Sunday, October 21, 2018

Interview: The Value of Drugging an Octopus

Retropus by Todd Anderson / CC BY-SA 2.0

Hey, remember last month when scientists gave ecstasy to octopuses and the media exploded? (BBC, The New York Times, The Atlantic, NPR, The Washington Post . . . ) In the wake of all the excitement, I caught up with study author Gül Dölen to talk about playful science and her hunt for the rules behind social behavior (no, not those rules). Here's our interview, edited for brevity and clarity.

How has it been to have this much attention on a study?

It’s been great. It’s fun for those people in my life, who know I’m a scientist but don’t really see what we do regularly, to pick up a newspaper and see my name. My dad was proud.

Do people think you’re an octopus scientist now?

Not so much. I’ve been doing mouse neuroscience for twenty years. People know that this octopus thing is a fun side project. In fact, I’ve had some very prominent mentors say, “What are you doing? That’s crazy! You need to focus on the things that are going to get you solid publications and move your lab forward. You can work on octopus when you have plenty of free time.”

But I just feel like life is short and this was exactly the kind of project that makes me feel like a scientist, like I’m doing the research because of the curiosity and the passion for the question, and not focusing on the rat race or any of that other practical stuff. I got into science for the creativity and the exploration and the playful aspect, where you’re going to work every day to figure something else out.

So this was almost an opportunity to do a kid’s idealized version of science: you have a question and you just go out and figure out the answer.

I’m not sure it’s just kids. I think most scientists would say that the reason they got into it was because they thought that’s what they were going to do every day. And then [they find out] the realities of having to run a lab and generate funding and dealing with management and personnel issues. Especially when you become a PI. You know, when you’re a postdoc, you still get to come in every day and do an experiment, and at the end of the day you have the answer to the question. But that all comes to a screeching halt when you become the principal investigator. And I, for one, miss it.

So how did this study get started? Did you contact Eric [Edsinger] or did he contact you?

Well, my lab studies social behaviors from lots of different perspectives. We do whole cell patch clamp electrophysiology and optogenetics and behavior, and we look at development mechanisms and synaptic mechanisms and circuit mechanisms, and we care a lot about diseases like autism and schizophrenia and addiction. But I had always wanted to study social behaviors from the perspective of evolution. The thing is, the brain doesn’t fossilize. The way we can study evolution of the brain is by looking at the genomes of different species that are spread out over the tree of life.

So when I saw that the genome of the octopus had been published, I got really excited. Most other invertebrates, that are ideal in terms of being separated from us by so much evolutionary time, they’re not doing problem solving. They do a lot of reflexive, innate behaviors, but not so much cognitively flexible behavior. We have a lot more to learn from an octopus in terms of comparing it to a mouse or a human, because you have two species whose brains look nothing like each other. A mouse brain and a human brain [both] have a cortex and reward circuits and motor circuits. An octopus doesn’t have any of those things, and yet it can do really, really complex tasks. So if it’s not the anatomy, what enables these two species to do these complex behaviors? Can we derive any rules? Like: you need this many synapses, you need this transmitter, you need this neuron talking to that neuron, you need this amount of complexity in the circuit to get that behavior. That’s why octopuses were super exciting to me.
Nathan Rupert / CC BY-NC-ND 2.0

So I got in touch with Eric and we started collaborating. He was an author on that [genome] sequencing paper, and he’s at Woods Hole, which has been putting a pretty serious effort into trying to establish a colony of octopuses and other cephalopods. At some point Eric said, "We have seven octopuses available. Do you want them?" and I was like "Yes! I know exactly what I’m going to do." He shipped them down, he flew down after them, and we had about a week to do the experiment and then we had to send them back to Woods Hole.

What was it like to have octopuses in a vertebrate lab for the first time?

It was actually amazing how so many of our things, especially in the slice electrophysiology lab, are exactly what you need to run a marine tank. We use artificial cerebrospinal fluid, which is made of the same things as artificial seawater--except the salt concentration is higher. We have all the same chemicals, we have the same fancy tools to measure the osmolarity of the solution and the pH, because we make slices of the brain and keep them alive in artificial cerebrospinal fluid by bubbling oxygen.

And all we had to do to adapt a mouse behavior to an octopus behavior was take the exact same tank, divide it up in exactly the same way, and just fill it up with water instead of no water. It was much easier to go between the two than I had worried it might be.

Another practical question: where does one buy ecstasy for octopuses?

