YouSaid · the spoken record

A. V. M. (Andrew) Moore

lines on the record: 44
first: 2019-09-17
most recent: 2019-09-17
sittings or episodes: 1
sources: podcast

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“There are always challenges, as is typical in biotech, there are going to be many failures. I think it is important that we go for risky because some of them will pan out. But the portfolio of potential possibilities is sufficiently exciting now that I do think this we'll be able to look back in the near future and say at last we both understand pain and we can now control it in a way that has just simply not been possible before.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“And where to go next, we are identifying other targets that are looking very promising, and I'm optimistic that in consequence, I think we are going to be able to make choices about which are the best targets to go for, find the means to identify the best modalities, to go for those targets, to develop new ways of running clinical trials that would be more sensitive, both to suppress symptoms, but also to prevent the evolution of permanent changes in the function the nervous system that is a big driver of the chronicity of pain.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Exactly, and that's helping us in our preclinical studies because, again, pain is extremely complex. There are many different features. If we study those neurons that are the prime initiators for pain, and we can actually grow using stem cell technology, we can take patient stem cells, we can convert them into neurons, we can look at the features of the function of those neurons. In the past, we used to look at one feature, say the firing of action potentials as a surrogate for their activity. Now we recognize there are tens of features of phenotypes, as we call them, that constitute the entire functional repertoire of these cells. And again, machine learning is helping us see the patterns and how they correlate with a normal state, a disease state, what kind of disease state, and the response to treatment. So we now have tools at last to embrace complexity.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“and correlating so it is reaching a point now that the signals we can get from those functional image will tell us that there's a very high likelihood that the patient has pain or not pain that also raises ethical issues because if someone says they have pain and your functional imaging says there's no equivalent how do you deal with that but the positive is that we now have tools to go beyond just relying on someone saying i have very bad pain or i have no pain to a point at which we can understand the changes that underlie that pain and the associated features because not only do you pick up the sensory experience but you do pick up the changes that reflect the anxiety the helplessness the other features that constitute the entire picture that a patient has”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“And it's extremely difficult. And what if the patient is a neonatal baby or an adult who has Alzheimer's disease who cannot report their pain? How do we measure that? So I think a crucial element is we need new objective ways of surrogates of pain, pain biomarkers. One of the most promising ways there'll be others for sure, but is to use functional brain imaging to look at the changes in the activity patterns in the brain. This has been around for some time. The signals have been very noisy, but using artificial intelligence as a tool to help us measure pain. Now, instead of having a human look at the patterns of changes of activity and say, ah, that constitutes the presence of pain, machine learning algorithms that are picking up patterns that we wouldn't even have detected.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“The greatest challenge for pain is that it is a subjective experience. I can't know your pain, you can't know mine. When I say my pain is nine out of 10 on a 0 to 10 scale, and tomorrow I say it's 5 out of 10, how accurate do you think that is?”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“It is exactly that. And that definitely is highly correlated with the intensity of pain that people experience. And if you can target that catastrophization where you can get people to overcome that anxiety, the sense of powerlessness and lack of ownership of that pain, then that is, again, a very good treatment modality.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“There's been a lot of work on this trying to identify all these confounders or contributors to pain. And the one that seems strongest is something what we call catastrophization, that this is a definable feature of our makeup, that there are some people who, if they have a problem, make it worse by...”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“It is a biological effect, and certainly anything that can switch it on is beneficial. It's more variable, it's more difficult to manage, but interventions such as acupuncture are very good at switching on the placebo.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Just a sugar pill, and they respond well to that, then how are you going to differentiate that from an active compound? But that placebo is not wishful thinking. It is the activation, and we know that from functional imaging of very specific parts of the brain, which”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“In the end, what we feel is the net result of the totality of our brain function. And so if you have pain and you're depressed, those will be additive. If you have pain and you are depressed and this interferes with your sleep, that will increase your pain. So you can get into vicious cycles where your pain gets worse and worse and therefore your mood changes. And therefore interventions such as distractions may not switch off your pain but can make it bearable and that certainly can be a big feature and should be part of the totality of treatment. We shouldn't just rely on medication. It's generally not enough. One of the breakthroughs over the last decade or so has been the recognition that placebo we see that as a problem because it makes it difficult when we do clinical trials to identify new treatments. In other words you give a patient.