Thursday, January 14, 2016

Model organisms and translational research

Ewan Birney (Genomic's Big Talker of ENCODE notoriety) has a new post called In defence of model organisms.

He brings up two points that are worth discussing.

What is a model organism?

There are two common definitions. Birney leans toward defining a model organism as one that models human biochemistry and physiology. This is a common definition. It emphasizes the meaning of "model" as "model of something."

The other definition is more like the meaning of model as "ideal" or "useful" as in Cromwell's New Model Army. The two definitions are not mutually exclusive but it's important to recognize the biases when you hear scientists talk about model organisms.

One of the first model organisms was the fruit fly, Drosophila melanogaster. It was easy to culture and had relatively short generation times. As more and more scientists began work on Drosophila genetics, it became a very useful tool for probing all kinds of biological questions. Back in the 1930s, nobody really thought of fruit flies as good models for the study of human diseases.

Later on (1940s), the phage group developed bacteria and bacteriophage as model organisms. They were used to study genetics and basic biological processes. They were convenient because so many different groups were working on the same systems and their knowledge could be readily shared. This is why we know so much about Escherichia coli—an otherwise unremarkable species.

Arabidopsis thaliana is another model organism. Many discussions about model organisms don't mention it. Nor do they mention Daphnia or Neurospora. That's usually because they are going with the first definition of model organism and they don't see these examples as being particularly relevant.

Ewan Birney's point is that more and more health research is directly involved in studying humans and human cell lines. According to him, there's still a place for studying some "model" organisms because we need to understand basic biological processes. In other words, some basic research is necessary in order to understand human medicine. That's why he's "defending" model organisms.

Translational research

Strictly speaking, translational research is research that's directed toward some useful goal or product. These days it's almost always used in the context of research that could prove useful in human medicine.

Ewan Birnely supports translation research and he's upset that there seems to be a conflict between basic science and translational research.
Crude arguments that play “translation” and “basic research”, or “human disease” and “fundamental discoveries” off each other are depressing. The idea that humans are the only model organism for the future is simply misguided mischief, and opens up the dangerous possibility that people might actually start to believe it – and it’s just as frustrating to hear some people claim that one can only do translational, healthcare related science in humans, and no profound basic discoveries will emerge from human investigation. Taking an extreme position to make either point is annoying, but it belies an underlying tension that needs to be resolved. I think these arguments are more about conflict between of tribes of scientists who are now interacting more and more. There is also an element of jockeying for position, both as individuals and as tribes. We need to get beyond this.

A ‘balanced portfolio’ sounds great, but there is no straightforward recipe for compiling one. What does the best ‘balanced portfolio’ of research look like? How much “pure” disease focus on humans, and what else to add? A tablespoon of yeast, a teaspoon of serendipity and a dash of electric eel? What part of that portfolio would a particular funding agency, charity, institute or scheme take on? How to assess a slew of wildly different proposals, each with different rationales?

There are no easy answers to these questions, but we do need to realise that the lines between ‘basic’ and ‘translational’ research are now fully blurred – both are essential parts of the same process of understanding life, with massive spill-over effects across many practical aspects of our world, our health above all.
My view is somewhat different. I think there really is a difference between someone who is studying speciation in Drosophila or the mechanism of photosynthesis and someone who is mostly interested in curing cystic fibrosis.

I think there's a huge difference between basic research and translational research. This does not mean that some of the discoveries of basic researchers will never be relevant to health and disease, of course they will, but that doesn't mean that the "lines are fully blurred." There's still a lot of fundamental basic research addressing questions that have nothing to do with health and disease and will never be relevant.

I don't think we should fall into the trap of justifying fundamental curiosity-motivated research soley on the basis of what it might contribute to the "really important" stuff like translational research. We should be supporting basic research because it contributes to knowledge and not necessarily to health and disease.


  1. Years ago when I was a grad student in a Drosophila lab people I met in day to day situations would invariably get around to telling me about some pain they were having somewhere in their body and ask for medical advice. Eventually I got tired of telling them that being in the life sciences didn't mean I had any medical expertise so I started to give medical advice. Whatever complaint they had I'd suggest it was a mite infestation and then mention that whenever our fly cultures were sick it was usually due to a mite infestation.
    For some reason Larry's musings above reminded me of this.

    1. When my flies got sick I used to kill them

    2. When my flies got sick I used to kill them

      That is because you are a godless atheist who doesn't realize these very flies are your and other folks' ancestors who haven't freed themselves from the wheel of reincarnation.

  2. I totally agree. We need to try to learn what diversity of organisms exist, how they all function, and how they all got here. We need to do this mainly because of our wish to know. Incidentally, we will learn unexpected things that will help us deal with human health, or food plants and animals, and managing ecosystems in a changing world. There's so much cool stuff to learn!

  3. This indicates to me that Ewan has a good understanding of how things sort out in regard to what emerges from what:

    Molecular scales
    Even with a complete parts list of proteins in humans, we are still clueless about what vast tracts of well-characterised protein coding genes actually do. For about 8000 proteins we have a good idea of at least one of their roles; for another around 7000 proteins we have some hints. But even this knowledge can be very partial. For example, the Huntingtin gene we know is involved in Huntington's disease via a trinucleotide expansion – yet we have almost no knowledge of its molecular function. We know other genes are key mediators in disease, for example C9orf72 in amyotrophic lateral sclerosis (of ice bucket fame), yet we know very little about about its cellular or molecular function. And this patchy knowledge gets far worse as we move away from proteins. Every year it feels like a new class of non-coding RNA is defined, but pinning down functions for them (including potentially no function, the hardest thing to show) is elusive, beyond some individual cases.

    Cellular scales
    Imagine we knew the full parts list of proteins and RNAs, and their individual functions. Somehow these proteins go on to make cells, and the cells form organs. Huge unknowns dominate the landscape of cellular structure and mechanism. For example, the massive, Death-Star-like Vault complex has a large RNA component, hangs around in the nucleus and is quite easy to visualise with electron microscopy - but we have no firm idea of what it is doing. Or take the host of vesicles and membrane-bound structures zipping around every cell. Presumably they’re doing some kind of cellular ‘housekeeping’ (specific to different cell types), but we’re gloriously ignorant of the details. How do they know where they’re going? How does the right thing get into the right vesicle? As soon as you start poking into even the easiest-to-observe cellular phenomena, there are a surprising number of unknown components and their interactions.

    Organ scales
    Research into nearly every combination of cells turns up far more questions than answers. Even ‘simple’ multi-cellular systems, like the gut, have mysterious ways of ensuring that the right cells divide and differentiate at the right time. In more complex systems, interactions between cells give rise to clearly observable (sometimes model-able) phenomena, for example beating heart muscle, or the capture and excretion of toxins.

    1. ...lately he is rebranding himself as a fish researcher and distancing from human research. He does not even mention his ENCODE accomplishment on his website.

      Speaking of 'understanding', I doubt he has any, and you can read his twitter channel to find that out. He possibly sees himself as a 'marketing genius' fooling scientists.

  4. I don't so mind when people funded from the NSF (or local equivalent) go on about the supposed purity of "basic science" (even if I think they should go read some Francis Bacon and learn that the distinction between basic and applied is a modern myth), but when it gets ridiculous is when people funded by the NIH (or again, local version) do the same. Seriously, if you don't care about helping people's health, why are you expecting an agency dedicated to exactly that to fund you?

  5. The confused Birney clown also talks about 'human as model organism' -

    which is an idea he stole entirely from Brenner -