• ALS Crowd Radio Episodes
    • Jul 19, 2014

    ALS Crowd Episode 2: Dr. John Ravits on ALS causes and new research targets

Dr. John Ravits, MD
UC San Diego School of Medicine
Interview Date: July 11, 2014



What causes ALS? Dr, John Ravits addresses the question of what we know and don’t know about its cause. He notes that ALS is not a genetic disease in the majority of cases. He describes how the disease might spread when it begins in a localized area. He shares some popular research theories and targets: that it may be connected to RNA messaging errors, may be affected by how cells discard or recycle proteins, may be connected to abnormalities of the axon-transport, or that proteins may be folding incorrectly. He tells the story of the 2011 discovery of a mutated gene called C9orf92 (also found in frontaltemporal dementia) by the Mayo Clinic Jacksonville and the NIH simultaneously in 2011. He shares that this gene creates a very big repeating mutation. He describes the promise and challenge of new stem cell therapies and notes the increase in ALS attention from pharmaceutical companies and researchers, but encourages patients to keep the heat on to help push the field forward.  


The live ALS Crowd Radio podcast with Dr. Ravits

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Full Transcript

Seth: Hello and welcome to Episode 2 of ALS Crowd Radio. I’m your host Seth Christensen. We are thrilled today that we have Dr. John Ravits with us in the studio, and I will have my co-host Amy introduce him.

Amy: Thank you. A graduate of Yale University, Dr. Ravits earned his MD from the Mayo Clinic School of Medicine and completed his internship and residency in neurology at UC San Diego. He then did fellowships in neurophysiology and neuromuscular disease: one year at the Brigham and Women’s Hospital, Harvard Medical School, and two years at the National Institute of Neurological Diseases and Stroke, National Institutes of Health.

In 1986 he joined the medical staff of Virginia Mason Medical Center in Seattle, specializing in neuromuscular disorders and neurophysiology. He served as the Director of their Clinical Neurophysiology Laboratory and, for several years, as head of the Section of Neurology. In 2004, he started a translational research program at the Benaroya Research Institute at Virginia Mason to focus on research of ALS.

Dr. Ravits has been a co-investigator for several ALS clinical trials. He is an ad hoc journal reviewer of Muscle & Nerve, Journal of Clinical Neurophysiology, Journal of Neurological Sciences and Acta Neurological Scandinavia.

Seth: Dr. Ravits, thank you for being here with us today. One second. Dr. Ravits, can you hear me?

Dr. Ravits: I can hear you very well.

Seth: We have you now. Thank you for being here with us today.

Dr. Ravits: And thank you for including me. Glad to be here.

Seth: We have a number of issues to talk about today, but I wanted to give our listeners a main thrust of the biology or mechanisms of ALS. So we will start off by asking a very loaded question: What is the cause of ALS?

Dr. Ravits: Well, it is a great way to start and challenges me and all of us. I think the first answer, of course, we don’t really know what’s the cause of ALS. We know what it is in about 10% of cases and it’s genetic so it’s a genetic mutation. We’ve identified about 65% of this 10% with genetic mutations. The reason that’s so exciting is because It gives us a clue as to really what is the cause, what’s the molecular mechanism, what’s the actual switch that happens in the disease. But of course it doesn’t apply to the other 90+% of patients where we don’t really know the cause. We can say it’s sporadic which means it’s out of the blue, so it just hits and we don’t understand that group which is the main group.

Seth: Of those 10%, could you explain a little further what the 65-35 split is comprised of?

Dr. Ravits:  Sure. Let me make a couple of points. Just interrupt me if you want to — I may pause longer on some things. I think one of the first things that patients always are concerned about is, “Did I get this?” or “Am I going to pass this on to my kids?” And so I just want to reassure that as we currently think about ALS, it’s not primarily a genetic disease. It’s only in the small 10%–it is actually probably growing maybe to as big as 15% or 18%–but the rest really does not seem to be genetic and does not seem to be transmitted to the children.

So for those of you who are worried about that, most of the time we define it on the basis that there’s been a sibling, brother or sister, or a parent or an aunt or an uncle or somebody else operationally approach it is just by the genetic history or the family history. And as I say most of the time, it’s not genetic.

So what a genetic disease is that you inherit it from one parent or the other and it’s a specific mutation or a change in the genetic code that gets transmitted. And then that single mutation somehow throws the switch into the disease. And so that’s where most of the research is now because we can understand that switch or what it is that that switch is doing, then we have a chance of understanding the biology of the disease and obviously ultimately trying to treat it intelligently so that we can really undermine more root causes of the disease.