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Pathophysiological changes that have occurred and now can design our treatment to intervene. At the moment, most of that treatment just switches off those changes, so it's symptom control, but in the relative near future, we will also get disease-modifying treatment where we can recognize that if a surgeon damages a nerve during the surgery, there is a high risk, particularly in those people who have a genetic predisposition for the development of chronic neuropathic pain. And we will be able to say this person is at very high risk, therefore we can give a treatment that will prevent the evolution of those pathological processes in the brain that will cause that persistent neuropathic pain.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“A big part of my career has been trying to identify the mechanisms of pain as a basis for designing a new generation of treatments that would mean that we could make opioids obsolete. The technological advances in biomedicine as a whole have really transformed the way we can approach even something as complicated as pain. We now know much more about the nature of tissue injury and the inflammation that occurs and the signaling molecules that are released and how to block them. We now know much more about the excitability of neurons and how they change and how we can target that whose signaling leads to the production of pain may be different from others and that enables us to get selectivity. But we also, as I've indicated, can recognize that in patients who have neuropathic pain, we now know the downstream effects of that damage. What are the”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“It's a case of serendipity or empirical observation. Pregablin was a derivative of an earlier drug called gabapentin. Gabapentin, as its name indicated, was designed to be similar to one of the major inhibitory transmitters in the brain. It was designed in this way to switch off overactivity of neurons in the brain in the case of epilepsy and pain and other similar conditions. But it turned out that it didn't actually act in this way at all, but it did have some analgesic signal. And even after it was marketed and approved by the FDA, it took a long time before it was discovered exactly what that signal was. And even to this day, it's not absolutely clear why activation of those particular targets produces analgesia in some patients and not in others.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Absolutely. You can identify the cause and you can target your treatment. What the challenge for us now is to find the equivalent of the thorn. These are changes in the function of the nervous system. But once we can find the mechanisms that are operating and use that to help us choose the most appropriate treatment for the patient, one of the big problems in pain management has been even those drugs that the FDA has approved such as pregabilin for treatment of neuropathic pain, the vast majority of patients, literally greater than 50%, do not respond at all. They get no benefit whatsoever.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Absolutely, and I'm very optimistic. I think we're going to move away from the blunt approach where we see pain as a single box and we throw only the same therapy at it to now having the means to identify in a patient what is the drive of their pain, what is their particular set of pathological changes that are causing their pain and that will suggest what is the most appropriate treatment and that's called the phenotype is the total pain presentation in the patient and all its features that will reflect the mechanisms that are driving it. And then we can use that to what we call segmentation. We can instead of seeing the population as a whole we can break it down. This is a patient where the pain is entirely periphery. It's been driven by, for example, if you had a thorn in your heel and you didn't remove it, whenever you walked you'd have pain.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“If you have a job that is not satisfying, if your family situation or your economic situation is dire and all these other features, then if you take a drug that makes you feel happy and then that becomes a driver of that.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Now I sort of understand the confluence of cultural and what you grow up around or how whole of a person you feel you are, right? The psychological and the cultural stuff, it's about the contrast. It's not necessarily the euphoria, but the contrast of the euphoria and the lack then of it.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“If you gave 100 people morphine, some of them would feel terrible nausea, some would feel they are floating on a cloud and happy and all their worries had disappeared and others wouldn't. And that again reflects how the genetic variation. But there are a group of people who when they are exposed to morphine feel so pleasant and on top of it when the morphine wears off, they feel so terrible that they develop that craving. So it's a combination of the positive feeling they get when they have the morphine and the terrible negative feeling when it wears off. It's actually the strength of the negative feeling that is one of the major drivers of addiction. If you ask addicts, they'll say their first exposure was intensely pleasant and they've never been able to reach that same high.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Not to pose a risk. It was done with the best of intentions, so the idea was if you have a patient with pain, give them appropriate treatment, so the prescription opioids were the avenue initially in our current opioid crisis. The means by which people could become introduced to opioids, although there have been many attempts to try and design drugs that only have analgesia if they act through the myopioid receptor. I think in the end, the risks are very high that you will always get the risk of addiction and abuse.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“So basically, this is not the first opioid crisis that we've had. In the 19th century, there was massive addiction, the famous opium wars. So the addictive qualities and the respiratory depression and all the other bad features of opioids have been around since the extract of the poppy was recognized. It was for that reason that in the middle of the 20th century, physicians were wary, highly wary of treating their patients with opioids. And that's why on my first exposure, there were patients literally crying in pain because the surgeons of that”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“What happens in the case of opioids, of which morphine is the typical example, not only does it reduce pain, but it produces the sense of well-being, of euphoria, of happiness, but you don't need to switch that system on to get the pain relief. So in a sense, it's extremely bad luck, the intertwining of pain and addiction now is largely through the fact that through opioid prescription has until very recently been the means by which people are introduced to opioids. So until literally a few years ago, if you had dental surgery, your dentist would give you 20 oxycodon.