Professor of Neurology at Harvard Medical School and Director of the Day Neuromuscular Research Laboratory and Muscular Dystrophy Association Clinic at Massachusetts General Hospital
“Searching the Globe for Disease Genes.”
Sarah Turgeon, associate professor of psychology: My name is Sarah Turgeon and I am an associate professor of psychology and neuroscience here at Amherst College. This morning I have the pleasure of introducing one of our distinguished honorees this year, Dr. Robert Brown, Amherst class of 1969. Dr. Brown is one of our most distinguished alumni in medicine and biomedical research, [and has a number of] prodigious research accomplishments focusing on motor-neuron disease and neuromuscular diseases, particularly Amyotrophic Lateral Sclerosis, or ALS, also known as Lou Gehrig’s Disease.
He is a compassionate physician who takes care of patients suffering from ALS and other diseases involving muscles and control of movement. He is currently director of the Day Neuromuscular Research Center, the Muscular Dystrophy Association Clinic, and the ALS Therapy Alliance, all at Massachusetts General Hospital in Boston. He is also professor of neurology at Harvard Medical School. However, as of October, Dr. Brown will be assuming the Chair of Neurology at the University of Massachusetts Medical Center, where he will be working with gene therapy experts to develop new therapies to silence disease genes.
After graduating from Amherst in 1969 with a degree in biophysics and magna cum laude honors, Bob Brown received his medical training at Harvard Medical School and then went on to earn a Doctor of Philosophy at Oxford. He returned to the U.S. after obtaining his degree from Oxford and has been in the Harvard system ever since, first as a neurology resident, and then as faculty member in the neurology department, moving up to the position of full professor in 1998.
His curriculum vitae lists numerous honors, including election to the selective and prestigious Institute of Medicine in 2001. He is author or co-author of more than 200 publications, not counting invited chapters in reviews in the most distinguished scientific journals, including Science, Nature and the Proceedings of the National Academy of Sciences.
In addition to contributing to his own research, Dr. Brown has been instrumental in setting directions for the larger research effort to conquer neurological disease through his work with charitable organizations, such as Project ALS and Cure ALS Initiative, and is a member and chair of NIH study sections. Most biomedical researchers make contributions to understanding one disease or a group of related diseases. But Dr. Brown has worked productively on many different diseases, with the common theme that they affect muscles and movement. His accomplishments include showing that mutations in muscle-ion channels cause hypercholemic periodic paralysis and collaborating with others in the seminal discovery that mutations in the gene for super oxide dismutase cause some forms of familial Lou Gehrig’s Disease. In addition, he contributed to our understanding of the ataxias muscle myopathies and dystrophies and sensory neuropathies.
Another Amherst alumnus who works in this field, Dr. Rajiv Ratan, class of 1981 and director of the Burke Medical Research Institute, has called Brown a “giant in the field of translational research.” An alumnus who also works in the neurology department at Harvard, Dr. Matthew Frosch, class of 1978, has noted, “Bob Brown is dedicated to helping patients with these difficult diseases, a side of his career that does not show up in publications and honors, but is noteworthy for someone who’s research and achievements might have been expected to consume his entire professional life.”
As if he weren’t busy enough, Dr. Brown recently made time to return to his alma mater in the spring semester of 2007 as a guest professor in Professor Steven George’s Neurobiology of Disease course. He lectured and lead class discussions on chanelopathy diseases and ALS.
Personally, I am keenly aware of the importance of Dr. Brown’s work as my father, who was Amherst class of 1964, was diagnosed with ALS two years ago. Ironically just last weekend, in fact, right about now, I was sitting on the stage of the commencement of my alma mater, Kenyon College, where my father has been professor for 36 years in the drama department, where I was receiving on his behalf an honorary degree commemorating his retirement as he was unable to attend the ceremony.
So please join me in welcoming Dr. Robert Brown.
Brown: Thank you so much, Dr. Turgeon, for this very kind introduction. I also want to express my gratitude to President Marx and the trustees for honoring me this weekend. I’m grateful to Pat Allen who has coordinated our schedules so effectively and welcomed up so warmly. I want to say that it really has been a great pleasure for me to reconnect with Amherst recently through Professor George and to have the opportunity to come back and participate in the neurobiology disease course last year.