Of the genetics, there are many different mutations. So there are some that are much more common than others, but there are many mutations that have been identified. So the research now is moving in many lines of direction because every time a mutation’s identified then that’s a research opportunity and people jump on it. And it’s showing us lots of different aspects of the cell or of the neuron that are vulnerable or that are pathways that it may set off. So it’s now looking like ALS is obviously very complicated, but multiple directions or multiple triggers can set up problems in the cell to create the disease.

Does that answer your question, you think?

Seth: Yes, very much. One question further on that. Do we know how these mutations take place?

Dr. Ravits: Originally, way back that’s more of an evolutionary question. Yes, mutations occur spontaneously, but it goes back thousands of years as to when the mutation started. I mean one of the discussions that’s being had at the science level is that as people live longer, mutations that have been there all along wouldn’t have had time to express themselves just because of life longevity of people. So as longevity improves, then people live longer and then it uncovers more mutations. So it’s been through evolution, through hundreds and thousands of years.

Seth: So for those families who do have a documented case of familial ALS, the mutation didn’t happen in the 1980s, for example.

Dr. Ravits: Correct. That’s correct. I think part of the change is that medicine’s improving, diagnosis is improving, communications are improving. So a lot of times people didn’t know what they had or they didn’t live long enough to show the disease, but it’s been there and we think it’s probably just the problem of early diagnosis or communication with the family as to what really happened.

Seth: With these families, are we able most often do identify the first family member and where the gene was manifest or activated?

Dr. Ravits: I’m not sure I understand your question.

Seth: In the family with ALS, is it hard to identify the first person who had the ALS symptoms?

Dr. Ravits: Yes. Well, some of that I think is the difference of a genealogy…how well is the history known. But I think if you’re asking how do we identify the genes… that’s going through a huge revolution right now in terms of our ability to identify and define genetic mutations. That’s been probably, I would say, about a ten-year revolution that’s been going on in terms of our abilities to find genes and to find mutations. And it continues to transform the research in terms of our abilities to identify this.

The genetic code is essentially like a book of letters. It carries all the information. It’s got 3.5 billion codes in it. We’re able to sequence that now, so you can essentially sequence the DNA, the entire DNA which at one point took years to do. Now it takes days to do. And then with advances in computers, their challenge becomes a computer challenge as to trying to identify the uniqueness and mine through all that data.

What’s happened over these last ten years has been this enormous technological and computer revolution in trying to identify genetic abnormalities.

Seth: Thank you for that. I know you could go on into areas that and others, like me, would probably be lost in. For our listeners, you can read a list of Dr. Ravits’ publications on the UC San Diego website.

Moving on to our next category, talking about the biology of ALS, I wonder what major systems that are involved in the biology of ALS? For example, is there a GI tract onset or a manifestation or a hepatic or lymphatic influence of ALS?

Dr. Ravits: I’m going to say that there’s a short answer and a long answer, a simple answer and more complex answer. First, let’s keep the simple answer and that is, fundamentally, ALS hits the motor system. So it’s a neurological only disease. It hits a specific part of the nervous system and neurologic system, and that’s the motor system. The nervous system is comprised of sensory and motor and cognitive and visual and auditory. You think about all the complexity of what we do.

ALS fundamentally hits the mobility or the motor system, the strength of the muscles and the rapidity and coordination and strength of muscles. That’s the essence of ALS. That’s the short and simple answer.

And just to now make it a little bit more complex, the muscles really control everything. So we talk about muscles of speech, muscles of our trunk and abdomen, muscles of breathing, muscles of the legs and for ambulation, muscles of the arms for coordination and dexterity and so on. Any of those can be affected. So it would seem like if it affects, say, your abdominal muscles, that it’s the GI but it’s really not; it’s the muscles of your abdomen and of your trunk that are affected. Same for breathing; it’s not really the respiratory system, it’s the muscles of breathing or the muscles of chewing and swallowing that get affected. So I think that to me, that’s the essence of ALS

Now, to make it even more complex though to bring it out a little bit, I think we are seeing as times goes on that it really is a complex disease. And we now see or understand that it can affect cognitive function or language function sometimes. It may affect metabolic functions, as a lot of patients that seem to have a problem with maintaining their weight, they lose weight. It doesn’t seem to be their swallowing or their ability to deliver nutrition in, but something else as if their metabolism has been reset. Metabolism may somehow be affected.

It gets more complicated as we study it. But still, fundamentally, the essence is motor effect.

Seth: Thank you. What do we know about why different patients are affected differently? One with bulbar onset, one with peripheral onset, what do we know about that today?

