An Expert’s View on Current ALS Research, TreatmentsAug 25, 2014
One of the biggest challenges with curing a disease is figuring out what causes it. Is ALS, also known as Lou Gehrig’s disease, caused by genetics, environmental factors, or a combination of other things? Researchers are trying to solve that problem. Dr. Mark Bromberg, director of the ALS clinic at the University of Utah, provides an insightful look at the state of treatments and research for the disease today, and what’s on the horizon for this debilitating disease.
Interviewer: In order to treat ALS, scientists and researchers need to understand what causes ALS. We'll examine that next on The Scope.
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Interviewer: Part of the problem when you're trying to cure disease when you don't know what causes it is, well, you don't know what causes it. We're going to find out what the current train of thought is when it comes to ALS, or Lou Gehrig's disease, from Dr. Mark Bromberg. He's Director of the ALS Clinic at University Utah Healthcare.
So it must be a challenging thing when you don't know what causes a disease to try to find a cure for the disease. What do we know so far?
Dr. Mark Bromberg: Well, you're right, it is very challenging, and in particular when a patient said, "Okay, if this is my diagnosis, how did it happen? What did I do? Who did what?" And so the clear answer is that at this point we do not know. It's certainly not contagious; you don't get it from close contact, so it doesn't go from husband to wife or wife to husband. We've obviously looked at environmental factors, and we have not really found any clear environmental factor that is linked to the development of ALS.
One clue we have in looking overall is that about 5% of patients will tell you they have a family history of the same disorder. So that suggests that there may be a genetic cause.
We've known about the family history for well over 100 years, and it's only been about 20 years ago that we found the first gene that is linked to ALS. The problem when we found that first gene was that it only accounted for about 20% of people with familial ALS. So that meant that there was more than one gene. And over time we've found a number of other genes, some of them rare, meaning very few families have the gene, and others are far more common.
Once you have a gene, the next task would be what does the gene do, what kind of protein does it make, and what does that protein do in the body, with the idea that if that protein is missing, or if that protein is faulty, that might be a clue as to why the cell breaks down and degenerates and dies. Despite knowing a lot about these genes, we still have not been able to find a direct linkage between either a missing protein or an abnormal protein and why it causes the cells to die as we see in ALS.
In addition, some of the genes code for particular proteins that have one function and other genes code for a particular protein that have a different function, so we're not seeing that much of a commonality. Although that is beginning to show as we're discovering more genes that may have similar mechanisms. The one main point is that trying to understand the genetics behind ALS is certainly going to give us clues as to how we may be able to intervene and alter that.
It also could be that it may not be a single environmental factor, but it may be a number of environmental factors, each one common but rare, so that an individual may be caught up with several of them. Then when you look at cells and how cells can degenerate for other causes, we do identify a number of steps. So though those steps have been looked at with the idea that maybe there is something that goes wrong with some of these steps, and maybe a cascade of events. So something small happens, and that begets another problem in a cell, and begets another problem, and then the cell begins to degenerate.
Another issue is that once one cell begins to degenerate, why does it progress, and neighboring cells begin to degenerate, so that a person becomes weaker? So how is that factor, whatever it is, if there is a particular factor, how does that factor move from cell to cell?
One thing we're finding is that in other neurodegenerative disorders, including ALS, such as Alzheimer's disease, and Parkinson's disease, there are accumulations of proteins inside of cells. Normally in a cell proteins get made, they get used, they get destroyed, and then new proteins take over. So how we get rid of these old proteins is something we're always doing, but some of these neurodegenerative disorders are characterized by an inability to get rid of them normally so they sort of pile up. It's as if the garbage collector didn't come around for a couple of weeks, and the household trash that you normally accumulate is not being gotten rid of and it piles up.
Now, we think that that piled up trash, or the accumulated protein, could have some toxic properties. If so, how does toxic property that builds up in one cell get moved to another cell and so on? So that's another theme.
And one point about this is that although ALS may look different than say Alzheimer's disease, this idea of these protein toxic aggregates is common to all neurodegenerative disorders. And if we find information about one in a particular diagnosis like Alzheimer's disease, it may be applicable to ALS and vice versa. But so far we've been very challenged in finding any drug that has a marked effect on slowing the rate of progression.
Interviewer: As of right now for ALS, it's just slowing the progression. It sounds like the best kind of course of action we have. Is there ever a chance for a cure in your mind?
Dr. Mark Bromberg: Well, certainly if we can slow it so much that it stops, that would be the ultimate.
Dr. Mark Bromberg: One has to be realistic, and like other neurodegenerative disorders, like Alzheimer's disease, we so far have not found medication or therapy that markedly slows the rate of progression. So at this point any demonstrable slowing would be good.
Interviewer: Yeah. What about stem cells? We all know that when a nerve cell dies it's done. But what about stem cells and infusing some new cells in there? Is there any hope on that front?
Dr. Mark Bromberg: I think people feel that with stem cells you could replace nerve cells that have degenerated. Unfortunately that is unrealistic because the nerve cells we're talking about in ALS that degenerate and die have very long processes. They may be a foot long. And so to put a new cell in the brain and expect that it will grow out a process that's a foot long is really not realistic.
Interviewer: What's your theory on the whole thing?
Dr. Mark Bromberg: That's a hard question. There certainly is a genetic aspect where if someone has the gene they've got a very high probability of having loss of nerve cells if they live long enough. Interestingly, ALS is the disease of adults, generally of older adults, although it can be in the age range of the 20s and 30s, but the most uncommon age range to develop symptom onset is in the late 50s.
Interviewer: So is there anything with that that might be something to look at?
Dr. Mark Bromberg: Well, I mean, people have certainly looked at that. There are normal aging processes; cells are less able to repair themselves in an older individual than in a younger individual. There are genetic changes that occur spontaneously in all of us, and we do tend to repair them so that may be a factor. It may be that there's an accumulation of these excess proteins that reaches a threshold, and once it reaches a threshold more garbage begets more garbage, and it piles up more.
So if I had to look back I would think it would be something where there's an inability to process these proteins that are broken down and to get rid of them efficiently. And then something in there kind of seeds it and that process gets out of hand and that toxic element of the protein is what brings on a cascade so that the cell becomes sick and dies.
Interviewer: Once again, not just one thing contributing to this; it's a bunch of different things.
Dr. Mark Bromberg: Correct.
Interviewer: Which makes it even more difficult to figure out what's going on.
Dr. Mark Bromberg: Yes, sir.
Interviewer: Any final thoughts, anything that we left out?
Dr. Mark Bromberg: I do want people who have ALS to know that worldwide there are laboratories devoting their entire efforts to trying to unravel this. And so although it's an orphan disease statistically, it's not an orphan and forgotten disease as far as research is concerned.
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