As Dr. Turgeon mentioned, I graduated from Amherst nearly 40 years ago and completed my graduate education by 1975. As I compare the world that I entered then, with the world that the Class of 2008 is entering now, I’m struck by a defining difference in the way the medical science that we now see around us is practiced. To put it briefly, medical science has, in effect, gone global. For the next few minutes I’d like to reflect on this difference. My theme is a revised version of Thomas Friedman’s idea that the world is flat. Just as social changes have flattened the economic world, it is clear that seismic changes, such as the Web and the Genome Project, have leveled and even democratized the world via medical science.
Let me say first, above all, I am a clinician. As you’ve heard, I run a large clinic for patients with neurological diseases—like Muscular Dystrophy or motor-neuron diseases—that cause weakness that typically lead to profound disability and very often to death. Most of these diseases are untreatable, so in a larger sense my task basically is to try to confer dignity and autonomy out of these individuals and even hope in the face impending death. But I can tell you that in ways that we have never predicted our clinical activities now turn out to have global dimensions.
Perhaps, most obviously, the first is that because we are a specialty clinic, of course we see patients from all over the country and from around the world. That in itself is very wonderful. But when they cannot come to us from abroad, often we can see patients via the web and conduct ongoing medical assessments and work with clinicians abroad to help manage such individuals. It’s amazing that, while the Internet can never take the place of a face-to-face interaction or a hands on examination, one could really monitor how status of these folks really quite well through the web and web-based resources.
Our clinical practice has gone global in another sense in that we now outsource many of our vital but routine activities. As you probably know, the radiologist who evaluates your X-ray when you go to your local emergency room at 2 a.m. is just as liable to be in Bangalore as in Boston or the Bronx.
In parallel with the clinical activities, I also run a research laboratory that studies these neuromuscular diseases with the long-term goal of trying to understand them, and of course, ultimately to treat them. I can tell you that in that capacity I wear many hats. One function in the lab is doing science itself, studying the diseases, trying to keep up with current concepts and technologies and running the science enterprise.
But it’s also the case that a major activity that I am almost continuously engaged in is fundraising, essentially keeping the resources available to keep the lab going through diverse mechanisms that involve the federal government, private agencies and even wonderful individual benefactors. I would say that to a degree—I certainly never anticipated when I left Amherst—most of us in this kind of biomedical research really are entrepreneurs in the sense that we have collaborations and projects which are products. We then market these or sell these to funding agencies, patients and consumer groups. In a way it really is extremely entrepreneurial.
And then finally, I am a teacher. In that capacity I work with young scientists and with physicians in training to try and go to the clinic and translate clinic phenomenology into hypotheses that can be readily tested in the laboratory.
As you’ve heard, for many years, for 30 years in fact now, our primary research interest has been in Lou Gehrig’s Disease, also known as ALS or Amyotrophic Lateral Sclerosis. This is a dreadful disease that typically afflicts people in mid-adult life, usually in years of peak professional productivity. It’s characterized by a process of death of motor neurons, which are very large cells that reside in the brain, the brain stem and the spinal cord and serve to connect the conscious and the unconscious brain to muscles and thereby to execute all types of movement. What one sees clinically in this disease is a process in which very focally some part of the body gets weak, either it’s a hand or foot, perhaps speaking, chewing or swallowing. Then over three to four years, the process spreads, slightly but relentlessly until there is complete paralysis. Unless one with this illness is put on a ventilator, this leads inexorably to death.
Part of the issue here—which gets us back to neurobiology—is understanding the targeted cell tied to the disease, the motor neuron. I’ll just say a few words about that, because this has consumed much of my attention, and it’s wonderful that in fact it’s now part of the curriculum here at Amherst. The motor neurons are extraordinary cells. They are among the largest cells in the body, so they are cells of an enormous diameter, unlike almost any other cell. What’s striking is the great mass of the motor neuron is not in a large cell body; it’s actually in a highly polarized process called an axon that emanates from the cell body to project a muscle. Something like 95 percent of the whole mass of the cell is actually out in this enormously long process. In fact, the analogy I like to use is the following: If this lecture hall here were a motor neuron, say, in the low part of my back, extending its process down to a toe muscle in my foot, three feet away roughly. In fact, this lecture hall-sized motor neuron would have an axon that ran down to Manhattan, so it’s just enormous and how it navigates is implausible. What makes it even more implausible is that this is a type of cell that is born essentially with a very limited capacity to regenerate.