Dr. Ravits: It’s become I think a very significant topic of discussion as to why it has such a range of the way that it presents itself. We think it’s all the same, it’s all one disease or it’s all ALS, but it looks so different from one patient to the next. Some will have everything normal except the foot drop, and some will have everything normal except their speech and then they have trouble with communications, and some affects the arms. So it hits different parts of the body, but we think it’s the same disease and it’s just breaking out at some place in the motor system.

The motor system for the brain at the brain level and at the spinal cord level is very complicated. They’re very ordered and it’s very well organized. Somehow it breaks out in some region. And then I think one of the things we’re appreciating more and more is that once it starts and it seems to spread to neighboring areas, so there’s a spread effect. That’s been a big motivator for me in my research, not just that neurons are degenerating and strength is being lost but that there seems to be a spreading phenomenon. And why does it spread and how does it spread and what is spreading?

So things like that would be very important aspects of the biology to try to understand. But I think that’s one of the essential aspects of the disease. It breaks out somewhere and then it progresses outward.

Seth: Do we ever see a patient with a breakout in one area and then a breakout in a different area?

Dr. Ravits: Yes.

Seth: Or is that all patients?

Dr. Ravits: No. What I presented is a breakout in one area and a spread is a simplification and it’s being discussed. Certainly, there are patients who have two or three areas, or it breaks at one and then it pops up somewhere else. So it is complicated and I’m not sure we understand it. I’m not sure we understand all the phenomenology of what’s going on. I represent it as a more simplified, just for the sake of trying to visualize it and trying to understand it. But I think you’re right, it can break out in other areas and it can skip areas and it can jump and do other things. But that becomes pretty interesting and important to try to understand. What is it that’s skipping or jumping and what is that phenomenon?

At one point, going way back to the — well, back to Lou Gehrig actually, when Lou Gehrig was diagnosed, they said he had a chronic form of polio. So there has been in the history of the disease this idea that it’s a virus. I think part of the reason that was a popular theory at one point was because viruses spread. It can start somewhere like an infection and then it can spread. So as an explanation, viruses seems to explain some of the observations that we make.

Seth: Thank you. I will give you a little break here and remind those who are listening that at the end of the call we will be opening the lines for Q&A with Dr. Ravits. The number to dial in to is 516-590-0362. For those listening online, you will have to dial in via phone. And then once you have dialed in, press 1 and you will be put in the queue to ask your question.

Dr. Ravits: Say the number one more time.

Seth: Sure. Amy can say it for me.

Amy: The number is 516-590-0362 and then if you have a question, you press the number 1.

Seth: Thank you, Amy. All right. Moving on, we have talked about sort of the wide end of the funnel. But at a cellular level or molecular level, could you talk about what we know about the ALS process?

Dr. Ravits: I can tell you what some of the popular theories are, some of the theories that are emerging. I think this goes back to our discussion about the genetics because the genetics — let’s take ten different mutations across ALS. It’s important to say that it all looks above the same. So when we diagnose a patient we can’t say “Oh, this is the pattern that we would see with mutation X and this would be pattern with mutation Y.” We can’t say that. We can say we diagnose — for the most part, we can say this looks like it’s this pattern and then we have to check all the different genes if it’s a genetic case.

So the point is that sporadic ALS and familial ALS and the different types of genetic ALS, all would appear to be the same. It can be the same things — start with the legs, start with the arms, start with the speech.

So then we can say that with the different mutations that they all cause different kinds of changes. So now we’re appreciating that some of the problems have to do with the way — it seems that it has to do with the way that the DNA that’s in the nucleus of the cell, as the center part of the — the heart of the cell, the way that it’s able to make RNA, which is sort of the working part of the genetic code.

So DNA goes to RNA and then RNA goes to protein, and it all gets shuttled back and forth to  different compartments in the cell. And so some of the biology is telling us it has to do with the way that the RNA is made or processed. So that’s one line of direction that probably started about 2006 when we started appreciating just how important that was.

Another line of thought about this, it has to do with the way the cell takes care of itself, the way it discards proteins or recycles proteins. It shuttles them out when they’re done with their business, how it’s basically housekeeping or house clearing of the cell. So that has to do with what’s called protein degradation pathways. So there’s a bunch of genetic mutations that seem to line up with something being wrong in that direction or that function of the cell.

So those are a couple of the theories. Another one has to do, you know, the neuron has this huge long axon which is reaching from one region to another, so from the brain down to the spinal cord, at the spinal cord out to the muscle. Those are huge pathways or huge reach for the cell. And so things have to go up and down the axon. So that’s called axon transport, so the way things are moved up and down. There’s things pointing to there being abnormalities in axon transmission. And there’s a bunch of others.

So more and more people with each new identification of a gene and a team of researchers come in and try to understand that, it’s pointing out at all these different aspects of the cell’s function.

