The Boy Who Cried Gold

Last 10^th of April the prestigious journal Nature published a novel imaging technique that allows the visualization of intact brain tissue in 3D. By getting rid of the lipids and using a polymer to fix the rest, the structure -with all its proteins and nucleic acids intact- can be preserved, while the whole tissue becomes transparent.

The paper had considerable media impact, and the following day the invisible brain was taking the online front page of many of the most popular newspapers worldwide. The opening of the article at the abc science site stated: “The era of slicing and dicing for neuro-researchers is over with the arrival of a see-through brain”. Incredible!

I immediately sent an email with the news to the whole institute, and then I headed towards the INI kitchen…. Although my skeptic self was trying to push this idea away, I feared for a moment to find Rita, John and Simone moaning in agony while looking with nostalgia old EM pictures at the screens of the zamel computer. Fortunately, I did not encounter this scenario, but I saw Nuno, who was preparing his morning coffee with his usual calmness, something that surprised me a little.

-So Nuno, did you hear about the news??? - I asked anxiously.

-What news? - He replied, with his eyes reflecting puzzlement behind his rounded glasses.

-About this new method, CLARITY! –I exclaimed- is it such a breakthrough??? Is the tedious EM going to be replaced forever???

-Oh… that …– Now his eyes had a sparkle of understanding, the same one that grandfathers have when children ask them too many why’s in a row- No no, it is not going to replace EM. It is an important new technique of course, as it offers some advantages, but we will still need the old methods to properly assess connectivity.

-B-b-but the news… - I bubbled. The sparkle at his eyes got stronger, but this time I could also see on it a trace of resignation.

-I know… -he said, and he accompanied that gleam with a half smile.

That day I found myself carrying the sparkle all over the INI. I was all the time being stopped by other excited master students, who had read the news and wanted to know more about this new and promising technique. We decided then to continue the discussion at our student’s monthly Apero, and to invite Nuno to talk about the real implications of the method.

Because of the transcendence of the discussion almost all of us were present -although I suspect that Asim and Dennis cooking abilities had also something to do-. After an hour of objective analysis, these are the main points that we extracted:

-The technique allows for deep light penetration imaging, as the processed tissue is transparent.  This seems very promising because 3D reconstructions can be made without slicing. One limitation however, is in the optics. Lenses that have a high numerical aperture -which will give you the resolution to image boutons- and large working distance for deep imaging are needed. As the authors themselves state in the paper: special adaptive optics for CLARITY need to be developed.

-The biggest limitation however comes from light microscopy itself. You cannot have as much resolution as EM, because a physical limit imposed by the light wavelength exists. EM would still be needed to image at the synapse level. The authors, aware of such limitation, manage to combine CLARITY with EM. Yet another problem arises here, as the lack of lipids makes the characterization of the synapses difficult.

- One of the main advantages of the technique is that it allows for molecular phenotyping while preserving the tissue intact for imaging. Furthermore, as it is very permeable-because of the lack of lipids- the proteins are more accessible, making the process way more efficient. The stability of the rest of the elements in the polymer also allows phenotyping for several rounds.

- Assuming that the adaptive optics problem is solved, it will be very useful to track long-range projections. The brain doesn’t need to be sliced, something that will make the reconstruction faster. However, if you additionally want to have information at the synaptic resolution, you need to use EM on smaller volumes.

From the points above, we see that this new technique presents some clear advantages. It may help us characterize brain circuits faster, but the key question here is, in Nuno’s words: how much faster is it going to make us?  CLARITY is great, but it is obviously not the goose that laid the golden eggs…

A couple of weeks after that event I received an email from my mum.  She was asking me about an article she had read at the newspaper that claimed: “Spanish researchers open a new path to prevent and mitigate epilepsy”.  As you may imagine, the sparkle came back to my eyes… In order to confirm my suspicion, I decided to check the original article. On it, the authors demonstrated that the transcription factor ATF5 is implicated in neural stress-induced apoptosis. By increasing ATF5 levels neuronal death was prevented, and as a model, they were using status epilepticus-induced neuronal death. I would define the correlation that the journalist made between this piece of research and its implications for epilepsy as “brilliant”. I proceeded then to write back to my mum, stating all the set of reasons that would turn the golden eggs goose into a humble fowl. More that an email it looked like a dissertation, so I don’t know if my mum actually ever read it...

The following week, however, she was sending me a pile of articles -you have to imagine me sighting now…- hoping, I guess, that I would approve at least one of them. I didn’t. This time they were related to Parkinson or maybe Alzheimer, apparently it doesn’t seem to make much of a difference. In all the cases, an excellent research gets conveniently filtered and embellished when fallen into the media circus. This is passively observed by the authors, who I assume find themselves “trapped” into the middle of the situation. Quite convenient I would say…


Nonetheless, you may ask, isn’t media impact something positive for research? Doesn’t it bring social awareness and gives importance to our work? Of course! And that should be promoted. The difference is in how we do it. And the key question in here is the following: Do we want to be more the herald or the storyteller?  Are we willing to sacrifice our personal glory in favor of the future of science? This is something we all- the present and the future scientists- should keep in mind if one day a journalist knocks at our door.  Otherwise we take the risk to become, inevitably, the boy in our own tale, and it will no matter how long we keep crying.


- S. Soldado Magraner