So once it sends its process out and connects with muscle, it has minimal capacity after injury to re-grow the process. In fact, if you know systems design, you would probably agree this is a terrible systems design. First of all, you make one cell instead of a lot of little ones. Second, they can’t repair themselves. One guesses that part of the reason this situation is as it is, is that this cell type evolved when we as a species were expected to live only 25 or 30 years, and not, Lord willing, 60, 70 or 80.
But the fundamental question in ALS then remains: Why is it that after 40 or 50 years, the power switch gets turned off in the cell and slowly it involutes and dies? I might add that this is the same question that arises in the context of Alzheimer’s Disease, Parkinson’s, Huntington’s—any brain degenerative disease in which subsets of neurons slowly undergo involution and death. Of course, one of our ancillary hopes is that any insights that are garnered in terms of ALS might play out and be helpful in these other diseases, [or reciprocal ones].
When we embarked on this work in the mid-1980s, there were very few plausible hypotheses about how a disease like this can occur. But we did know that about 10 percent of the cases arise because of inherited gene defects. In a pattern that suggested that one need only one abnormal gene to trigger the disease, one of the questions then was, could one find a way to go after those genetic forms and look at them as a keyhole through which you might view all of the forms. It was very fortunate that in the mid-1980s a remarkably powerful tool became available to allow one to track down genes in families. A tool that really anticipated the power of the genome projects and lead to the identification of many, many disease-causing genes during that late ’80s and early ’90s.
You’ll recall the great discoveries, for example in Cystic Fibrosis and [Muscular] Dystrophy; they all used these kinds of techniques. The technique is basically very simple. What it involves is looking at normally occurring variants in DNA that are spaced all along the 3 billion base pairs of DNA that make up our genome, and asking a simple question: If we have a large family in which some people have the disease and some don’t, can we find DNA variants that are only seen when the disease is present? And if you find that kind of correlation, you will know that that DNA variant resides in a neighborhood in a genome that has to be near the disease-causing gene. So if you find a variant and if you find a correlation, then you can hone in and figure out what the gene is. It’s a little bit, for example, like trying to find essentially a burning house by looking first from a satellite. Where with a Google image, you might see a little tiny plume of smoke but if you then fly over with an airplane you can figure out is it in the Northeast? What state is it in? What town is it in? Then you can track down the street and ultimately the burning house. That’s a little bit what gene-linkage is like.
The issue then becomes how we can generate enough collections of families that are large enough to do this kind of technology. I can tell you that ALS itself is pretty rare, which is a big problem in getting funding for research in this country. But familial ALS is even rarer. The way we dealt with that then was, in this pre-Web era, to simply write letters to hundreds and hundreds of neurologists around the United States, Europe, South America, and ask them “Do you have families where this disease runs over many generations?”
I’m just delighted to say that in fact many clinicians who were incredibly busy found time to go through their records and get us information on such pedigrees. So by the late 1980s, we had collaborators from the U.S., Canada, England, Scotland, Belgium, France, Israel, Sweden, Saudi Arabia, and more recently we have wonderful collaborators from Turkey, Mexico, China.
As you might imagine, this set of collaborations has been just incredibly rewarding. For one thing, as you can accurately predict, this led to wonderfully close and enduring friendships with these investigators. They opened not only their clinical records, but their hearts and their homes. Often when we’d visit these families, we’d stay with these physicians and reciprocally they’d come to see us.
It’s also been a source of research fellows. We’ve had perhaps 25 or 30 research fellows from abroad who come and spend two or three years in the laboratory to help study not only our families but theirs as well. Then, of course, perhaps the most important point is that these collaborations have led to scientific insights and the identification of many gene defects that cause not only ALS but other neurological diseases as well. What we think is that knowledge of these defects is beginning at least to give a glimmer of hope that we may be able to understand some of the cascades of events that lead to a disease like ALS. How is it that one single [unintelligible] that gets changed out of these 3 billion can reside silently in the genome for 30 or 40 or 50 years, and then trigger a process, which like falling dominoes, leads first one, and then 100, and then 100,000 cells to die?
