ALS Research Today:
A Conversation with The ALS Association’s Chief Scientist
Dr. Lucie Bruijn came to The ALS Association in 2001. As Chief Scientist and Vice President of Research, Dr. Bruijn directs The ALS Association’s diverse research program, which is seeking to unravel the mysteries of ALS. Holding a bachelor’s degree in pharmacy, a master’s degree in neuroscience and a doctorate in biochemistry, Dr. Bruijn developed and characterized one of the mouse models of ALS. Dr. Bruijn spoke with HOPE about the state of research into ALS today, and her views about the future.
HOPE: Why are you excited about the current state of ALS research?
BRUIJN: ALS research has changed dramatically over the last ten years. There are many more investigators looking at the disease. People with a variety of expertise are coming on board, in part, because we have the tools to address many of the problems. The technology has matured, and a lot more is understood about the disease. And most importantly, we have an animal model that makes it much easier to study the disease. This is an environment where researchers are now collaborating much more extensively, and projects involve many institutions. There also is good collaboration among many of the ALS organizations. I think the spirit of working together is making much more of an impact on the research.
HOPE: How would you describe The ALS Association’s research portfolio and its approach to fighting ALS from the scientific viewpoint?
BRUIJN: The ALS Association is funding a broad range of projects covering topics in ALS today. Our research portfolio encompasses many different ideas and approaches. We invite investigators to submit proposals. In addition, we proactively seek investigators for specific projects. All projects are peer-reviewed. We entice new people into the program, and we work with investigators to develop new projects. We view ALS as an open horizon for researchers. Limited initial funding for what appears to be risky ideas may blossom into full-scale projects if the start is successful. Beyond funding research, we focus on workshops and creating venues for investigators to exchange ideas. Our approach is inclusive, collaborative and innovative.
The Association believes it takes many different kinds of research programs to achieve success in finding treatments and a cure.
HOPE: How did you become interested in ALS?
BRUIJN: I’m a pharmacologist by training and my graduate studies focused on Alzheimer’s disease. I always had an interest in trying to understand disease pathways, and how to find drug therapies to treat disease. That led me into both a scientific career path, and by coincidence really, into the ALS field.
I came to the United States after completing my graduate studies in the United Kingdom. At that time, the SOD mouse for ALS was being developed, and it seemed like a really exciting time to be involved with ALS research. After doing my post-doctoral studies, I went into the pharmaceutical industry because I was interested to see research go from basic science into the development of therapies for disease. I led a small team of scientists developing models for diseases that could be used to test compounds. So, when I was asked to lead the ALSA science program, it seemed a logical combination of all my previous experiences both in doing basic lab research and leading teams trying to solve problems. The excitement and challenge of leading such a significant effort attracted me immediately and continues to be a rewarding enterpris.
HOPE: Describe the progress made in ALS research over the last decade?
BRUIJN: In many ways, it appears that there’s been more progress over the last decade than since ALS was discovered in 1869. Before the discovery of the mutations in the SOD1 gene and the development of an animal model of ALS, it was more difficult to test various disease theories. Previously, most researchers focused solely on one cell type, the motor neuron. We’ve now accepted that the disease is much more complex. There are many more cells, such as the neighboring cells astrocytes and microglia that are responsible for and integral to how the disease occurs. Because of the ability now to mimic human ALS in a mouse model, we were able to consider what happens in the disease prior to the onset of symptoms.
When physicians see ALS in humans, the disease has already started, and they are unable to see how the disease developed prior to symptom onset. With animal models, you can study these developments over time. So, there has been an incredible increase in our ability to understand the disease. With the ability to test compounds in the ALS model of the disease and our increased understanding, there are a greater number of clinical trials now as compared to 10 years ago. With this has come a huge increase in the number of investigators and academic institutions focusing on the disease.
HOPE: Many patients and families ask, “When will we find a cure?” How do you answer them?
