April 10, 2019 / All Stories

Things That Make You Go Huh? Episode 6

In the sixth episode of our podcast, our clueless host gets schooled on … why Alzheimer’s disease is such a formidable foe for researchers.

Let’s face it: science can be hard.
 
Our host, Brett Hellman, former soap opera producer and current AbbVie employee, lacks any sort of scientific background and has recurring nightmares of his high school biology class. Now, he is tasked with talking to biopharmaceutical researchers about their work and translating it for the rest of us.
 
In each episode, Brett will explore some of the toughest and most relevant topics in medical science. This may be, at times, an exercise in frustration for the scientist being interviewed, but listeners will be rewarded with a new understanding not only of science, but about the scientific community at large – with all pretenses stripped down.
 
EPISODE #6

Confronting Alzheimer’s Head On: The Quest for Answers

It happens to all of us – car keys go mysteriously missing or a name on the tip of your tongue can’t be recalled. One of these moments of forgetfulness gets Brett wondering about more serious forms of memory loss, like dementia or Alzheimer’s disease. He realizes he’s not even exactly sure what Alzheimer’s is. Is the disease hereditary? How is it diagnosed? And can you do anything to prevent it?
 
In our sixth episode, James Summers, Ph.D. vice president, neuroscience research global pharmaceutical discovery, AbbVie, helps Brett understand why neurodegenerative diseases are so difficult for researchers to triumph over. As he nears retirement, Summers reflects on a long career and leaves Brett not only with a better understanding of Alzheimer’s, but also hope for the future of this field of research.

Bio:

James Summers, Ph.D., currently serves as vice president, Neuroscience Research in AbbVie’s Global Pharmaceutical Discovery organization. In this capacity, he leads a research organization of about 200 scientists located in Ludwigshafen Germany, Lake County, IL and Cambridge, MA. The organization is focused on the discovery of new drugs for the treatment of Alzheimer’s and Parkinson’s diseases and other neurodegenerative disorders.  Under his leadership more than twenty drug candidates have entered clinical trials. 
 
Summers began his career with Abbott Laboratories within the immunologic disease and cancer research areas.  He participated in or led programs that resulted in several drug development candidates. 
 
He also served as divisional vice president, Advanced Technology with Abbott where he was responsible for a broad range of technologies and core services that have enabled and accelerated drug discovery research across all of Abbott’s therapeutic areas and sites.
 
Summers earned a Bachelor of Science degree in chemistry from Denison University and a doctorate in organic chemistry from Harvard University.

Brett Hellman: Did you ever wonder … what causes Alzheimer’s disease? Is there a way to know if you’ll develop dementia? What’s with this amyloid theory I keep reading about? And why do we keep hearing about failures in Alzheimer’s research? Find out the answers to this and more on Things That Make You Go Huh?

‘THINGS THAT MAKE YOU GO HUH?’ INTRO MUSIC PLAYS

Brett: Hello, everyone ... it’s your science-challenged host Brett Hellman, and I’m back here in the frozen tundra of North Chicago, Illinois. Now that we’re all slowly thawing out from this polar vortex, I thought it was time to venture back out into the wild to once again challenge my limited knowledge of science.

So the other day, my car keys went missing. I searched high and low … in the bedroom, in the washer & dryer, even in the various dog beds of my two beloved English bulldogs. Of course, after what seemed like hours of searching, I finally found them … right on the front seat of my car. I was laughing about this later to someone as, let’s just say, this isn’t my first rodeo with key loss, and a friend made a casual comment to me about having an “Alzheimer’s moment.”

And although I know my friend meant this in jest, it got me to thinking … is this actually something I need to worry about? I’m not gonna lie … I can’t tell you how many times I’ve heard others casually mention the possibility of having “Alzheimer’s” when forgetting a name, a word, or where something was located.

In my case, I don’t have a family history, and quite honestly, I don’t even know if this is a hereditary disease. With my limited knowledge, I do know one thing however, which is Alzheimer’s research is not progressing as researchers had hoped.

Thankfully, I have an inside tract to experts on this very subject, a group right here at AbbVie committed to this area of research. So with this in mind, I grabbed my microphone, my sound guy, my producer and I took to the streets to get to the bottom of this very complicated topic.

So with that, let’s introduce our guest today … Jim Summers. Jim, can you tell us who you are and what you do?

Jim: My name is Jim Summers. I lead the neuroscience research group for AbbVie. We have been with the company now for about 35 years leading the group for the last decade here and based in Chicago. But we have research sites that I'm responsible for in Cambridge, Massachusetts and in Ludwigshafen, Germany.