Let me just give you some brief examples of how this has played out. From [unintelligible] in Belgium there was an enormous family which, it had been published in the literature, that over many generations half of every generation had had Lou Gehrig’s Disease. It was that family, more than any other, that led us and our collaborators in 1993 to find a mutation in a protein anti-oxidant called superoxide dismutase—as you’ve heard—can trigger one form of Lou Gehrig’s Disease. It turns out that this protein is expressed in every cell in the body and it’s expressed in every organism on the face of the Earth. It’s really important for detoxifying free radicals that we all generate as a consequence of breathing oxygen to survive. Indeed, its mutation leads selectively to motor neuron disease.
From Tunis in North Africa, another family highlighted the presence of a protein which we and others call alsen that signals several steps in the process whereby an axis grows out, finds its pathway, and connects into muscle. And a family in Alabama led us to identify an amazing gene called dynactin, which is like a V-8 engine, a diesel engine, that sits on top of an axon and carries cargoes back and forth from the cell body here in the lecture hall to the distant terminal, wherever it may be. Of course, this has all been very exciting and has begun to define pathways that we think may be incriminated in this disease process. And it’s been helpful in other ways.
For example, again because of new technologies, it’s extremely exciting that if you [identify] a mutation in a gene that acts to trigger cell death, you can very often take that and put it into an animal model and create an animal model of the same disease. One of the things that others did, shortly after the first ALS gene was defined, was to take that gene defect and put it in a mouse of all things, in the [germline] of a mouse. It turned out that the mice then went on to develop adult-onset, first focal and then spreading motor neuron disease and to die of a disease process that looked incredibly like, eerily like, our patients in the clinic.
There are now rat models, worm models, fruit fly models, even fish models of these diseases, which are powerful. They are powerful in part because you can take them apart. You can dissect them; you can look at the molecular biology of the disease in a way that would of course be unmanageable in a human. You can also use them to test drugs. You can test a drug in a mouse in six months for a thousandth of the cost of a full trial in a human, for example. You can also take the genes and put them into Petri dishes and recreate small elements of the disease. In dishes that are so small that in a plate this size you might be able to do a test of anywhere from 300 to 400 different drugs. And the Petri dish assays can typically be done in 24 hours. That, of course, enormously accelerates the drug discovery process.
What I would say is that the benefits of our interactions with so many of these wonderful collaborating [collisions] have been palpable. While we don’t have the treatment yet, at least we have some ideas about where to go. There are about 25, 26 drugs queued up in the pipeline for clinical trial in humans, but I thought I’d just share one or two or three other quick lessons that we’ve learned from this process. I think these are perhaps obvious, but at least are compelling.
One lesson, which I have learned again and again, is that the human body has a limited repertoire of behaviors and responses to disease. So if you go to Riyadh, or Lima, and see someone who’s dying of ALS, the whole process of weakness, the indignity of disability, the pain of shortness of breath and the agony of the death itself is exactly the same for the patients and the family as it is in Amherst or anywhere else.
On the other hand, it’s also instructive to see that there are some diseases with unique features that you only see in certain parts of the world because of cultural issues. For example, in some parts of the world, first cousin inter-marriage is promoted, which means that in those regions, one has an opportunity to see recessively inherited diseases of the type that we rarely ever see here. For example, the ALS form that we see in Tunis… Incredibly, the disease starts at about the age of 5 or 6 or 7 years of age, very early. That’s terrible, of course, but the good news is that it has a very long course so the people who get that disease survive 20 or 30 or 40 years.
I would mention, parenthetically, that another lesson that has been reinforced in every medical field trip abroad that I take is the uniqueness of the infrastructure for my biomedical research here in the United States. The concept that’s espoused here is that someone can be a clinician, seeing patients with the disease, and also run a laboratory and somehow bring these two activities coherently together. I can tell you that you see this concept in some degree in Western Europe, but it does not exist anywhere else in the world. One of the reasons it exists here is that we are blessed by having an extraordinary institute of health, which spends something like $26 billion or $27 billion a year on biomedical research, including spending it on many mechanisms exactly to bridge this chasm between clinical worlds and laboratory investigations.