BRUIJN: I would do a disservice to actually give a timeframe that we don’t know and we can’t meet. First, we have to remember that ALS is a very complex and difficult disease. We have made huge progress in understanding how the cells of the brain work and how things network in an organism. However, ALS is a very complex network of different cells, and all these cells have to wire up exquisitely to ultimately cause muscle contraction. It’s not as if we can just give an antibiotic and get rid of a bacteria. It’s likely that there are many different causes of the disease. We have made remarkable progress and now have the ability to test compounds. But, we’re not waiting for one outcome before we learn about the next. Many approaches are being taken in parallel, so there is no timeframe that we can give. Two years ago, we hoped that stem cells would be in the clinics this year. This hasn’t happened. It’s not a straightforward process, but we have a worldwide enterprise focusing on the challenges.
| In addition, it is crucial that ALS organizations work together, setting aside competitive differences, in the effort to find treatments, help patients, and ultimately find a cure. |
HOPE: What are the most important discoveries in ALS over the last 10 years?
BRUIJN: The first and most important breakthrough was the discovery of the mutations in the SOD1 gene, which accounts for 20 percent of familial ALS. This led to the development of a model of human ALS in animals that initiated investigation into how the disease operates. Initially, it seemed we would solve the riddle of ALS very quickly; however, we found it to be very challenging. Even though we know how this gene functions, we learned that the mutation is an acquisition of a toxic property. We discovered that the disease is caused by a function that the gene has gained, rather than the loss of its normal function. We still are unclear about what that gain of function is. The second big discovery was the fact there are multiple cell types involved in ALS. It’s not only the motor neurons, but also the supporting cells surrounding the neuron. This led us to think more carefully about the muscle itself as an important target. So we now think about the disease in much a broader context. A third important discovery is that the disease is likely to have multiple causes and/or triggers. In addition, it is likely that there is interplay between genetic and environmental factors in ALS.
HOPE: Where do you see the most exciting and promising research?
BRUIJN: There are so many unknowns, and the answer could come from an obscure area. ALSA’s research program aims to fund efforts in many different areas of the disease. I believe many clues lie in understanding more about the genetics of the disease. We only have the very beginnings of the puzzle by having found the SOD1 gene mutations, which accounts for 20% of familial ALS, so there’s 80% that is still unknown. If we find more problem genes, we might be able to put these all into a pathway and understand how the disease works. And, of course, any one of these genes could provide a new drug target. Interest continues in the various approaches to therapy. Our biggest wish would be for a drug to come along that’s similar to an aspirin. You pop a pill and your condition would be improved. But in reality, we’ve got to keep an open mind. Currently, the only FDA approved drug we have is Riluzole (Rilutek®). Stem cell biology is a very promising area. Stem cell research can be viewed as a different means of therapy. It could be utilized to replace cells that are unhealthy, or it might be a means to bring compounds to the unhealthy cells by putting therapeutic compounds in these stem cells. These cells would migrate to a damaged area and act as a sort of a “mini pump” to provide medication that in many cases cannot easily reach the proper cells.
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Astrocyte, one type of cell |
Also, gene therapy is becoming a much more exciting, mature field. By its very nature, gene therapy has always been a challenge. It involves delivering genes by a viral vector or carrier, and of course, the virus is no longer infectious. However, there are obviously concerns about administering viral vectors for any discipline, including ALS. There are currently clinical trials in other diseases using these viral vectors, and there’s one in the planning stages for ALS. Gene therapy is very important because it allows substances such as growth factors to reach dying cells. These growth factors, unfortunately, cannot be administered by tablet. There have been unsuccessful clinical trials in using growth factors like GDNF and BDNF for ALS. Most investigators believe that it’s probably because these factors are not getting to the appropriate area. Using gene therapy, you’re able to target more effectively and take the product that you need right to the damaged area. Another promising development is the increasing involvement of academia in the development of assays and screening drugs. A key to success is developing the best assay system, which is basically a model of ALS in a dish that mimics one aspect of the disease. Here, you can use compounds to test how to modulate that particular disease mechanism. With the assay system, you can study many different drugs in a very short space of time. These drugs can then go into an animal system, where you can test which of the compounds would be valuable to take to clinical trial.