Seth: And which area of research are you focused on right now?

Dr. Ravits: Well, I think in my laboratory there’s two main directions. One has to do with the spread phenomenon. So I’m hugely interested in how that may occur and trying to characterize it and understand it and, to some extent, exploit it. Pathologically, we’re trying to understand it. So that’s a big part of my research.

The second has to do with a new mutation that was identified three years ago now, 2011, which turns out to be single most common genetic cause which is called C9orf72, and that’s become a real exciting story in ALS especially for about the last three years. So maybe we can spend a minute and I’ll tell you a little bit about that story if you want.

Seth: Yes, please. We like to hear anything that’s considered exciting.

Dr. Ravits: Okay. This gets into this overlap of ALS and dementia so that’s probably — maybe this is a time to talk a little bit about how we used to say that ALS doesn’t affect the mind; that it really just affects the strength and never affects the mind. I think we’re realizing over time that it can affect the mind. It can affect what’s called frontal temporal function–so language, sometimes behavior, sometimes executive functions, judgments, things like that can be affected and it’s more common than we realized. Oftentimes when it does happen it’s not severe; it’s a mild problem but for some occasional patients, it’s actually a very severe part of their disease.

Now you’re asking about other functions like kidneys and liver and things like that but we now see that ALS can affect other functions within the nervous system and that’s called frontotemporal dementia. It turns out that there are families where if you look at the family and you say — we used to not pay attention to the dementia part of it but all of a sudden if you start overlapping them and say it’s either dementia or ALS, it turns out that there’s families that have both and it turns out it’s a significant part of ALS. It’s probably about 6% of sporadic patients and maybe about 40% of the genetic patients — up to 40% of the genetic patients. So it’s really the single most common gene that we’ve identified.

That was identified in 2011 when two different teams; one, a team at the Mayo Clinic in Jacksonville, Florida and the other is a research team at the National Institutes of Health simultaneously identified this gene. It was called C9orf72. Just to tell you how exciting this is, the C9orf72, what that means is that it’s on chromosome 9, C9 is chromosome 9, orf is O-R-F, is open reading frame, so it means that the computer showed that there was a stretch in the DNA, a long stretch of the DNA that predicted that a gene was there but nobody really knew if a gene was there or not. And then 72 means there was number 72. So there are thousands of these all over the genome areas that the computer would say this might be a gene. An open reading frame means that you can read along and it looks like there’s sensible code in that region.

It’s only thought to be a gene, nobody knew for sure. And then in 2011 two teams simultaneously identified that, in fact, there were mutations in there that were the cause of ALS. And it was also the cause of frontotemporal dementia. So all of a sudden it brought at the genetic level ALS and the frontotemporal dementia field together because one gene could do either. It was common in both of these diseases together at a genetic level.

And the third thing that was so striking about it is that it was a totally different kind of a mutation. Usually, a mutation is you just have a single letter that’s changed, a single letter in the code has changed and then that just skews the whole meaning of what that stretch does. But in this case, there wasn’t a single letter that was changed. It was a whole group of letters that were repeating and this repeat which is not abnormal; that there’s a repeat, but it was huge, it was a huge repeat. So rather than just being a small little stretch where there was repetition. That repetition became extremely large. So it was a totally different kind of a mutation that had never been thought about in ALS.

But the fourth thing is that this particular kind of a mutation had already been recognized going back to the 1990s for other diseases. So there’s a bunch of other diseases like muscular dystrophy, myotonic muscular dystrophy. There’s a disease called Huntington’s disease. There’s about 20 or 30 of these disease, all characterized by these large repetitions, these large expansions, they’re called.

And so all of a sudden now, ALS was in – and that had been an area of very productive, very active research for, say, 20 years. And so all of a sudden, it brought ALS now right into the ground zero of that area of research or that part of the scientific research. So that was a huge explosion for the field.

I guess the fifth thing is that, separate from this, there had been people — drug companies and biotech companies — that were able to think of strategies in which you could actually target that gene and try to actually alter and silence or quiet the gene so that it wouldn’t do its badness, so to speak. And so all of a sudden now, the C9orf72 has the potential of being a treatable aspect.

So it’s a huge activity right now, trying to see if we can target it with these new gene therapies and then, of course, trying to figure out what’s the right way to target it and then quickly trying to get that into patients. So that’s what’s happened in that particular area over the last three years, a huge transformation of us now trying to think about some very fundamental treatments for the disease.

Seth: Now, perhaps a question that will show my lack of a scientific background, but how confident are we of ALS symptoms in those patients with the C9orf72 mutation? How confident are we that those are a one-for-one match? Do all C9orf72 cells end up manifesting in ALS?