Brett: To start us off here. Can you tell us what is neuroscience?

Jim: Well neuroscience is the study of the nervous system, the brain and the peripheral nervous system, the nerves in the extremities. It's a very broad set of science which leads us into a lot of different diseases. And you think about diseases, psychiatric diseases, depression, anxiety, agitation, things like that. Could be epilepsy is included in neuroscience, also pain. And then finally neurodegenerative diseases where people are afflicted with memory loss or other loss of the nervous system. And one of those is Alzheimer's disease.

Brett: So, that's a perfect segway actually because I want to ask you some questions about Alzheimer's today. So I think the first question I have for you today to start us off is can you explain to me in simple terms, what is Alzheimer's?

Jim: Alzheimer's is a really devastating disease. I'm sure many of our listeners here probably are familiar with it on some level having a family member or a loved one that was involved with – either as a caregiver or as a patient – with the disease. It's one of these neurodegenerative diseases that I mentioned before. It's a form of dementia which basically means, if you're familiar with this at all, you would recognize of course memory loss, people unable to remember names of objects first of all and recall things quickly, but quickly going on to not being able to remember people and events even in their life. But it progresses beyond that to having the inability to be able to manage activities of daily living ... not being able to balance your checkbook, not be able to find your way back from a location, maybe not even be able to find your home again if you're out and eventually it also can lead to agitation, aggression, psychotic behavior or things like that and more advanced patients.

There's about 5 million people in the United States who are afflicted with Alzheimer's disease. Obviously it's a disease that mostly affects the elderly, but not entirely. And it's a disease which is a huge burden on our society. The sixth leading cause of death in the United States. It's the only form of major illness like that that we can't slow down, we can't treat really, we can't prevent. In fact, it's a huge societal burden that's only going to become bigger. Right now I think the estimates are something like a quarter of a trillion dollars are spent in the United States caring for Alzheimer's patients and that could go up to a full trillion dollars by the middle of the century. So that's going to put a huge demand on not only the U.S. health care system but around the world. This will be a major economic factor for countries.

Brett: So you just talked about the problem increasing. Can you expand on that a little bit more? Why is that?

Jim: Yeah I think that first of all, the population is growing and as we go through the next coming decades there's going to be more people encountering the disease for that reason. But of course I think as we're all aware, people are generally living longer these days and as we make progress against other diseases, heart disease, cancer and other places, it sort of pushes patients to have to succumb to something and Alzheimer's disease becomes, as they live longer, becomes a factor. About 50 percent of the people who reach age 85 will have some form of dementia. So obviously this is going to become an increasing problem with advanced age.

Brett: Okay, here's another one for you. Do we know what causes Alzheimer's?

Jim: Yeah I'd love to tell you that we had a real clear picture of that ... a real clear cause. But we don't unfortunately, and this is one of the reasons why we don't have great therapies available today because until we understand it well we're not going to be able to come up with therapies. We do have some hints. One of the hints that we've had this for about the last 20-25 years has been given to us by some patients with a very rare form of Alzheimer's disease – we often talk about it in terms of early onset Alzheimer's. These are a fairly small number of people who get the disease in their 30s, 40s or 50s ... much younger than we think about the typical Alzheimer's patient being. And these people carry a gene or actually more correctly a mutation in a gene which gives them 100 percent probability that they will develop the disease. And it's a gene that is involved in the production of a protein in our brains called beta amyloid. And this has led us to believe that if in these small number of patients that carry this gene, beta amyloid's involved with them, maybe it's involved in everybody else as well. And that has been the focus of a great deal of research over the last 20 years or so.

Brett: So let's talk about genetic factors … you were just talking about early onset Alzheimer's. Are there other genetic factors involved?

Jim: Well, there are no other factors that lead to this 100 percent instance of getting the disease. There are other genes, many other genes, that have been identified that increase a person's risk of developing the disease but far short of being the 100 percent. So a relatively common one is a protein that's called APOE and there's a form of that APOE-4 for which you have either one or two copies of that gene. If you have two copies, you have a very high probability, but you still may be as much as 80 percent by the time you're 80-85 years old … but still not a clear sentence to receiving the disease. Other risk factors have been identified, but they often have a very modest increased risk of developing the disease. So genetics plays only a small part.

Brett: So if not genetic, then what are some of the other risk factors?

Jim: There are certainly a number of factors that have been implicated in Alzheimer's disease, but nothing that definitely leads to the disease. One of the more interesting factors that seems to be a preventative factor for Alzheimer's disease is education. The individuals who are more highly educated seem to develop something called cognitive reserve and that will, if not prevent it, will delay the onset of Alzheimer's in those individuals. So environmental factors like that may have some influence as well.