I’ll also note that our tax structure, to a degree I never appreciated until I started traveling, promotes philanthropy and makes it possible for very wealthy people to benefit by giving their money to private endeavors like medical school research programs. Again, you just don’t see this in even Western Europe. This is quite extraordinary.
The point is not only to laud our system but in a sense to argue that we need to protect it to the best we can and make sure that the system remains intact in the face of sometimes competing and adverse alternate use of resources.
The final point I want to emphasize is that over the last five years this process of gene tracking has been accelerated beyond any of our expectation by the completion of the Genome Project. We know that in 2003 the entire sequence of all the DNA molecules of human beings was completed and published, probably the most extraordinary science project in the last 50 years. Perhaps the equal of the discovery of theory of relativity or the double helix. I think it’s a testament to the egalitarian view of the planners of the genome project. That virtually all of the data that it has generated has been put on the Web where it’s freely available to anyone. Literally, anyone in the world who has a laptop PC and an Internet link can download the entire genomes now, not only of humans, but of many, many other species, as well as all of the appropriate software to analyze. It’s not surprising—again to quote Thomas Friedman—that it may be that the next great breakthrough in biomedical science may come from a 15-year-old in Egypt who has a powerful laptop. I hope that’s the case.
For those of us in the lab, the immediate consequence is, of course, that we now can do the kind of work I’ve just outlined to you far rapidly than ever before. We have an unprecedented tool set for these sorts of research projects. We’re now heavily engaged, just to give you one more twist on this, with colleagues from five different countries trying to find gene variants that predispose not to familial Lou Gehrig’s Disease, but to sporadic disease, and maybe even that affects how rapidly it progresses or where it starts in the body. We have a collection of more than 5,000 DNA samples in this analysis and it’s just one example of how one can use this new type of genetic information.
Critics of the genome project hold the reductionist view that this repository of genetic information somehow relegates humans to a set of pre-determined sets of states and behaviors devoid of free will. I think the point those of us in medical research make is that you can view alternately the genome databases, a kind of gargantuan library; it’s a testament to human diversity and to unpredictability and changeability of humans. And certainly, of course, it’s a phenomenal tool for discovery of medicine.
Perhaps the most important point I can make, in conclusion, is that these are really exhilarating times to be in biomedical research. Between the Web, which has truly transcended national and academic boundaries and has bypassed many language barriers, and the Genome Project, new consortia for research have just unprecedented resources for this kind of biomedical discovery. This is true in my own domain of research; it’s true across medicine. To any of you in the room who may be graduates embarking on careers in this brave new medical world, I think one can predict with very, very high confidence that you will novel opportunities that are intellectually engaging, scientifically very, very rewarding and even aesthetically gratifying. All of which, make this a most promising field for endeavor. There’s no doubt that the result will be accelerated progress in trying to understand a realm of human diseases like ALS, and ultimately to alleviate the corresponding suffering.
Thank you again for your attention. It’s a great honor to be here.
Audience member: Are there any obvious obstacles, bottlenecks, or difficulties in getting the money to the researchers in collaboration? If you were in charge of all medical research in this area, what could you do better that happens now with the system with the way it is?
Brown: There are some sort of obvious limitations. In general, the system works very well. The most obvious is there are competing uses for our tax dollars. The federal government, this NIH [National Institutes of Health], is really extraordinary and has a level of funding for research that you just don’t see even in the UK, for example. But obviously, to be blunt, with the war, and other sort of national budgetary items, the pay line for research over the last two or three years have dropped dramatically. We need a committee that I chair at the NIH three or four times a year to review grants. Grants which people pour their hearts into. They spend months preparing these grant proposals and we will look at 50 of them over a 2 ½ day orgy in a darkened room somewhere and maybe five of them now will get funded. Or four. So the pay line is just below 10 percent. That’s a big limitation in terms of research momentum.