We had been working on ecstasy in mice for the last three or four years. You have to have a Schedule 1 license because MDMA is illegal. And it’s not just a little illegal, it’s as illegal as a drug can be. It took us about a year to get all that licensing. The DEA had to send people over to make sure that our lab was properly equipped to safely and securely store the drug, and we had to show them that we were taking accurate logs and everybody who was going to be handling the drug had to be vetted. So we already had MDMA in the lab.

But because we weren’t sure how much we were going to need, we contacted the organization MAPS, which is funding the human clinical trials, and asked them to send us the drug. They just gave it to us because the amount that you would give to an animal is so ridiculously small compared to what you would give to a human. I think they were really curious, because they didn’t know anything about octopuses. They asked, “Are they going to give an eight-armed hug?” I said, “We’re just hoping they won’t kill each other.” And they were like, “What? Octopuses would kill each other if you didn’t give them MDMA?” And I said, “Yeah, maybe, they’re pretty asocial.” So that was fun. They loved the results.

Most people think of MDMA as a recreational drug, but it’s being studied for treating mental health issues in humans like PTSD. Is there anything about the work with octopuses that might inform or model medical treatment?

People are seeing some pretty amazing benefits of giving MDMA for psychotherapy. And yet we don’t know exactly how it works. We have a good idea of the first steps, like what it binds to. But what happens after that, and why the effects are so profound and why they last so long--we really don’t have much idea. So that’s what inspired our mouse studies.

MDMA molecule
My lab spends a lot of time focused on neuronal circuits: this brain region synapses to that brain region, and those two brain regions are both required for this social behavior, and you can block the prosocial effects of MDMA if you block it in those brain regions. We’re sort of obsessed with brain regions. And it’s not just us--I think the whole field is so focused on circuits right now, partially because we spent so many decades focused on synapses and then we got a bunch of new cool tools that made it possible to look at circuits in new parts of the brain that we couldn’t look at before. And it’s also easier to connect to what’s going on in a human, because you can’t look at molecules and synapses in human brains the way that you can in animals. But you can do fMRI and see a brain region light up with drug X or behavior Y.

The big surprise of this [octopus] study is that if you have the molecule MDMA binds to, then the particulars of the anatomical brain don't matter. If you’re an octopus, you don’t have those regions, and yet because you have the serotonin transporter, MDMA has the same effect. What this says when we’re trying to understand the therapeutic effect is that we maybe need to reorient ourselves to focusing once again on the molecule. Because the circuits are--they’re important, they’re necessary, but they’re what I would call contingent. They’re accidents of history. You could assemble a different set of circuits in a different way completely and still get this behavior. I’m very affected by it, and it’s forcing me to rethink a lot of our strategy.

So these results with the octopuses might reshape or influence the future work you do with mice?


Do you think you’re also going to keep working with octopuses or other cephalopods?

I’m still very interested, and I think we’ve just barely scratched the surface of what we can do with octopuses. We’re sequencing the genome of two other species which I think will be really useful in terms of comparative genomics.

Are those the larger and smaller Pacific striped octopuses? [I wrote about these two species in 2015 for KQED]

LPSO hamming for Dave Maass / CC BY 2.0
That’s right. Octopus chierchiae, the smaller one that’s asocial, has all of the benefits of Octopus bimaculoides, which is the one we used here, in terms of the potential to be bred in captivity. And we can compare that species to the LPSO [larger Pacific striped octopus], which is very similar except that it is social instead of asocial. In rodents, we learned a lot about how social behaviors are encoded by comparing prairie voles and mountain voles, which are very closely related, but one species does pair bonding behavior and the other doesn’t. We’re hoping we can do the same thing with octopuses.

And I want to start trying to understand the rules. Are there similarities between, say, the mammalian nucleus accumbens, which is where we think a lot of these social behaviors are encoded in the mammalian brain, and whatever brain region in the octopus that’s encoding these behaviors? And by comparing those two brain regions, can we start to derive rules? Like: you need to have serotonin, you need to have glutamate, you need to have two or three synapses converging at this that come from that.

I’m looking forward to following along. One more question: The EU recently adopted legislation to protect cephalopods on par with vertebrates as lab animals. What are your thoughts on that?

I’m sure there are people in the US that are going to be upset that I’m saying this, but the truth is I think it’s absolutely ethically appropriate to adopt the same set of rules that we have for studying vertebrates. We want to reduce the number of animals we test, to use the bare minimum of animals we can learn something useful from. We want to reduce the amount of pain and suffering they have, so if you’re going to do surgery, you make sure to use anesthetic. I think all of those things are appropriate for an octopus because they are very intelligent. I think it’s only a matter of time before the US will adopt the same exceptions that Europe has already.

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