Brett: That's interesting. Let's say you know you have a family history of Alzheimer's. Can you get some type of test to tell you that this is something that you may need to worry about in the future?

Jim: Well these genetic factors that I mentioned a minute ago are certainly things that can be tested for and you can determine if you had, as you said, a history of Alzheimer's disease in your family, particularly early onset Alzheimer's, and then it might be something an individual would consider to have happening under the proper genetic counseling. The challenge that people have to confront, knowing about their status in these situations, is without a therapy available, what are you going to do with that kind of information? And I think it's good to think through how you would react to the information one way or the other before you decide to have the test.

Brett: So my friend's grandmother had what they assumed was Alzheimer's, but was told they couldn't be sure until after she died and there was an autopsy done. Is this still the case? And can we diagnose the disease? And if so how would you go about doing that?

Jim: Well it's certainly true that the best way to be certain about the diagnosis only is available after death. And in that case what a physician is looking for in the brain are deposits of this protein we mentioned earlier, the beta amyloid, there'll be plaques produced, or deposits produced, in the brain which are a hallmark of Alzheimer's disease. The problem in diagnosing it during life is that many of the symptoms that are seen in Alzheimer's patients are very similar to those seen in other types of dementia. There's Lewy Body Dementia, there's vascular dementia, there's a number of these frontal temporal lobe dementia and so on. And as I say all the all the patients tend to exhibit similar symptoms. It is possible today to do some imaging with the brain and look for the presence of these amyloid plaques through something called PET imaging. And that is often used now in clinical trials to make sure that the patients that are enrolled in the trials actually have Alzheimer's and don't have some other form of dementia, and that can become available to the general population as well.

TRANSITION MUSIC

Brett: Okay, so not to be such a downer, but every day we hear of more companies dropping out of Alzheimer's research, or another failed trial so I guess my question would be: why is this disease so hard to treat?

Jim: I think there's a couple of reasons why it's been challenging up to this point. I think first of all it goes to the fact that we haven't yet understood the exact cause of the disease. So in order to target a therapy to a particular cause we have to understand that cause and that is still emerging, and part of the way we'll figure that out is actually trying different approaches and seeing whether they are effective in patients. I think the other big challenge is that this is a disease that actually begins 15 to 20 years before a person is symptomatic, before you start displaying really obvious memory loss or other cognitive issues, the disease is brewing away in the brain. These deposits of beta amyloid that we've been talking about are already present 15 to 20 years earlier. So the best analogy I think in this case is to cardiac coronary artery disease where you’ll be familiar with the fact that you have high cholesterol or a fatty diet or genetic factors, you might be developing blockages in your arteries of your heart which could lead to a heart attack eventually. Well you don't want to treat the patient when they've had the heart attack, you want to treat them early on while those blockages are developing. And the same is true with Alzheimer's disease. You'd like to be able to be treating in that 15 to 20 year pre-symptomatic period. The problem of course, is how do you know that someone has the disease when they’re not symptomatic, and we don't have a test today like we have for cholesterol or high fat and so on to be able to differentiate those patients. As clinical trials have been moving forward over the last 10 or 15 years, we are moving to earlier and earlier patients, but we still have a way to go to be able to identify pre-symptomatic patients on a large scale.

Brett: That's so fascinating. Have they done any studies to show that there are early signs or ways to tell whether somebody may be developing it or yeah, if they will develop any symptoms?

Jim: Today there's really no way to know if somebody in their say 50s, is going to develop the disease in their 70s. I'm optimistic that over the next several years that there will be for example some imaging methods where you could go in and have a brain scan and show that there was early signs of the disease developing at that kind of cellular or molecular level before it actually becomes symptomatic. I think it's important though to comment here that just because you may be experiencing some difficulty in remembering a word or trying to remember the name of somebody you met 10 or 15 years ago, that is not a sign that you're developing Alzheimer's disease. As we age it's quite normal to have some minor loss in memory or cognitive function that's just a normal part of aging. With Alzheimer's disease it becomes much more accelerated and you'll probably never be able to remember those words, versus somebody who is just aging it might take them a few minutes or an hour later before it pops into their head.

Brett: So you previously talked about failures. So I guess my next question would be, have we learned anything from these failures?

