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| Eric Kandel, MD |
Nobel Laureates don't come to Minnesota very often but they apparently come at least once a year to Gustavus Adolphus College and the annual Nobel Conference. This year's conference was particularly interesting to me because it starred the only modern psychiatrist to be a Nobel Laureate - Eric Kandel. He shared the podium with his wife and research collaborator Denise Kandel. Eric Kandel is a giant in neuroscience and has continued to extend his research well into the time in life where most people have been retired for years. In my addiction lectures, I use his well known paper Psychotherapy and the Single Synapse published in 1979 and his recent work on nicotine exposure and the risk of cocaine use entitled A Molecular Basis for Nicotine as a Gateway Drug published in 2014 as lecture references. Kandel has been a neuroscientist and a psychiatrist longer than I have been a psychiatrist. The other aspect of Kandel's more accessible work is his ability to integrate basic neuroscience and cognitive neuroscience into a coherent story of possibilities. The best example is the book The Age of Insight that I briefly reviewed on this blog. It is clear from reading Kandel that he has a lot on his mind and he is actively seeking answers and organizing his observations. Another feature that piqued my interest in this case was why he was presenting at an addiction conference in a state where many people believe that addiction treatment was invented. I did not find out about the conference until it was too late to take time off of work to attend. I was very pleased to find the presentations and Q&A sessions by Eric Kandel and Denise Kandel available online. There are a total of 4 videos and they will load and play in succession. There may be more videos with the Kandels but I only watched these four.
In the first session Kandel discusses some of the early discoveries in brain systems and how the idea of localization of brain function played out. For most physicians with a passing knowledge of aphasia and strokes it is a bit tedious. Eventually he gets to a discussion of memory localization and talks about implicit and explicit memory. That allows him to look at different features, animal models and the molecular biology of these types of memory. He goes on to look at age-associated memory loss and Alzheimer's Disease and the different brain substrates and mechanisms. At that point some of his slides illustrate chromatin and transcription sites but he does not get bogged down in the details as he defers the chromatin issue to a later presentation and discusses RbAp48 as a critical transcription factor in the formation of long term memories. He showed a plausible mechanism for exercise leading to osteocalcin secretion from bones and improvement in memory as one possible humoral factor associated with vigorous exercise. In terms of style points, he had great graphics especially the diagram of the DNA strand wrapped around histone octamers and how the transcription process is affected by various molecules. He was clearly there to present a lot of information to non-molecular biologists. He was a little hurried at times. He makes a few misstatements and gets distracted like all of us do during presentations. He interjects some humor along the way. As the presentation continues it is clear that this is important information.
The Q & A session was focused primarily on the question: "Is addiction a brain disease?" The other panelists and their biographical sketches can be viewed at this page. I did not realize it until after I had viewed all of the sessions that the lectures were not a good fit in terms of answering that question. The lectures were focused on the neurobiology of learning and how epigenetic changes due to nicotine exposure lead to other addictions. They were not lectures on the neurobiology of addiction per se, but there were some partially suggested mechanisms related to Kandel's work on memory. Addiction being a brain disease was really not the point of the lectures. It was obvious that the other panelists were at the minimum resistant to the idea but there was also open opposition. If you read the biographical sketches one of the panelists has written a book on why addiction is not a disease. If they really wanted to argue that point they could have brought me down for a Neurobiology of Addiction lecture and I could have dissected the arguments about addiction being a disease or not. A much better idea would be to bring Eric Nestler in for the lecture.
The panelists seemed of the opinion that plastic changes in the brain were normal and therefore plastic changes in the brain caused by addictive compounds was not a sign of pathology. Some seemed not to be focused on the brain at all but cultural or social factors that they thought were important. In at least one case, they seemed to suggest that addiction needs to occur in a certain context - that all addictions are not created equal. The example given was a wealthy white guy with a cocaine addiction could just jet off to the Caribbean and go swimming as a way to deal with his addiction. Someone else would not have that opportunity. Kandel had a singular focus that all human behavior, that everything that we are occurs because of what is happening in the brain. He kept going back to this idea and pointed out that alterations in brain plasticity certainly occur during addiction but they are negative and not positive changes. He of course agrees that social and psychological processes are important intervening factors but all of the processing occurs at the level of the brain. Some of the panelists seemed uncomfortable with this basic idea and he got into it with one of them, but eventually summarized the problem as a lack of a common culture. He extended that comment to include the idea that the panel is discussing these problems so that younger generations in the audience will not have to start at that contentious point. To me it came back to the mismatch between the Kandels' lectures on the epidemiology and molecular biology of nicotine as a gateway drug and the other panelists arguing that addiction was not a disease.