HOPE: Are we moving closer to clinical trials and finding new drugs to treat ALS?
BRUIJN: There is an increase in the number of clinical trials. However, are we finding the drug that’s going to make a huge difference? We still have many challenges. Not every person manifests the disease in the same way. The time of onset and the speed of progression are variable. The duration is very variable. Importantly, we are able to bring more drugs to the clinic because of 10 to 15 years of solid research focusing on disease mechanisms that has gone on to this point and because we have different mechanisms to test.
We also have compounds that have come from other neurodegenerative diseases that we can test on ALS. I believe an important way to improve clinical trials would be to identify good diagnostic biomarkers.
HOPE: What role do you think the environment plays in ALS.
BRUIJN: The environment is likely to play a role, but I believe the disease is caused by an interaction between environmental factors and a person’s own genetic make up, explaining why one person may be more vulnerable to the disease than another. It is difficult to pinpoint what genes and environmental factors are involved, but more emphasis is being placed in this area of research.
HOPE: Is The ALS Association’s research relevant for those who have the disease now?
BRUIJN: Absolutely. ALSA’s program covers all aspects of ALS. We fund areas of very basic research because it’s through the understanding at the cellular level that we can drive therapies into the clinic. At the same time, we have developed model systems for ALS to test therapies with the information we already know about potential ways in which the disease operates. ALSA is funding a diverse research portfolio addressing projects that will impact patients now, as well as making sure we fill the pipeline for the future.
HOPE: Why do you think the scientists are so eager to work in the field of ALS research?
BRUIJN: This is a very exciting time for those of us working on ALS. We now have the tools to test the important questions. We have several animal model systems-a mouse, a fly and a rat model. There is also the ability to test aspects of the disease in a worm. Scientists from fields of Huntington's disease and Parkinson's disease are bringing their expertise to the ALS field. In many ways, neurodegenerative disease research tackles similar questions. Although the cells and genes involved are different, the processes are similar. In addition, similar model systems can be developed across the different diseases. Several compounds are being used in a number of neurodegenerative diseases.
HOPE: What do young scientists bring to the effort?
BRUIJN: Young scientists are incredibly important. This is when their enthusiasm is peaking, and they are making career choices. The ALS Association realizes the importance of attracting young scientists. We offer workshops that enable young scientists to come and talk about their work in a friendly, nurturing environment, and they have the opportunity to collaborate and initiate new projects with colleagues and peers. These young scientists are explorative and eager to investigate new ideas. They represent the future of ALS research, so their excitement is critical for our success. ALS presents huge challenges with many tantalizing areas to explore, and the young investigators can bring their own, fresh hypotheses to the table. Today, many scientists are working together and collaborating, and this also attracts young people. This disease is fascinating, and yet so devastating. The need to make an impact is absolutely compelling.
HOPE: The Milton Safenowitz Post-Doctoral Fellowship for ALS Research is the only ALS-specific post-doctoral fellowship program in the country. The inaugural fellowship was recently awarded with support from the Lawrence and Isabel Barnett Charitable Foundation. What role will this post-doctoral fellowship program play in bringing in new scientists?
BRUIJN: This is a very essential program that has great potential for finding answers to ALS. In fact, it was a post-doctoral fellowship that launched me into ALS research. The ALS Association's fellowship program offers a great opportunity to recruit new investigators for ALS research while their minds are open to "out of the box" thinking. Although they will be working in a large laboratory, the fellowship recipients feel a strong sense of ownership of their project. They perform the hard work in the lab with the guidance of the principal investigators. This is an incredible way to get new people excited about exploring new ideas.
