Monday, October 17, 2011

Where do all the nice mice go?

I wait for mice. I wait for them to wake from anesthesia; for them to replicate the viruses I inject; for them to copulate, conceive, gestate, give birth, and ween new mice. And I wait for mice I don't even have; for my boss to order new strains, for the paperwork to be filled, the courier to ship, and the vet to quarantine.

Unless (until?) we can shorten mouse gestation or virus replication, the day-to-day waiting cannot be mitigated. But those other delays - those not bound by nature - seem solvable. What I would like to see is a way for individual researchers (or labs) to have access to a wide variety of mice in a timely fashion.

Beaucoup de souris

This logistical issue only became incipient recently. In olden times, most people worked with WT mice, so you never had to order mice, nor worry about maintaining multiple lines. Now there are dozens of  mouse lines with Cre- or GFP expression in interesting subsets of neurons, like specific cortical layers, neuromodulatory centers, or inhibitory neurons. And this issue is accelerating, as new mouse lines are constantly developed. For example, in last month's Neuron, Josh Huang announced a batch of mice that express Cre in GABAergic neurons. The Feng lab released a batch targeting neuromodulatory centers. And that's not counting ongoing projects like GENSAT or the Allen Brain Atlas that generate, collect, and distribute lines.

You might be thinking, "Options are a good problem. Just be selective, and only order the mice that are interesting." Which is what we do. Yet, it's impossible to identify how useful a mouse line is without testing it. For example, if you want to use a mouse line expressing Cre in a specific cortical layer, you have many choices, which differ in terms of density, and selectivity. The only way to differentiate them would be to test them all.

As it stands now, if you guess wrong and order a lemon of a mouse line, you have no recourse. Just months of delayed projects, and the decision whether to maintain that line for possible future use, or just to end it.

Costs defined

In economics terms, I believe these issues can be categorized as transaction and variable costs. The transaction costs include those beyond the price of buying mice, like the time spent filling paperwork, or  the time waiting. And the variable costs are those involved in housing more mouse lines.

The way research is organized now significantly increases these costs. Research is performed in small labs in small departments spread around the world, each of which maintain their own mouse colonies. While some of these colonies are unique, most are redundant. Whenever a lab wants to work on a new mouse line, they have to wait months for the colonies to breed up (increased transaction cost), and incur thousands of dollars in housing costs.

Given the increasing importance of mouse lines to research, the explosion in the number of mouse lines, and the costs associated with maintaining independent mouse facilities, it may be time to rethink how we organize research. (I am entirely aware that reorganizing all of neuroscience research for easy mouse access is crazy. But bear with me.)

Cutting Costs

Two solutions spring to mind, both focused on reducing transaction and variable costs.

First, instead of transferring mice, we could transfer people. If I want to work on the KX25 mouse line, I could pack my electrodes and lickometer, and fly to the lab that has them. No quarantine, no breeding, just TSA screening.

This solution is, of course, impossible. On the human side: who gets credit/authorship for the experiments? do we want to burden people with moving every few months? etc. On the technological side, it would require a quantum leap in equipment standardization or portability, so that one could perform experiments anywhere. (It's never a good idea to bet against technological progress, but for now techniques are evolving too quickly for this to be feasible soon.)

The other way to reduce these costs is to simply reduce the number of locations, and concentrate more science in fewer locations, maybe a dozen around the US. Each location could be specialized to further reduce costs. For example, you could group together everyone interested in cortical systems neuroscience, have all the mouse lines they typically use. Then whenever someone wanted a mouse, they could check the availability, and have something available the next day, or within a month. And if the mouse didn't work, it would not be a problem, since you didn't spend too much time or money ordering and housing them.

Costs and Benefits

What are the downsides or risks to this idea? There are certainly cultural issues. If we reduced the number of research institutions, would we lose diversity? Would people in the mega-facilities collaborate, or compete? What would the academic career path look like without the grad-student, post-doc, faculty progression? (Wait, ditching that would be a bonus.) What would the funding process look like? Would people accept having even fewer choices of locations to work?

There are political issues too. The smaller research universities would be losing significant federal funding, which would displease congressmen. And the universities themselves might be scared of losing so many teachers, but then again, most researchers hate teaching.

Yet, there might be additional benefits beyond simply reducing costs. Paul Graham writes about tech startups, and has noted the right environment is essential for startups to thrive. In Silicon Valley, people think start-ups are cool rather than risky; the social network of useful people is denser; there are venture capitalists to pitch to.

By concentrating research in fewer locations, neuroscience may benefit in similar ways. If you're working in olfaction, you can discuss new experiments every week with others, rather than waiting for conferences. Or if you have an idea for a set of experiments, the funding agency might be there for you. Imagine the seminars!

Given the government sure as heck won't do this, who might? The best bets are Howard Hughes, or very large research universities (Harvard, UCSD, Penn). Right now universities generally try to hire people with a diversity of interests, rather than focusing on specific subjects. Instead, they should probably narrowly focus. Once you have 5-10 faculty all sharing mice, those costs might be half of what they would be otherwise.

I should really be a department chair. I've already figured out how to boost a department's reputation by authoring wiki textbooks. And now I've figured out how to reduce a significant non-payroll cost. Only problem is my short Trail of Papers.

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