Denise Kandel began the third session reviewing the epidemiology of when people start using addictive substances and what the relationship is to nicotine. In general, nicotine use is a strong predictor of cocaine use and ongoing cocaine use. She analyzed three databases that are essentially cross sectional surveys of substance use including the NSDUH (National Survey On Drug Use and Health), MTF (Monitoring the Future) and NESARC (The National Epidemiologic Survey on Alcohol and Related Conditions). She discussed the concept of Translational Epidemiology or making population wide observations and then looking at models to explain the observations. She had what I would call a critical observation on the observed drop in cocaine use and cocaine related mortality and cigarette use. The recent drop in cocaine related mortality seems to correlate with a decrease in smoking. Eric Kandel stepped in for the basic science section to elaborate on the mechanism of histone acetylation and how that occurs from nicotine exposure. Denise Kandel returned to talk about the problems with e-cigarettes as potentiating factors for the use of other drugs and also as probably not a good way to stop smoking. If you had time to watch one of the videos I would recommend this one.
The final Q & A session was an interesting one. One of the panelists talked about the sociological theories of drug use rather than a gateway involving a biological substance. For example, the fact that you take a substance that makes you feel good, increases the likelihood that you will take additional compounds that will do the same and that you will associate with people who have common interests and they will encourage further drug use. Kandel had three comments during this session that I thought were very interesting. The first involved the scientific rationale of a reductionist approach. When you hear it explicitly stated rather than being used in a vague and rhetorical manner - it makes a lot more sense. The second had to do with a painting by Gustav Klimt called Judith beheading Holofernes (Judith I and the head of Holofernes). He tells the story about this biblical incident and discusses how this is a painting that combines elements of aggression and sensuality and how recent work by Anderson has shown that there is a 20% overlap between areas of the brain that govern aggressive behavior and areas that govern sexuality and reproductive behavior. At one point Kandel seemed frustrated by some other panel members and made a reference to reproducibility that may have startled a few of them. Denise Kandel had previously alluded to the bias against reductionism in her discussion with the statement: "It's a reductionist approach to which some members of this audience are going to object strenuously"
The videos were very affirming for me. When I think about the lectures I give on Kandel's work and some of the posts on this blog - I am confident that I have come to the same conclusions that he comes to about the brain and about reductionism. Of course it is easier for me, because he provides the conclusions and I merely teach them. I don't think that everybody has come to those conclusions either at a scientific or philosophical level. It is too easy to get hung up on polarizing questions and political debates about science these days, especially using imprecise definitions like the word disease or claiming that reductionism is a fatal flaw rather than a good way to do science. It is too easy to mistake journalism - in many cases hatchet-job journalism - for science. The other striking factor is that this is a brain centric view of the world and that seems like the only logical approach to me. Various critics will attack the brain centric view of neuroscience or psychiatry in ways that seem to miss the point. Much of the criticism comes down to the definitions of diseases or disorders and the idea that a biomedical approach to the brain means that only biomedical treatments are possible.
I think that it might be easier to reconcile the brain centric view if the ultimate result of that view is considered and that is tremendous computational power that results in billions of people with billions of unique conscious states. That is the ultimate product of what Dr. Kandel is talking about in terms of human learning - how it affects the conscious state and the associated brain substrate. That may have something to do with biomedical treatments, but it also applies to every other intervention that can be brought to bear to facilitate recovery. To make an even more obvious argument - the cure is in your head - not out in the ether somewhere. The corollary is that it is important to know what those mechanisms are.
If you have time, watch these videos. It is a rare chance to see one of the brightest guys in psychiatry and neuroscience in action. I would also encourage reading The Age of Insight. It left me with the impression that this is a scientist at the top of his game and it is inspirational reading.
George Dawson, MD, DFAPA
References:
1: Kandel ER. Psychotherapy and the single synapse. The impact of psychiatric thought on neurobiologic research. N Engl J Med. 1979 Nov 8;301(19):1028-37.
PubMed PMID: 40128.
3: Anderson DJ. Optogenetics, sex, and violence in the brain: implications for psychiatry. Biol Psychiatry. 2012 Jun 15;71(12):1081-9. doi: 10.1016/j.biopsych.2011.11.012. Epub 2011 Dec 29. Review. PubMed PMID: 22209636.
Attribution: The picture of Eric Kandel is By Bengt Oberger (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons. The file URL is: https://upload.wikimedia.org/wikipedia/commons/c/ca/Eric_Kandel_01.JPG.
Supplementary 1: I am fully aware of the fact that Denise Kandel and the other participants in the conference were there and are all scholars. The title of this post reflects that fact that the Nobel Laureate came to the Noble Conference.
Supplementary 2: This is a blog and it should be obvious that none of the speakers, institutions, or content producers mentioned in this blog post endorse this work or even know about it. This statement is for anyone who does not think it is that obvious. I did not attend this meeting and had no input into its content.