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Big problem with opioids is that in addition to reducing pain, they produce a euphoria. The addiction comes from that euphoric signal, which occurs in the brain in a different part of the brain from where they act to reduce pain. And so you have two parallel systems. You have pain and it's a reduction by opioids, and then you have the pleasure centers that are activated by morphine, which gives someone a high and not everyone has it, but those people who do then initiate a craving behavior. And again, there are certain individuals who have a high risk of craving who then become dependent and addicted. But analgesia does not mean that there's going to be euphoria.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“There's both peripheral sensitization where the threshold is reduced and within the central nervous system there is an amplification of the signals such that inputs that would normally not be painful now begin to drive pain.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“cord and brain are involved. We also know that in the presence of inflammation as part of the tissue injury, there's a massive recruitment of the immune system. These produce signaling molecules that act on the neurons. But there are also changes in the central nervous system as well. As it becomes activated, there are changes such that the transmission of input can be amplified. But actually, the tissue surrounding it, which is not injured, that is also hypersensitive, and that is a manifestation of the presence in the central nervous system of what we call central sensitization and abnormal amplification.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Right, the breakthrough came when we realized that acute, noiseceptive protective pain was different from inflammatory or neuropathic and then what we call dysfunctional pain, there's been a whole set of data looking at the mechanisms that drive each of them. What exactly happens when you have a noxious pinch? Which sets of neurons are activated? How does this environmental mechanical stimulus get converted into electrical activity? Which neurons transmitted? What are the signals that they use to transfer the input from the periphery to the central nervous system? Which parts of the brain do they activate? Which circuits? All of that we're beginning to dissect out. And as we do that, we're revealing potential points at which there could be therapeutic intervention. I think our greatest understanding now is the protective pain, how it's switched on, which sets of neurons are responsible, which parts of the spinal.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Absolutely precise. And you can then dissect out the role of each sets of neurons in particular circuits in a way that just wasn't possible. So this is a very exciting technological breakthrough. And the same thing with recording. We can genetically put calcium sensitive dyes into specific sets of neurons and use little microscopes from that can see the activity of broad populations of neurons in different circumstances. This is an extremely exciting time in neuroscience with these technological breakthroughs are enabling us to dissect out the function of the brain.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Technology now does enable us to interrogate the function of the nervous system in a way that wasn't impossible. We can see activity using a number of indicators. We can also optigenetically activate specific parts of the nervous system. It is now possible in preclinical models to genetically target a light sensitive protein into defined sets of neurons and you can then use a laser light to activate those sets of neurons in a very controlled way.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Overall for most clinical pain conditions, there is actually a very strong heritable component, something like 50% of the risk of developing pain is heritable. We know that from twin studies. So if you look at identical twins, if one of the twins has clinical pain, there's a very high chance that the identical twin will have it. If they're non-identical, it's lower. And if they're not related, then it falls way back. So something like 50% is driven by genetic variances that we get from our parents.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“And there's one fourth one. Oh, really? Okay. And this is a group of patients who tend, not exclusively, but tend to be women. There's no noxious stimuli. There's no tissue inflammation. There's no damage to the nervous system, but they may have chronic widespread pain. And for a long time, this was labeled as psychosomatic. And there was almost a blame feature to that label to the patients. But now we realize they too have an abnormal nervous system. The reason they feeling pain is because it is as if someone has switched up the volume control in their central nervous system such that what would normally be a soft sound is now very loud and for them a soft touch now produces pain. So this is a pathological functioning of the nervous system in the absence of damage to the nervous system. System”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Not protecting you from the external environment and potential danger to your tissue, it's protecting the injured body part from further injury, allowing repair to occur. And so, funnily enough, the pain that I thought I first wanted to cure postoperative pain or post-traumatic pain. So you do want to try and reduce it to make people feel comfortable, but at the same time, if you eliminate it, that would be a real problem. But that then leaves our patients who may not have any surgery, they have no tissue damage, and who have pain that just persists for years and years and years. One of the commonest causes of that is damage to the nervous system itself. And we call that neuropathic pain. And we now appreciate this is no longer telling us about the presence of noxious stimuli or the presence of an injured part. It is the malfunction of the nervous system itself.