As a part of the 3rd BEB Symposium, in Coimbra, Portugal, José Miguel Diniz and Ana Cunha, from Porto Biomedical Journal, interviewed MIT Research Professor Tomás Ryan on some topics regarding your research on memory and engram cells, delving into the problems of the current scientific investigation, as well as some possible therapeutic applications.
Professor Tomás John Ryan is a senior investigator in MIT and HHMI (Howard Hughes Medical Institute). His research is mainly about the mechanisms of memory storage and about the memory recall. His investigation in this field is deemed a breakthrough in neuroscience, due to new perspectives on the concept of memory, memory formation and anterograde amnesia – as found in Alzheimer’s disease.
We are very honoured for the Professor Ryan's insight and collaboration with us, and would like to share it with the scientific community.
Porto Biomedical Journal: Professor Tomás Ryan, you talked about memory and a lot of your research revolves about what is memory and all the processes involved on the formation of memories and amnesia. What is the current scientific perspective on what memory is?
Tomás Ryan: The dominant perspective on memory is that it is plasticity in the weights of synaptic connections in the brain, so that means - how strong one neuron is connected to another, in regions of the brain that are known to be important for memory. The reason why this is believed to be the case is because of the logical assumption that plasticity of some kind must be important for memory. This is considered a truism in neuroscience. Synaptic plasticity is broadly conceived as the changes in synaptic weights that are caused by a learning episode. This plasticity is one of the many types of biological plasticity which has been observed in neuronal circuits and in other cell types too. Plasticity is ubiquitous and fundamental to biology. But synaptic plasticity, as we currently conceive it, derives from theories posed by Donald Hebb and others, that [suggest] the changes in synaptic connections between neurons may be what is actually encoding a particular memory.
So, just because you disrupt the fundamental biology of the brain itself doesn’t mean that the particular physiological phenomenon that you looked at is really underline the behavioural disruption that we are interested in.
TR: The evidence for this has been almost entirely based on paralleling disruptions of memory, which cause amnesia, with disruptions of models of plasticity, or artificial models of plasticity. So, a broad range of biological disruptions that are known to cause amnesia in experimental situations also tend to disrupt the cell biological processes that are necessary for many things, one of which is synaptic plasticity. That and also a smaller body of correlative studies of people who have looked on what is happening in the brain during learning. And indeed, in many cases, synaptic plasticity seems to occur due to experiences such as the activity of the animal in a particular behavioural task. These are all facts and, generally speaking, nobody in the scientific community disputes any of these facts. But, in many ways, there are not sufficient in my mind to account for memory itself. Many of the disruptions used to disrupt synaptic plasticity are [of] incredibly low specificity. We know that thousands of genes are necessary for the operations of synaptic plasticity and many other things that are activated by experience. We disrupt all of them with a lot of interventions that we look at. So, just because you disrupt the fundamental biology of the brain itself doesn’t mean that the particular physiological phenomenon that you looked at is really underline the behavioural disruption that we are interested in.
(...) you can destroy the screen, you’re not going to see anything. Would you conclude the information was stored in the screen?
TR: And I think that the reason why we found ourselves in this situation is because we started from questions posed by groups of psychologists and physiologists in the middle of 20th century, who were not necessarily thinking about how ubiquitous plasticity is in biology, and we had ideas that were very compelling. At the time and at a surface level it seemed to work well, but in fact it’s the same kind of logic as if we wanted to figure out how a computer works. So imagine you’re an alien anthropologist from another planet – you come down and you want to understand how a computer works. And the information that you’re reading is coming from the monitor of the laptop and so you go disrupting things and you disrupt the power cord and without electricity going in, the information doesn’t come out. Would you conclude that the information was in the power cord? Similarly, you can destroy the screen, you’re not going to see anything. Would you conclude the information was stored in the screen? Maybe if it was you would get that result, but many other things can also cause you to get that result. And at the same time if you were to come down and start damaging particular parts of the computer you would cause a lot of damage to things, as well as damaging the hard drive, as well as damaging memory, but many of the things you’re interfering with actually had nothing to do with memory information itself. Or you could completely eviscerate the computer and, of course, you will destroy the memory and the information, but you also destroy a lot of other things. So these are the kinds of limitations we in the field of memory has been dealing with and we haven’t focused enough on working out how to solve which biological mechanisms, which kinds of plasticity, are actually storing memory. Now, there is no doubt that this process [synaptic plasticity] is extremely important for the brain, helping in brain development. If you chronically disrupt the main genes involved in synaptic plasticity, the brain does not develop correctly. This is a very basic brain process. Physiological plasticity processes do many things and if you were without them of course you couldn’t properly operate memory, but you also couldn’t do many other things.