Jim: I absolutely think we've started to learn some things from the failures. If you look at the research that's gone into this area over the last 20 years it's something almost all focused on the beta amyloid that we've been mentioning periodically. One for example is that they often try to prevent the production of new amyloid and that ignores the existence of amyloid plaques and deposits in the brain already, which are continuing to do damage to the brain. So that apparently is not enough just to limit the production of new amyloid. The other challenge is – we've talked a little bit about it – is the idea that people are developing the disease much, much earlier than they’re developing symptoms and unfortunately, out of trials in the early days of research around amyloid we were treating people who are already symptomatic. But of course if they were developing this biology, this pathology in their brain 15 years earlier, then that's probably too late. We need it to start as early as possible. And so what you're seeing the field do now, is to try to focus on earlier-stage patients that have a chance to be treated by the therapies that we're investigating.

Brett: So how is your team approaching Alzheimer's research?

Jim: Well we're not currently working extensively in the amyloid area. We're looking at therapies beyond amyloid, which has, as I said, been the focus for the last 20 years. There are three basic areas that we're working on here. One is an area called tau biology. Tau is another protein which gets deposited in the brain, but had been largely ignored for a number of years. And we're trying to develop drugs that would either remove the tau deposits or prevent their spread from one part of the brain to the next. Second area that we're working on is looking at neural inflammation or looking at the role of the immune system in the brain. We know from a lot of the work that's been done that the risk factors, the genetic risk factors that we talked about before, many of those are associated with something to do with the immune system, but 30 percent of the genes that have increased the risk of Alzheimer's disease have some immune connection. And the third area that were interested in is field of science called proteostasis and this is just an area of biology that's in which cells use to remove unneeded proteins or other cellular components when they're done with them. And you can imagine that in diseases like this we have a lot of misfolded proteins like amyloid or tau, there might be something wrong with that system that's preventing them from being cleared as they should be. So we're looking at ways to be able to treat the disease by improving that clearance.

Brett: Forgive me Jim my brain did not process one of the things you just said, so can you tell me what you mean by misfolded proteins?

Jim: Sure you can think of a protein as a long chain, but in fact in nature that chain wraps up around itself to form a particular structure. There is a normal structure that the protein should adopt, but when it wraps up in the wrong way then it's misfolded and that can lead actually to aggregates or multiple protein molecules coming together and actually eventually being large enough to form these deposits that we talked about before that happened in the brain, characteristic of the disease.

Brett: Perfect that helps me. That I understand. Thank you.

TRANSITION MUSIC

Brett: Okay, so let's change track a little bit here. As someone who's been involved in this research for quite a bit of time, how do you stay positive when I feel like there's so many false starts and so much negative news surrounding this topic.

Jim: Well, yes there has been a lot of negative news and problems in the past but I'm actually very optimistic about how the future looks and I say this for several reasons. I think first of all the science behind Alzheimer's disease and understanding the cause of the disease is beginning to become more evident every day. And I'm very optimistic that's going to continue to grow exponentially and in a way that will continue to give us more insights on how to treat the disease. I think also as we've talked about, we've learned a lot from the failures of what's gone before us. I think that also we have many more tools available to conduct our research in a more productive way with a higher probability of success. For example, we have ways I've mentioned several times today about imaging the brain and being able to show that patients have deposits in their brain and that these patients would be the right ones to treat for a particular therapy. Those things weren't available just a few years ago and when the early trials were being run. And there are many more tools like that that are becoming available, so I believe you put all these things together and you have to be optimistic about how things are going to go in the future.

Brett: So this next question may be weird but I always think about how hard it must be when you've invested all of this time and energy in developing, whether it be an idea or a study, and then you see it fail and I guess my question is how do you deal with this on a daily basis, with failure on a daily basis?

Jim: You know, failures are just honestly part of the business of doing research whether it's pharmaceutical research or any type of research, if you're exploring fundamentally new things which are not understood – you're going to have a lot of failures as part of that. But with perseverance and determination I think people realize that you may take one step back, but you also take two steps forward, and over time progress will be made and new areas of science will become understood.

Brett: So this next one is a two-parter. Is there an area of research in Alzheimer's that you're most excited about? And what do you think is the next frontier in research?

Jim: Well, I think there's several areas I'm very excited about, but if I were to pick one I might mention tau biology again, something we talked about a minute ago. I'm really interested in this because I think that there's a … first of all, there's a very high correlation from the presence of tau deposits in the brain and the amount of the progression of the disease. The more tau the more memory loss, and that tells us there's something really important going on there. We also know that tau tends to spread through the brain so it tends to start these deposits that developed and start in sort of the center or the lower center of the brain, and then over time as the disease progresses they start to reach out throughout the entire brain, and the spreading occurs not randomly but occurs from neuron to neuron across the circuits in the brain and in a very predictable way. So this just, I think, gives you a sense of something where we're beginning to understand a little bit more… we know that the presence of tau can cause the cells in the brain to die. And so the combination of the presence and the ability to cause neurodegeneration is a clear sign that this is a very likely to be a very fruitful area of research.