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Absolutely. The nervous system has changed. It's become hypersensitive such that normally innocuous stimuli are now activating the pain system and we have a tenderness, soreness, a heightened sense of pain. This is an adaptive thing. For example, if after major abdominal surgery, if there were a way to completely eliminate the pain and you say, fine, I'll go for a jog, that would not be a good idea because you've got this wounded tissue. It needs time for the wound to heal, to repair itself. And the same with if you've got arthritis where there's damage to the joint, if you excessively use the joint, if you were pain-free, you would damage that joint.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“The protective mechanism of pain requires an intense stimulus to activate it, a noxious stimulus. And we actually call this noceceptive pain, which is the pain that is initiated by a noxious stimuli. Now, the big difference, coming back to our post-surgical”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“That is true, but that is not for that kind of pain. If you're drinking your coffee and it's too hot and it burns your tongue, you will stop drinking it immediately. You won't even aware of it. We've all learned to take a little sip and maybe not even put the coffee in our mouth. So we've been trained by our experience. We try and avoid that pain for that protective pain to work. The pain has to be unpleasant. And in order for it to work, you can't say I'll deal with it later. You've got to deal with it immediately. So it demands our attention and it's intense and it's unpleasant. And in that sense, it is that analogy of a switch. You have switched on something that focus your attention. I have to do something. I have to avoid this situation immediately. We're talking a matter of seconds.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“It's surprisingly similar that if you measure it in a situation where you remove all the emotional aspects of pain, the threshold at which someone feels something has been warm and then hotter. And then when it switches to actually painful, is it 42 degrees with a surprisingly small variation?”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“No, that was the confusing element We use the same word pain to describe both and therefore physicians and patients felt this is the same phenomenon. But in fact, the pain that we're experiencing does not reflect what is initiating and sustaining the pain. In the case of a pain as a protective mechanism, you need just an intense stimulus, one of sufficient intensity that it potentially can damage our tissues. And we have this very elaborate system that has been designed to detect that danger. So we have specialized sensory neurons that are activated only by intense stimuli. And when they reach that threshold, which is just below the point at which damage can occur, we feel a pinprick or the point at which something that is too warm and it has the risk of burning us.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Terms of understanding. And unfortunately, the reality is those smiley faces would not be smiling if they saw how complicated pain was. The notion that there's a simple switch is just incorrect. The notion that pain can be defined by its severity as mild, moderate or severe is incorrect. And the notion that the treatment should be based on that is also incorrect.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Exactly. And at that time, if you had mild pain, then you took a nonsteroidal anti-inflammatory drug like tylenol or advil. If you had more severe pain, you added a weak opioid to your ensade. And if you had severe pain, then that's the point at which you'd give a stronger opioid. And the World Health Organization had an analgesic ladder that it literally was there, mild, moderate, severe pain, increasing the strength of the analgesic. And again, in keeping with this notion that pain was a unitary system activated by different triggers of different intensity.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“The alarm system is activated by the surgeon's damage that is created in the patient, and then the alarm system continues until that tissue injury is repaired. But what is happening in a patient who has persistent pain for years and years and years, why is that pain alarm activated continuously? And there really was no explanation at the time.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Well, the city was appreciated that pain has two facets. One, it is an essential early warning device. It tells us of danger in the environment. And without it, there's a high risk that we may injure ourselves. So you need this alarm system, if you like.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“We thought there was a peripheral trigger which could be mild like a pinprick or touching something too hot or too cold or larger in the sense of major trauma or post-surgical. There was something that was activating that the pain switch and that all the triggers of pain acted on a single system in a single way and therefore pain really was not present or mild, moderate or severe. And that was the full range of the understanding of pain.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“At that time, I just thought that all pain is similar, that you either have no pain or you have pain. And if you have pain, it's an unpleasant sensation. The closest analogy would be like flicking a switch that switched on the pain sensation in your brain.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“Absolutely. I was just thought you have surgery, have pain, and then you put up with it until the pain goes. And I just thought to myself, that doesn't sound right. At that time, there was very little understanding of the mechanisms of pain. And indeed, very few treatment options. Now, as we have much greater understanding, but unfortunately the treatment options haven't really expanded and they are also accompanied by undesired effects, particularly in the case of the opioids.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source
“When I was a medical student, I was on the surgical ward and at that time there was minimal treatment for postoperative pain. So I came into the ward and there were a group of patients who had had major surgery and all of them were in severe discomfort. And I said to the attending surgeon, what are you doing? Why aren't you treating them with pain? He looks at me as if I was crazy. And he said, they've just had surgery. What do you expect? They're in pain.”
2019-09-17 · a16z Podcast · a16z Podcast: The Biology of Pain · IDENTIFIED FROM THE TRANSCRIPT · source