We should start from a point where we are confused about something and then we can try to make sense on what is going on. That’s not a kind of behaviour that’s rewarded in the current scientific environment.
TR: So, why is it that we’re in this situation? Why did it go like this for so long? I think the reason is partly because we don’t have, or for a long time we didn’t have, the tools to properly engage with testing this hypothesis. Secondly, because of the way modern science works is that it’s drowned in and addicted to funding. Previously everyone was getting funding through academic positions and their main livelihood was teaching and they would normally source money locally and they would not need to hold major conferences, purchase expensive apparatus, or hire a great amount of people to execute their research programs. And now, you need to have a lot of money to do science, and you need to be doing it just to survive, just to keep your employment going. And when you have this much money with grant cycles, 5 years or less, and high impact journals, which are basically a forum for competition, for short-term competition between peers, you drown everything, because everything becomes about survival in the short term. And, in doing so, people are effectively co-opted. They are co-opted into going along with the status quo, in my opinion. And it means that if you are a young research scientist and you want to work on a particular scientific topic, you need to be somewhat in agreement with the leading people in the field - otherwise, you won’t get funded. You have to be moving very fast and you have to be very productive in the short term. This is not necessarily the most damaging thing, I think, in certain fields it works and many people often work better in this kind of environment. Genomics, cancer, infectious diseases – these are fields that today don’t always have a lot of major controversies - and there’s a lot for people to explore and to do. But neurosciences in general, and memory, in particular, are fields where we’ve been behaving like we already know an awful lot. But we are basically resting on some very shaky philosophical premises that have not been really properly tested, or perhaps there are discrepancies that are just ignored. And, in my opinion, progress of science should focus on the discrepancies, and should focus on where things don’t seem to make sense. We should start from a point where we are confused about something and then we can try to make sense on what is going on. That’s not a kind of behaviour that’s rewarded in the current scientific environment. What’s rewarded is going along with what’s generally thought, and you work out your details. Currently in neuroscience it’s a wonderful time, because we have so many new technologies that have come on board and it creates many opportunities. But the easiest way to make a successful career now is to take as many new technologies as possible and to use them to find out things that we already know, to vindicate things we already know - and that is not always the most progressive way to do science.
PBJ: You talked about, during the keynote, the gap between what scientists say that’s memory and all those axioms that are pretty stable along centuries and then you have this individual perception of memory. Do you think that gap has been insufficiently explored and that the exploration might be quite relevant for figuring it out what’s missing to make sense of what we already have?
TR: So you’re asking about the gap between memory in science and what we understand as a subjective experience of memory? This is a question that borders on what many people call consciousness. When we study it, in the third person, it’s very difficult to be scientific about it. A lot of people are attempting that, but you’re relying in human studies of self-reports in other humans. How much you actually learn is debatable. Is there a gap between subjective experience and scientific approaches? I think that there will always be - I mean you’re never really going to explain your experience scientifically, not because it’s mystical, but just because it’s too complicated. The laws of physics, for example Newtonian mechanics, are pretty well worked out and for the orders of magnitude that you deal with on Earth - there are no problems there. But is there a gap between that and what you see when you go out to the traffic and observe five hundred cars moving in different directions? Yeah, there is a gap. You can’t possibly superimpose what you know about physics onto what you’re observing in real life in your intuitive perception. It’s not that there is an explanatory gap, there’s no explanatory gap, it’s just too complex. Comprehending subjective experience in terms of scientific laws is not something that we are built to do and it’s not something we need to be able to do, it’s not useful to us. I think the same is true for memory. How we understand it in the scientific description, will never really replace how we experience memory. It doesn’t mean that there necessarily has to be an explanatory gap. Once we understand the biological laws of memory it will be the same apparent gap as physics, just a different way of perceiving ordered laws from the mess of everyday life. And I think the gap that does currently exist is because of two reasons. It still exists because we don’t really know what memory is and we don’t know enough about how it works, but also because most people still cling, consciously or unconsciously, to the assumption that there’s something vitalistic about our subjective experience, and neuroscientists are not excluded from that category.