Dr. Ravits: Yes, okay. Actually, I want to say two things about that. But first, to answer your question directly, the answer is it’s not known. You can carry the mutation and not get the disease. So that’s true for all the genetic mutations. In the phenomena, we call that penetrance, if you carry the mutation what’s the likelihood that it’s going to penetrate through and actually cause a disease or just stay silent. We know that all of the genes have the potential of not penetrating, and so you can carry the gene and not necessarily get the disease. That’s certainly true for C9orf72. You can be a carrier and not get the disease or it may be waiting to happen or maybe it doesn’t ever trigger. So those are big questions we’re trying to understand.

One thing I just want to back up and add to that too which is we’re saying before is that a lot of times, the scientists and research communities are all excited about these genes but they’re actually a rare part of the disease. So if 90% of ALS is sporadic, why are we spending so much time and resources on this small little niche group?

I think the answer is twofold. One is that’s where we have possibility. The sporadic patients are so complicated. We don’t really know how to treat it. So anything we learn in these genetic patients will apply to the sporadic patients as we gather knowledge and momentum. That’s one aspect. The other is that if we can engineer these genetic therapies for these genetic patients and we can find some sort of genetic switch for the sporadic patients, then again we’ve done a lot already to get us into the sort of Holy Land of real gene treatment.

So we’re all learning. We’re all growing. We’re all in this journey but the reason that the genetics is getting its share of attention has to do with the possibilities are nobody’s forgotten the greater group which is the sporadic patients. That’s what we’re really – that’s the Holy Grail.

Seth: Thank you for that. For those of our listeners new to genetics, is a gene like the C9orf72 something that will show up in an over-the-counter or a popular genetic mapping service?

Dr. Ravits: I don’t think so. It’s tricky to do the testing. So if you mean where people mail in and get their genome sequenced for a fee? No, I don’t think this will show up then because it’s too – the routine test wouldn’t pick it up. It has to be specifically sought after.

Seth: Great. Thank you. Back to my question earlier about what you were focused on today. Are there trials coming out of UC San Diego on your research?

Dr. Ravits: There are discussions for that, yes. I think, I would say, in the background for all of these, ALS has really attracted the attention of lots of big pharmaceutical companies. So that’s been a pretty exciting switch over the last couple of years as well where it used to be – we felt as a community, the ALS community, that we’re not being paid attention to by the pharmaceutical companies. And because there were bigger markets and more common diseases and things like blood pressure and back pain and diabetes, heart disease, we’re getting, you know — because it’s affected so many more, hundreds and millions of patients.

But now, I think there’s been kind of a sea change. I think the different diseases — there’s been lots of breakthroughs in cancers and heart and diabetes and so on, and I think some of the drug companies anyway are really trying to make a difference. ALS has really emerged as a disease, as a challenge for drug development. So it’s exciting that so much attention it’s drawing and how the pharmaceutical industry is really increasingly motivated and interested in trying to do something meaningful for ALS.

So there’s lots of discussions, lots of things being tried, lots of trials that I think are being thought about and we’ll see develop over the next couple of years and we’ll see more and more. Certainly, you see, we’re part of that discussion as much as we can be.

Seth: Thank you.

Dr. Ravits: I think stem cells is another one. I guess it is going to be a complicated one. But of course, it’s got lots of attention. Maybe this is a good time to just spend a minute talking about what’s happening in the development of stem cell therapies.

Seth: Yes, please.

Dr. Ravits: So the stem cell therapies are looking at a lot of different diseases – again, heart, musculoskeletal, arthritis, diabetes, for pancreas replacement and things like that – but clearly the neurodegenerative diseases is a big part of what’s thought to be potential for stem cells . Of the degenerative diseases, ALS is certainly one of the top ones that the stem cell enterprise or the stem cell research groups are looking at.

So there’s lots of things that I think everybody’s heard on the news, different companies, different products, different approaches, different trials. And there’s a bunch more that are waiting to happen or trying to get funding or trying to get their cell lines better developed or more predictable and things like that. So I think we’ll see a lot of that developing also over the next five to ten years. We’ll see a lot of different approaches to stem cells.

I think stem cells is going to be a hard application in part because of what we’re talking about earlier is the local properties. If it begins in the leg, then where are you going to put the stem cells? Would you want to put it in, say, the lumbar spinal cord? But if it begins in the arm, then you have to go to a different region. So some of the issues that have to do with how far will these stem cells reach in terms of what they’re going to rescue, and so some of the strategies are going to be pretty complex. You combine that by the fact that to get them in, they have to usually — most of them are being delivered surgically so there’s a surgical implantation or transplantation to get them delivered in the first place.