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Motor Neuron |
HOPE: As we continue to face a tight economy, what are the challenges that you see in obtaining funding for ALS research, both from the public sector and private industry?
BRUIJN: Budget cuts and the economic situation present an enormous challenge. We must make sure that the government and the private sector maintain a strong focus on ALS. They need to understand the promise and the excitement of this disease as an area for investment. In the future, I believe there will be increased industry involvement. Admittedly, ALS impacts a smaller number of people than, say Alzheimer's disease. This is due in part because so many people succumb to ALS within 2 to 5 years. However, the visible characteristics of ALS make it easier to score test results on an animal model. For example, if you can find a compound that will change the progression of the disease, you will be able see a change in hind limb weakness. That's easier to score than many other degenerative disease models. With tangible results, industry is likely to want to get involved. For industry, neurodegenerative diseases and diseases of aging are very important, but there haven't been very many success stories. A highly effective drug for Alzheimer's hasn't been developed. There are drugs for Parkinson's, but we still don't have a cure. So a successful investment would be attractive to industry, even if the market is smaller. Small biotechnology companies, rather than large pharmaceutical companies, are investing in ALS research, recognizing the high risk but high benefit for their companies. They are able to develop the technologies and focus on ALS as a proof of principle. The likelihood is that many of the mechanisms in ALS are occurring in other neurodegenerative diseases, so we believe there may be one compound that will treat many neurodegenerative diseases. My message to industry is that ALS is a disease worth vesting in.
HOPE: Do you see pharmaceutical companies playing a larger role in the future?
BRUIJN: Our grant programs indicate there is increased interest among the biotechnology companies. We're forming partnerships with academia and industry, and I do think that there'll be an increased role that they'll be playing - especially in clinical trials of compounds that have been used for other diseases, such as the current trials of Celebrex.
HOPE: What are some of the things we know about the disease?
BRUIJN: We know the disease is likely caused by multiple factors and manifests itself very differently from patient to patient. Many cell types are involved besides the motor neuron. The cell death processes are now more clearly understood providing potential drug targets. Some of the unique properties of motor neurons, such as their long axons, are likely to be the reasons why they are vulnerable. And, there is increasing awareness that axonal transport is disrupted, which is a critical process for providing nutrients back and forward from the muscle to the neuron.
HOPE: What has the development of the mouse model done for the ALS research?
BRUIJN: The mouse model for ALS has certainly advanced the research in the last several years. It is striking that by introducing a piece of human mutant SOD1 DNA in every cell of the mouse, it develops disease similar to ALS affecting specifically the motor system. The progression is rapid and easy to follow. First, it affects one hind limb, spreads to another hind limb, and then the fore limbs. The model has provided investigators with an incredible tool. Until the discovery of the gene associated with ALS, there had not been a model that resembled the human disease as closely. When patients come into the clinic, they already have the disease. Consequently, we can't tell how long they have had the disease or how fast it is progressing. The current thought is that this disease happens by a slow accumulation of something, and at some point, the cells can't take the load anymore, then the patient's condition goes downhill very fast. We have been able to track this in a mouse model. With the mouse model, we now can see the affect of compounds administered well before disease onset, as the disease begins to develop, and after the disease has taken hold. You can introduce a compound into the model and look to see if there is a reaction. This also applies to stem cell therapy and gene therapy. You can attempt to change the course of the disease. This dramatically opens up the possibilities for understanding ALS.
HOPE: What is the landscape for discovery in the next few years?
BRUIJN: I think discovery of new genes are on the imminent horizon. That will open up a way to develop new disease models and begin to piece the puzzle together. Human drug testing in the clinic will increase. The challenge will be to sort out which trials to run and which are the more promising drugs. We have begun to accept the complexity of stem cells, and investigators are thinking about applying stem cells in a more innovative way, not just to replace dying neurons, but also to replace healthy neighboring cells.