Brett: So as you look back over the past couple of decades to the research in the field of neurodegeneration, what has surprised you?

Jim: I think I'm always a little bit surprised at how much longer it takes to be successful and deliver new therapies than we thought about. You know, we talked a lot about the amyloid hypothesis, and Dr. Alzheimer in the early nineteen hundreds actually identified these plaques in the brain of an autopsy of patients. In the 1990s, we first became aware that there were genetic factors related to amyloid that were leading to patients getting the disease. And I think many people in the field at that time felt we were just around the corner from being able to develop therapies because we really understood what was causing the disease. That hasn't been the case. I think we understand it much better than we did then, but it was more complicated than we thought at the time. And so it's taken longer.

Brett: So is there any other disease that you can think of that is comparable to how long it took to figure out?

Jim: Well I think if you look at the last 100 years or so of pharmaceutical research and the development of new therapies for many different diseases, we made tremendous progress. And in a sense, the easiest diseases have been the first to come. I'm thinking of infectious diseases where we've really changed the course of human life by eradicating a lot of, or developing great treatments for infections. We've also made great progress in cardiovascular disease, I think, in terms of regulating blood pressure, being able to control lipids and limit development of cardiovascular diseases that way. Oncology is … cancer research is beginning to have new insights and in many cancers now, new and novel treatments are coming forward that are extending the lives of patients. Neuroscience is one of the toughest areas. The brain is very complicated and it just takes longer for us to understand how that system works, and how the diseases of that system develop before we treat it. But I remain, as I have done throughout this discussion, very optimistic about our increasing knowledge and our ability to translate that into new therapies.

Brett: So given that it's this difficult, why is AbbVie still making a commitment to it?

Jim: Well in part it is because it is that difficult. This remains to be what I would say is probably the largest unmet need in all of medicine. There's certainly a lot of diseases which aren't treatable. But in terms of the numbers of people that are afflicted with this and the numbers of people that are going to continue to be afflicted with it, it really stands out among all diseases. And for that reason I think it's the place that AbbVie needs to be. We are based on the idea that we're going to develop transformational therapies for the people in the greatest need, and Alzheimer's disease is right there.

Brett: So word on the street is that you're retiring soon. So what do you see as your greatest accomplishment in your career?

Jim: It may seem odd to say this but I actually believe the greatest accomplishment is yet to come. And I don't mean that by something I'm going to specifically do in the future, but by the fact that I think that over the last few years in particular we've laid the foundation for a lot of great things to come forward. And we've got science moving ahead that has the potential to develop great drugs. Unfortunately, it's a process that can take decades, 10-15 years from the beginning of an idea to the availability of a drug broadly to patients. So I'm hopeful though, as all of my colleagues continue on behind me, that the things we've put in place are going to continue to deliver and eventually be really important new therapies for patients.

Brett: So my last question for you today is … what would you tell a scientist just starting out with AbbVie in neurodegenerative research?

Jim: Well, I think it's important to talk to them about, remind them about how valuable the work that they're doing is, and that they really are the people that are executing the hope for millions of people who have the disease; to think about the patient. Never forget that there are patients and caregivers who are waiting out there, and that's our responsibility.

TRANSITION MUSIC

Brett: So, to close us out today we come to my favorite part – or at least my producer’s favorite part – where she makes me just kind of talk about some of the things that I've learned today. So Jim, if you can kind of help me along here, I'm going to talk about two or three things that hopefully I have learned from today's discussion. And here goes. Number one: one of the reasons this area is so challenging is that we still don't exactly know what causes Alzheimer's and we aren't able to definitively diagnose early which would – or which could – give us the opportunity to prevent it.

Jim: Yep, you got it. Very good.

Brett: Yes. One for one here. This is one I can easily remember … just because someone doesn't necessarily remember a word or a name does not mean that they have Alzheimer's.

Jim: And if you remember that you probably also don't have Alzheimer’s.

Brett: That is right. Good. Now I'm two for two. So that's good on that end. Last, but not least … so while we've been hearing a lot about failure in this area, you mentioned that science is evolving, we're learning from our mistakes and there are new tools to hopefully increase our probability of success.

Jim: Absolutely.

Brett: Awesome! Thank you so much for your time today.

Jim: Thank you.

'THINGS THAT MAKE YOU GO HUH?' END MUSIC PLAYS

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