So it’s got a lot of challenges as a field to try to get this, particularly for a disease like ALS. But we’ll see that happening and more and more people are coming up with new approaches.

Seth: Thank you. We started off with a very loaded question. Maybe we’ll move to the end of the interview with a really tough question. What is the greatest factor hindering your research today?

Dr. Ravits: Well, probably the single biggest challenge has to do with just the complexity of the disease, trying to really understand and model it and test it. So the disease itself is really the biggest challenge. We could talk about funding and things like that, but I think the bottom line is even if we had unlimited resources, it’s still a hugely complicated disease and we need to understand it.

To me, we need to be smarter than ALS if we’re going to beat it. So just trying to do things, we really have to understand it, be smarter than it, and then get there first with our treatments or with really fundamental root therapy. So I think that’s I see as the biggest challenge.

Obviously, funding, getting people in the field, trying to get young investigators, trying to get people with the clinical training to come into the field, get young scientists, get the old scientists, get everybody involved, and trying to get a share of the research funding. So that’s obviously another constraint.

Seth: So the mystery of ALS itself is the biggest hurdle… we understand the complexity of that issue. Thank you for your answer.

We will prepare to go to callers now. Again, the phone number to dial in to, Amy, if you could read that one more time.

Amy: The number is 516-590-0362 and press number 1 for your question.

Seth: So while we allow people to dial in, I’ll ask a wrap-up question of you, Dr. Ravits. What, in your view, is the greatest opportunity for our listeners to get involved or help?

Dr. Ravits: Great question. I think it’s different for everybody so I think probably the best advice or the most important thing you can do is to, first of all, take care of yourselves; the patients take care of themselves and their family members and so on and just fasten your seatbelt and make the best of it and the most of things and to realize how hard everybody’s trying and so to get your house in order in terms of just taking good care of yourselves.

But beyond that, obviously, I think the second thing probably would be to keep the heat on. Patients and families need to speak out, need to speak their minds, need to speak freely and openly. It’s an open community. The ALS community is very open and we have lots of different voices and to keep speaking out and keep putting the pressure on and keep asking good, hard questions. It’s a very easy community to be engaged in. I mean, everybody wants the same thing.

So in terms of as a community, it’s really not very complex as to what we want and need. It’s just how to get there that’s the challenge. It’s a great community to be a part of. It’s an open group and everybody needs to hear ideas. Our ideas change and it changes because people speak out and they’re part of it. I guess that would be an important opportunity and an important thing that everybody can do.

And then I think a third thing is people need to be assertive with their care providers to make sure that they’re being heard, that they’re understood, that they’re assertive in what they need. And if people aren’t paying attention or aren’t hearing, then to not be shy about it and speak out. This is important. It’s important for the providers to hear, and it’s important for you to be heard. So I think that’s the third thing.

And the healthcare system does care but it’s complicated and it’s not going to care if people don’t speak out and don’t assert themselves because in part, ALS is a niche disease and ALS is a complicated disease. It’s a different model then we have with some of the other diseases.

Then, of course, the last thing is fundraising and research. For both, actually, a lot of the resources not only are needed in research but are needed in the clinics too that are providing bed care. So that’s a huge part of it. A lot of the patients will want to give to research but realize that the clinics that are providing the care are oftentimes badly in need of support – financial support. Most of the care is not reimbursed and so clinics do have to justify themselves in their medical centers and need a lot support. So it’s everybody – the doctors and the scientists that need the financial support.

Seth: Thank you for those answers. We’ll now go to our first caller. Caller number 1, you are live with Dr. Ravits.

Caller: Yes. Hi, Dr. Ravits. Thanks so much for taking time today.

Dr. Ravits: Sure.

Caller: I have a question for you about what you talked about earlier when you said you were specializing on how it could potentially spread. And I wonder how’s that involved with or what factors might be that cause this spread. Could you elaborate more about what you have learned about the spread? And are there other triggering events or things that ALS patients could control like diet or things to minimize the spread when that occurs?

Dr. Ravits: Sure. That’s a great question. So I think this concept of spreading disease is also a theme that’s emerging in other diseases like in Parkinson’s disease and Alzheimer’s disease and in frontotemporal dementia. Some of the other degenerative diseases, more and more we’re hearing about this concept of spread. Probably, the area that’s the most popular right now scientifically has to do with this phenomenon called protein folding. I don’t want to get too complicated here, but basically a protein is just a sequence of chemicals and then it folds into a shape and then the shape does different functions. It can do structural, it can be part of a membrane, it can be part of signaling, it can be a part of housekeeping inside a cell — lots of different aspects of proteins. But it’s folded into a shape and the shape seems to be an important part of how it functions.

