of neurologic diseases at Brigham and Women’s Hospital and fellow HNDC cofounder, also made his groundbreaking discoveries into Alzheimer’s using these new tools. One of the most cited Alzheimer’s researchers in the world, Selkoe revealed insights into the normal and abnormal functions of the two signature dysfunctional Alzheimer’s proteins—tau and beta-amyloid. His work has greatly influenced the field and serves as part of the basis for numerous clinical trials currently under way.
“The results for the world’s biggest clinical trials ever in Alzheimer’s will be released this year. I don’t think they’ll hit a home run. I don’t think it’ll be a double. But if we can at least get a single out of it, we’ll know that we’re playing the right game, and then we can design trials that can treat milder patients earlier,” Selkoe said.
“Neurodegenerative disease research has taken a long time, and it’s gone slowly. It’s only now really blossoming,” he said.
Is it the system?
Despite extraordinary advances in everything from genetics to molecular biology to brain imaging over the last few decades, there are still glaring deficiencies in the tools available to researchers and patients. There are no reliable biomarkers, such as cholesterol for heart disease, that can indicate early on whether a person has, or is at risk for, neurological diseases. Imperfect animal and laboratory models for these diseases lead to minimal impact in the clinic. And though the need for their involvement is great, biomedical and pharmaceutical companies have been pulling back from research into neurodegenerative diseases due to the high costs and low success rates for developing drugs.
“It just suggests that our system of research is going to take a lot longer because of the complexity of the brain, or that perhaps the system is not as well suited to studying it. Or both,” said Adrian Ivinson, a geneticist by training and former editor-in-chief of the journal Nature Medicine.
In traditional biomedical research, labs in academia and industry work independently. They tackle problems they find interesting or that they think will be fruitful with separate staffs, technology, patients and other resources. Positive data and results are shared through published papers, but the lessons learned from attempting experiments in dozens of different ways, or the invaluable insights from negative results and failures, are not. Laboratories or companies often must learn these time-consuming and expensive lessons on their own. Multiple labs or companies could work on the same problem for years, asking the same questions and making the same mistakes.
“We never know where the next green shoot will sprout in our garden, what the next breakthrough will be, but once I know with some specificity what I want to achieve—biomarkers, drugs, a new imaging modality, if a mouse model is good or not—then I want my resources coordinated,” said Ivinson.
“I want them brought together in some way so I avoid unnecessary duplication, so that I take advantage of efficiencies, and so that I can take advantage of all the different technological and technical know-how that is needed to solve this problem,” he said.
Building a community
As director of the HNDC, Ivinson, along with his colleagues, have confronted the issue for more than a decade. Founded in 2001 by Martin and Selkoe, and funded by private philanthropists, the HNDC was established with the idea that, while traditional research has been fruitful, there must be a better way to collaborate and to coordinate and share resources. Joining Selkoe as co-chair last year, Michael Greenberg, chair of the HMS Department of Neurobiology, reinforces HNDC’s goal of bringing together researchers from basic science all the way to the clinic.
Toward this end, the HNDC raised money for training and education, organized symposia and journal clubs, helped recruit subjects for large studies, participated in large international studies and awarded pilot grants for collaborative research projects. The HNDC also established several core facilities that give researchers access to technology and resources that would otherwise be cost or time prohibitive.
The HNDC includes facilities for high-throughput drug discovery, a biomarker-discovery center that houses one of the most comprehensive sample and data repositories for Alzheimer’s and Parkinson’s, biostatistics consultation, tissue analysis and a mouse neurobehavior facility. These core facilities serve as a source of guidance and of communal data and knowledge.
The Laboratory for Drug Discovery in Neurodegeneration, for example, reduces the time and cost requirements for initial drug-discovery assays. The lab provides a high-throughput robotic facility and full-time staff that can lead the development of drug-candidate screens, to complement researchers’ expertise and experience. Pharmaceutical companies hesitant to shoulder the significant investment of these screens can then benefit from these services as researchers license their discoveries.
And even if unsuccessful, the lessons learned by both the researcher and facility staff during the process are shared with all the other members of the HNDC community. In this way, without having to directly collaborate, researchers and laboratories can still benefit from each other’s work—a principle that applies to all the HNDC resources.
Bernardo Sabatini, professor of neurobiology at HMS, runs a renowned neuron-imaging laboratory and is an HNDC collaborator. Sabatini has looked at topics ranging from Alzheimer’s to autism, using techniques from electrical engineering to biochemistry. A highly interdisciplinary researcher, Sabatini’s lab bench is strewn with electrical components and stripped wires alongside dishes of cells and vials of viruses, as though he’s actually building some cybernetic organism.
“Basically every project now involves a very wide spectrum of approaches,” Sabatini said. “But it’s impossible for one lab to be an expert at all of those things.”
With that in mind, Sabatini is consulting with the HNDC on the development of a new technology core that will provide software, engineering and optical support for researchers who lack that specific expertise.
With expensive and difficult-to-purchase microscopes, for example, Sabatini sees many benefits.
“For a lab like ours, which specializes in imaging, it’s really not that hard to build one,” he said. “By working with the core, we would get a machine, and the core would get the knowledge of how to build such a machine—then help other labs do it.”
Through this model of mutually beneficial community building, shared resources and shared knowledge, the HNDC has aided researchers in raising nearly $150 million for their projects, contributed to almost 300 publications and helped license drugs and intellectual property to pharmaceutical companies.
A model collaboration
The HNDC’s model of collaborative neurological research can be found in other academic settings, such as the Kavli Institute for Brain Science at Columbia University, and the Gladstone Institute of Neurological Disease at the University of California, San Francisco. But when Governor Patrick, academic and industry representatives and patients suffering from neurodegenerative diseases walked on stage together last month to launch the new consortium, the model overcame an important barrier. Rival companies, used to closely guarding secrets and intellectual property, declared their intention to work together.
“In our community, this is a breakthrough. These companies are going to get together in the same room, ask the same questions, and have the same discussion together,” said Ivinson, who helped launch the initiative.
“Let’s identify specific projects or specific aims that we want to achieve, and let’s do that collectively,” Ivinson said. “Let’s each put our funds and resources into a common pot, define the research agenda and decide who among us should do various parts of it. For an area that has proved too much for us individually, let’s see what we can achieve together.”