The others are also sort of obvious. Even within the world of medical research there are competing needs, so orphan diseases like Lou Gehrig’s tend to fare very badly in terms of the whole pie chart of dollars spent. The third one, which is again obvious, is that for this reason I just mentioned. Big pharma typically only wants to invest in diseases where there’s a robust market share. There are some exceptions, but what’s also wonderful is that we have a flourishing biotech industry here with very, very creative people fueled by entrepreneurial capital dollars who are taking some very novel ideas in orphan disease settings and pushing them forward. What’s interesting is, I think, that the real gruel that’s going to allow big pharma to expand is not its own internal research. It’s going to be buying biotechs that have done the creative research on risky dollars. Those are three issues that I think are important.
Audience member: Just to follow up, the government is not so good at delivering our mail or water bottles to people in need in a hurricane. How can the NIH be an exception to that? Is it really that good and why is it different?
Brown: I’m coming across a little like a defenseman or an [unintelligible] for the NIH and I hadn’t quite planned it this way. For one thing, for better or for worse, it’s an enormous bureaucracy and so it has a tendency, sort of like the bureaucracy that runs the British government, to be immune to changes in the White House. So programs that are put in place that have a five- or eight- or a 10-year lifespan tend to endure, albeit with some variations in total dollars, independently of who’s in political favor at the moment. It’s a remarkably egalitarian organization. It goes out of its way to essentially disassociate all of the potentially biasing financial relationships with anything in the private sector, be it big pharma or other groups. I think for those reasons it has managed to remain pretty objective and pretty steadfast in its overall design and program — its so-called roadmap.
Audience member: Do you get a paycheck?
Brown: Somehow I survive. I’ll leave it at that. Why do you ask?
Audience member: Because you said last night that you won’t get your first paycheck until later this year.
Brown: Different institutions have different ways of paying their investigators. Some are more entrepreneurial than others. Again, I’ll leave it at that.
Audience member: What are some of the more, most promising, experimental therapies for an illness?
Brown: I think there are several, and some of these are kind of obvious. For those of us who look at these familial forms of disease, where we know that the presence of, if you will, a toxic or a killer protein is actually what causes the problem. What one would like is some way to reduce the burden of that toxic protein in cells and what I think is incredibly exciting is both old and new technologies that are now allowing one to go in and turn off the sick gene.
So there’s an old technology that have been around for 25 years called anti-[unintelligible] that will potentially do that. There’s a new one called inhibitory RNA, for which the Nobel Prize was just given two years ago, which will also do that.
Just to give you an example, it’s now been shown that in these ALS mouse models if one infuses these re-agents, either the old one or the new one, into the spinal fluid at the base of the spinal cord, one can achieve enough of a shutdown of the protein and reduction of its levels to actually extend the life of these mice longer than it had been previously possible. We’re very excited now about trying to do that in the patients that have these forms of the disease. Maybe that’s just one part of the pie, but it’s a start and I think a very important start.
There are many other things and I’ll just tell you briefly that one, for example, is the use of gene therapy to deliver growth factors to the nervous system. It’s still in its infancy but some promising early results. Then the tools for the sort of higher [unintelligible] discovery have gotten better and better. Big gamble, but potentially fruitful. Certainly a gamble worth taking.
Audience member: Any differences between men and women?
Brown: In this disease? There are some differences. One of the things that has been known for a long time is that in the non-inherited forms of the disease, the ratio of males to females is almost two to one. So gender clearly makes a difference. That’s up until the time of the age of 55 or 60. After that period, whether that’s because of the influence of menopause or something else, it’s a one to one ratio. There is a difference and I would say we don’t understand it.
There are other differences. If one looks, for example, at motor nerves that project to the eyes, or the bowel and bladder, they are immune to this disease, whereas motor neurons that are only two centimeters away get the disease. Within the neuro-access of each patient, there is an answer to the disease if we’re smart enough to break it down and decode it. These differences are actually a very important link to the study.
Audience member: You mentioned the connection between these various diseases where subsets [unintelligible] die. Do you have examples where ALS work has helped MS or Alzheimer’s or Parkinson’s?
Brown: We don’t. I’ll start right out by saying because ALS work has not lead to any therapy thus far, I can’t substantiate that claim. But I can say that the insights that have come from the analysis of molecular vents in the cells as they die turn out to have many common features.