So there’s a whole theory that somehow the protein gets misfolded so it changes shape and so it gets a kink in it and all of a sudden then it’s not functioning. But not only that, that that kink in the protein is able to take it’s like proteins, the same proteins and then induce them to similar misfolding so that the kink that started in one protein then rolls out to another protein, same protein, not just any protein but it’s the same specific protein. They start misfolding and then one misfold leads to another and then that is an idea of what’s called propagation, so that it can then propagate.

So that’s become a very exciting area of does this occur? How does it occur? What functions are lost when the protein misfolds? And then how can we stop it from misfolding? So I think that’s probably one of the most popular. There’s a lot of other ways in which you could explain the spread, but that’s I think the one that’s got most of our attentions right now, most of our imagination.

In terms of what triggers it in the first place, nobody knows. So the short answer is we don’t know. When you think about like a computer and when your computer gets a lock on it, somehow it crashes. And I think it’s because of all this electricity that’s going on. Some random thing gets thrown in and then it gets thrown off. So it’s possible that in all the maintenance of a protein. It’s just a statistical phenomenon and then once it starts, then it starts cascading.

So the trigger is not known. Maybe it’s just a random event. People have looked at diet, looked at trauma. Trauma is becoming a big area of research right now, like the brain injuries and does that somehow set things up for problems. Exercise has been looked at as there’s something in like high athletes or in excess physical activity that might do it. These are all the areas that — environmental exposures, toxins, agricultural products. So all of these things have been looked at but nobody’s really been able to get the goods on any of it to identify what it is. So the answer is we don’t know what triggers it.

Caller: Well, thank you. That’s great information. And can I ask a follow-up question?

Dr. Ravits: Sure.

Caller: Now that genome sequencing is kind of opening up this whole new world and the C9orf72 is a fairly recent discovery, is there a way of taking the genetic markers from multiple patients that don’t have the sporadic ALS and kind of overlaying them to see if there are any other genetic mutations that pop up?

Dr. Ravits: Yes and that’s being done. Big time it’s being done. So it started actually probably maybe ten years ago. They’re called the Whole Genome Association Studies. So you take, basically, all the sporadic patients — thousands of them — sequence the genome then basically line it up and then try to look at every space or every column and see if they’re a mutation. And that’s going through different iterations.

So it started with what was called in early generation of these high throughput technologies and it showed a few things, but not as much — we all thought it would show some really powerful insights and it didn’t really. It was kind of disappointing. Now it’s being redone and it will continue to be redone as the technologies improve, as we try to comb through it and see what’s possible in the genome of sporadic patients that’s maybe different than other patients. And it’s a huge computer challenge. So a lot of the work is being done not only by geneticists, but by the computational biologists.

But I can assure you that it’s a highly active area of research, very competitive, which is good for everybody because we have big groups in different parts of the world kind of competing trying to break the code on ALS to see if there’s something there. So that’s a very active area of research right now.

And the groups are getting together. I guess the other good news is that as competitive as research is, science in ALS kind of works both ways. It works to everybody’s good because groups are competing to try to have breakthroughs, but they’re also working together, and so sharing information and sharing approaches and sharing materials and things like that so that people are working together as well.

Caller: And then is t all information kept in one system? That seems to be a database challenge.

Dr. Ravits: It’s a huge database challenge and a lot of it’s just done through the cloud exchange. But then also some of the challenges what you call wet labs. So you actually have the DNA and then as a technology improves your way of sort of sequencing the data, then it has to be redone because then it’s not — you have to generate the data all over again. So the DNA is being shared and stored and sequenced by different groups.

Caller: Okay. Well, thank you so much. Thank you very much for taking my call.

Dr. Ravits: Sure. Good questions.

Seth: Thank you, caller 1. We’ll now open that line for caller 2.

Caller: Hi, Doctor. You spoke about the way ALS affects the different systems specifically the metabolism. How does nutrition play a part in treating ALS?

Dr. Ravits: Oh, great question. Probably, if there’s one single — I don’t know if you call it a breakthrough but one single factor we’ve recognized in terms of quality of life and duration of life is trying to deal with the nutritional challenges from ALS. And I’d say the challenges are twofold. Some patients have a lot of trouble chewing or swallowing food so it’s primarily an intake problem. And that’s where feeding tubes and things like that help compensate for the ingestion and the intake of nutrition.

But then we talked about this other group who, independent of that, seemed to have trouble maintaining their weight. And to me that’s a bigger challenge with the patients because putting in a feeding tube is not going to solve it because the problem is not the intake in the first place. And then I guess there’s a third group who just have loss of appetite. They just lose interest in food and it’s trying to stimulate the appetite. There’s actually a couple of drugs that will help with that.