TR: For me the acid test is not just “Can you accept that animals are conscious at a certain degree?” but “Can you accept that a machine can be conscious?”. And if you pose that question to some neuroscientists they will immediately say “No, you cannot really make a machine that is like a person, you can’t really do that, even with yet to be invented technology.” And if you ask “Why can’t a machine do that, why not?” they will say “Oh, because it doesn’t have what the brain has or doesn’t have what the mind has”. Okay, but once you know everything about the brain why can’t you replicate enough of that in a machine for that machine to think, so the machine can have a memory? Why not? And you constantly meet with inertia against that idea. And that is, as far as I can see, a remnant of vitalism that is still there; and people who take that position are saying that there’s something in the brain that is connecting with something outside of the brain that can never be replicated in a machine. So that bias, which is not just a problem of neuroscience, it’s a problem of everyday philosophical biases, and a lack of basic knowledge of memory is what accounts for the current explanatory gap. But what I’m saying is even if you take a purely evolutionarily materialist view of mind and consciousness, and even then if we work out the true biology of memory, in the way we already have for genetics, there will still be an apparent explanatory gap between the subjective experience of memory and how memory actually is, because of the limitations on how we can perceive complexity.
PBJ: So, many of your works are about the engram cells. Do you think that the activation of those cells is the future solution to some diseases like Alzheimer’s?
When you start talking about dementia, Alzheimer’s and brain degeneration, the problem is that even if you know the memory is still there, the cause of the amnesia is persistent and chronic and is often getting worse all the time.
TR: I think that manipulation of engram cells will potentially lead to treatments for cases of retrograde amnesia (amnesia for memories you had in the past), but it probably will only be valuable where the cause of the amnesia is acute. By that I mean brain trauma, drug use, Korsakoff’s syndrome, anything that was due to particular event or limited time window of cause. When you start talking about dementia, Alzheimer’s and brain degeneration, the problem is that even if you know the memory is still there, the cause of the amnesia is persistent and chronic and is often getting worse all the time. So even if you can do something to get at those cells they’re constantly being attacked by whatever the cause of the amnesia is. Maybe it will be possible to ameliorate amnesia or to wrestle with it, but until you eliminate the cause of it, you’re never really going to be able to solve the problem entirely. But I think that this type of conceptual approach for dealing with amnesia would be valuable, because amnesia has many, many causes. Obviously, a range of neurological conditions and psychiatric conditions: multiple sclerosis, Parkinson's, Alzheimer’s, Huntington’s, Schizophrenia, all have amnesia associated with them, and then trauma, drug abuse, et cetera. Completely different causes, but the same effect which is amnesia. Like cancer it has a pathophysiology that has a huge range of causes, so it’s a case where treating the symptom maybe is more valuable than treating the cause, because if you have a way of dealing with it then it translates to so many different conditions. And the challenge would be to find non-invasive and effective ways of dealing with that.
PBJ: You also talked earlier about if we destroyed a certain part of what we perceived as the fundamental structures of the memory creation [process] it does not mean that those are essentials: you used the example of the power cord and the screen. Do you think the way we should approach memory is not by destroying things, but trying to mimic those processes that we find on natural systems?
TR: Yes, I think that the intervention strategy is essential but it needs to be complemented with what you just described. A very famous developmental biologist in Oxford, back in the 1960’s, used to say to his students: “you don’t understand a mouse until you can make a mouse”. The same is true in engineering - you don’t really understand it unless you can build it. It doesn’t mean you can understand everything about it. An engineer who can build a computer doesn’t necessarily need a huge great level of knowledge in the physical chemistry of semiconductors, but they need to know enough about the functional parts to be able to put it together into a functional thing from scratch. In the case of memories, if we really want to say we know how they work, then we should be able to build them.
PBJ: So, as an ending question, what is the next step of your research work? What are the questions and specific directions that you want to take from what you already found out?
TR: The engram field is a rapidly evolving area and the most exciting questions change rapidly - every six months to every year. Right now, I’m dealing with the daunting task of setting up a research group, recruiting people, getting everything functional, animal ethics issues, materials, trivialities. By the time, I’m making independent progress the field will have evolved more, but broadly I’m interested in trying to identify how to understand the information that is encoded through specific memory engrams. What are the mechanisms of its induction and how do we go from piggy-backing on genetically encoded information (instinct) to learned informational contingencies?
PBJ: Ok. That’s all for now. We hope that you have much success setting up the lab.
TR: Thank you.
Porto Biomedical Journal would like to thank the BEB Symposium Organising Committee for our great partnership, at this year’s event. We are looking forward for the 4th Edition!
More information regarding BEB Symposium, please visit the website: http://www.uc.pt/en/iii/bebsymposium