Just to give you a couple of examples, it’s clear that in most of these diseases one of the major problems in the cell is aberrant folding or unstable behavior proteins, which then get [unintelligible] or aggregated and then in one way or another confound the body’s protein garbage disposal system so that other proteins can become abnormally either [unintelligible] or metabolized. That kind of theme looks like it plays out over all these diseases. Another theme is that, for example, mitochondria which make energy in the cells turn out to be defective, albeit in different ways, in most of these diseases. There are still other commonalities, but thus far because none of these have been substantially treated. We can’t give you a good example of the cross-[unintelligible].
Audience member: Has anybody tried the stem cells?
Brown: The world of stem cells is—I debated whether or not to put that in my comments—it’s clearly going to have an enormous impact. The science-fiction view, which may not be so much fiction or science anymore, we’ll have to see, is that one ought to be able to take stem cells and convert them into precursor cells for the types of neurons that die in these diseases. Put them in the brain or the spinal cord and replenish the missing population of cells. When you see someone who’s got fairly advanced Lou Gehrig’s, it could be argued that the only therapy that will recover lost function will be to replace missing motor neurons. While that is a kind of visionary statement, in fact, I wouldn’t rule that out at all. That may be something eight, 10, 12 years down the line that will be quite important.
But stem cells have already proven quite important in other tenses. Just in the last year, for example, it’s been shown that one can take a very primitive stem cell, let’s say from an ALS mouse, and turn it into a motor-nerve on the one hand and supporting cells, called Leo cells, on the other, put them together in a dish and study how they interact together. Are they supportive? Are they adverse? What’s the nature of the interaction? How can you use that to think about therapy? That’s already happening. It’s very, very exciting.
Even more exciting are reports just within the last six months that you can take a skin cell from a patient of any disease and by manipulating the nucleus of the cell, turning that skin cell into a stem cell. What that means is whether we are talking about Alzheimer’s or Parkinson’s or ALS or Huntington’s—or anything—you can take a skin biopsy from a patient and in six months be studying that patient’s motor nerves in a Petri dish.
So you will have, for the first time, the ability to look at the behavior of the cell in the full genetic context of the patient who has the disease. And you can then look at diversity of effects of different genetic contexts on the behavior of the cell as well as the variety of therapeutic implications. When we talk about stem cells there are many senses of which that whole world of new biology is going to make an enormous difference.
Audience member: [Unintelligible] autoimmune is not involved?
Brown: Autoimmune processes? For some diseases—someone mentioned Multiple Sclerosis—it’s clear that there is a sort of flagrant activation immune system that participates in a major way in accelerating the whole disease. We don’t know the degree to which that’s true in most of these degenerative diseases. Ten years ago I would have said no involvement at all, but now I can tell you that it’s very clear that in any of these, there is a process of subtle, what we call, neuro-inflammation. So there is activation of [unintelligible] system and the degree to which they participate in the disease is not clear. There’s a kind of cell called a [microbial] cell, for example, which could and can accelerate the disease. But we don’t know yet with what impact or how to manipulate that usefully.
Audience member: In animal models, is there any factor in the disease that can be transferred from an older, diseased animal to a younger animal? In other words, can a diseased neuron effect new, healthy neurons?
Brown: That’s a really, really important question. The short answer is not that I know of. There’s one report from 1962, a man named Zilka, I think it was, or Zilba, from Russia who said that he took ALS brains, ground them up and injected the material into rabbits and produced ALS in rabbits. I can tell you that many labs have spent hundreds of thousands of your tax dollars trying to reproduce that without success. The notion there’s a propagatable, “infectious,” a propagatable element has not been born out.
Audience member: And that in one sense is a promising thing. Because if this is only affecting certain neurons, the spread within a particular person or particular animal then is something happening in each one of those cells individually as opposed to …
Brown: What seems pretty clear to me is that, sort of like the domino model that I mentioned. That it sounds like there’s a cellular contagion which is that the cells may have a propensity to go down but some triggers starting the process and in some way or another, perhaps through supporting cells, the process spreads almost like a toxic bloom. You see that if you look at the pattern of spreadings. Without getting too esoteric, if the disease starts in the right foot, it usually spreads to the left foot or the right arm. Rarely from the right foot across the body to the left arm. You know, when you map out the anatomy, that suggests that there is some notion of a contiguous, or spread among contiguously located, populations of cells. Which is still not to say there is an infectious element so much as there is a propagatability within the nervous system once the disease starts.