But I think the short answer to your question is we don’t know of any one specific nutritional factor that’s important. It’s just nutrition in general is important. So just trying to maintain nutrition, maintain weight seems to be an important part of taking care of patients or patients taking care of themselves.

Caller: Okay, great. Thank you.

Seth: All right, thank you, caller. Moving on to our final caller, caller 3, you are now on the air with Dr. Ravits. Please go ahead, caller 3.

Caller: Am I hearable?

Seth: Yes, you are. Thank you.

Caller: Okay. Dr. Ravits, first of all, I would like to thank you. It’s a delight to hear you. Your reputation precedes you in this area and we are very grateful that you would take time to share here.

My question kind of overlaps one of the previous callers who asked about the coordination, the database and the coordination of information. And what you shared is that it was quite exciting that people are hoping to go forward and consequently almost competing to find the key, the code that would unlock this disease.

May I ask, are you adequately pleased with the level right now of the sharing of research and of findings? Do you think it could be improved? Do you think that it’s about as best it could be? And just as an uninformed person I think, okay, are we talking about nationwide researches happening in ten centers? Is it happening in every medical school? What are we talking about? What’s the coordination challenge?

Dr. Ravits: Okay. So let me break that into different levels if I could. One level would be the genetic testing that we were talking about earlier, and I’m not a geneticist so I’m not involved in those DNA studies. My studies are more at the RNA level so it’s a little bit different.

So if the DNA where you have big — trying to sequence the genome and then search through it, I would think there’s I think probably two big groups in the United States and a bunch of European groups as a confederation, a couple of different European groups. I think one, mainland Europe. I think there’s an active group in England and an active group in Ireland. I think those are the major and Italy has got great research and the Japanese have great research. So I think these groups are — I’m not in the know on that. I just know the people who are doing it, and they always seem to be trying to pull their data or to share the data and then try different computational approaches.

I’m not aware — I mean there’s always competition, but I think it’s pretty good the way they’re sharing and trying to pool it because the idea being the more numbers you have, the more likely you will find something. I think the problem has just been it’s not showing us as much as we thought was there or that we would find.

Caller: I see.

Dr. Ravits: So I think to me that’s the biggest problem is just what we thought before we got there would be a greater area of exploration isn’t just revealing it. And a lot of it is not done by people necessarily in the ALS field as well. I mean it’s people with the genetic tools and their computational power. So I don’t think collaboration is impeding anything that I can see. It’s always slower than we wish and it’s not as rewarding as were hoping. I think that’s the major thing.

At the more science level in the stuff that I’m doing, I would say I’m kind of new to science. I was mostly in clinical work for most of my career. About ten years ago, I started converting and I’m more and more converting. I’m kind of reinventing myself and rediscovering. I’m coming into a new world where I thought it would be wickedly cutthroat and competitive. And it is very competitive, but I’ve never yet had an encounter where I thought somebody was unpleasant or not sharing or wasn’t smart or careful or diligent, I think.

So we compete with each other but at the same time we know each other and we work with each other. I’m actually hugely impressed at the level that this is conducted. I think one of the things — people start holding — there’s too much data. It’s not that people aren’t sharing. There’s just too much to do and too much to share. I’m hugely impressed.

Caller: I greatly appreciate that and I’m encouraged by it. Again, thank you so much.

Dr. Ravits: Sure.

Seth: Thank you, caller 3, for that question. That brings us to the end of our call. Dr. Ravits, is there anything you would like to share in the closing?

Dr. Ravits: Well, I think as I’ve been trying to highlight, I guess the thing I’ve been trying to communicate is how exciting things are. I think the flipside of that is how slowly it’s moving. It’s not ever moving fast enough for any one patient. That’s always the balance is to try to keep people’s hopes up and convey how truthful things are now but to also realize how complicated the problem is. And it’s not going to be easy to beat this.

So I think we’re all on the same side. That’s a hugely important thing. We are working as fast as we can. But at the same time, we got a big challenge ahead of us.

Seth: Thank you for being on our show, and thank you for your research and dedication. We sincerely appreciate you. For those who were not able to cast the phone call today, please go to alscrowd.org. The audio from this call will be archived there, and the transcript for the call will be posted there one week from today. Again, we thank Dr. John Ravits of UC San Diego for your time. Please tune in for our next show. Thank you.

About Author


ALS Crowd co-founder, friend and ALS patient supporter. Jenny launched the CrowdCare Foundation in 2012 to bring patient involvement into the acceleration of a cure for rare and orphan diseases.


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