Audience member: Can you test family members with familial ALS to see if they have the gene? Can they prevent the onset?
Brown: Yes. In settings where we know there is a positive family history, and we know the disease-causing mutation in some may affect individuals, we can then test others to see whether or not they have that mutation. We are heavily engaged in that we have now in our overall collection close to 700 families with ALS. Of course, now there are hundreds and hundreds of offspring in those families who are now at risk. One of the reasons we care about this question about new interventions to turn off the gene is that clearly for half of all of those at-risk offspring we need something that allows us to go in and shut off the offending gene. The short answer to your question is we can only know that when we know what the gene is in that family. These strategies will only work when we can target that particular gene. That’s still pretty much in the early days.
Audience member: When you start talking about spreading, and I presume we know it’s not infectious, then that brings to mind [unintelligible]. What about them?
Brown: We have wondered about this prior disease model notion being that there are proteins that we all make, that every cell makes, which under certain circumstances can misfold, and in so doing, trigger other proteins in the same family similarly to misfold. I will tell you that I don’t think we have a good tool now to test a [unintelligible]-like model. We’ve not fully applied them. There’s work to do there and that model may be relevant. The one comment I make is it’s true that [unintelligible] diseases can be propagated by animal-to-animal inoculation, but without testing material, and that at least has happened in ALS. But the [unintelligible] model as a model, I think, has not been adequately explored. An extremely important question.
Audience member: If a person suspects they have ALS, how do you diagnose?
Brown: That hearkens to another important point which is for any of these brain degeneration diseases, what we need apart from gene mutation tests are good markers, good so-called bio-markers, diagnostic markers that say the disease is here or it’s not here. Or, by the way, we’ll tell you how active it is because if you have a marker like that and you can try and draw it and see if the marker gets better before the patient gets better, than that’s very helpful in assessing the impact of the drug.
Right now, to get to your question, the process of making a diagnosis is abysmally slow. In 2008, the time interval from first symptom to definitive diagnosis in a specialist clinic is 14 months. If the window for treatment is early on in the disease, it’s pretty much closed then by the time we get to it. We have to do much, much better. The way that a diagnosis is done now is by excluding everything else. Is there a [unintelligible], for example? Is there a tumor? Is there an autoimmune nerve problem? Once those are all excluded and the clinical picture looks like Lou Gehrig’s, then we make the diagnosis. It’s kind of primitive.
Audience member: So people, you just sort of give them the kiss of death? I mean, is that …
Brown: When the final diagnosis comes down, that strikes at the heart of what it means to be a clinician, frankly. Is it a kiss of death? Is it a hug of life? I’m not quite sure what you call it. You communicate a diagnosis which has an incredibly dire set of implications and the question is how you deal with that, how do you share hope without being misleading and so forth. But yes, that’s essentially what happens.
Audience member: You mentioned in discussing stem cells that it’s not possible for recent discoveries to study a disease in the context of an individual’s genome. Does that suggest that maybe the future treatment for ALS or other diseases might be tailored specifically to individuals?
Brown: Absolutely. I really expect that will be the case. We already know that that’s the case in some cancers, for example, that the terrible cocktails of sledgehammer drugs we give suppress dividing cells and can be now tailored and refined in ways that are much less injurious and have fewer side effects for cancer patients. I find it very easy to believe that that will be the case for most of the neurodegenerative diseases. Already, the notion that for the inherited forms you will use different forms of RAI or [unintelligible] for different forms suggests that. I think it will be a much more complicated, but much more broadly applicable, approach, as you’re suggesting, down the line. Some will arise because too much of one growth factor. Some will have too little of another. Some will have heightened sensitivity to copper or metal. Some will have heightened sensitivity to an insecticide. Depending upon which category we can define, then the therapies will almost surely be different at some point.
Thank you again for your attention.