When size matters (100 years, Part VI)

Neat process diagrams of metabolism always gave the impression of some orderly molecular conveyer belt, but the truth was, life was powered by nothing at the deepest level but a sequence of chance collisions. (1)

Zoom down far enough (but not too far – or the Aladdin merchant might complain) and all matter is just a soup of interacting molecules. Chance encounters and interactions, but with a high enough probability to happen. In essence, life is a series of molecular interactions (that, in turn, are atomic interactions and so on and so on…)

The form of the cellular framework of plants and also of animals depends, in its essential features, upon the forces of molecular physics. (2)

Quite often, we can ignore those small-scale phenomena, but only as long as the system we are describing is large enough. As in physics, in biological systems size does matter (*insert ambiguous joke here*). We have to adapt the governing physical rules depending on the scale that we are observing. Do we consider every quantum-biological detail, can we use a cell as the smallest entity or even use whole organisms as the smallest functional entity?

Life has a range of magnitude narrow indeed compared to with which physical science deals; but it is wide enough to include three such discrepant conditions as those in which a man, an insect and a bacillus have their being and play their several roles. Man is ruled by gravitation, and rests on mother earth. A water-beetle finds the surface of a pool a matter of life and death, a perilous entanglement or an indispensable support. In a third world, where the bacillus lives, gravitation is forgotten, and the viscosity of the liquid, the resistance defined by Stoke’s law, the molecular shocks of the Brownian movement, doubtless also the electric charges of the ionised medium, make up the physical environment and have their potent and immediate influence on the organism. (3)

Observing life at the smallest scales (by which I mean cells and unicellular organisms) at least has the advantage the rules driving form and structure can, at least in many cases, be considered relatively simple: surface-tension.

In either case, we shall find a great tendency in small organisms to assume either the spherical form or other simple forms related to ordinary inanimate surface-tension phenomena, which forms do not recur in the external morphology of large animals. (4)

While on the topic of size, as many things in the universe: size is relative. I have noticed in conversations with colleagues and supervisors that what is considered small or large, definitely depends on the point of perspective (and often: whatever the size is that that person typically studies). I could assume that for a zoologist, a mouse is a small animal, but tell a microscopist they have to image an area of 1 mm² and the task seems monstrous. For a particle physicist, a micrometre is immense, but for an astrophysicist, the sun is actually quite close.

We are accustomed to think of magnitude as a purely relative matter. We call a thing big or little with reference with what it is wont to be, as when we speak of a small elephant of a large rat; and we are apt accordingly to suppose that size makes no other or more essential difference. (5)

Undoubtedly philosophers are in the right when they tell us that nothing is great and little otherwise than by comparison. (6)

There is no absolute scale of size in the Universe, for it is boundless towards the great and also boundless towards the small. (5)

That’s the amazing thing about science: we strive to understand the universe on all scales. The universe is mindblowing in its size, in both directions on the length scale.

We distinguish, and can never help distinguishing, between the things which are at our own scale and order, to which our minds are accustomed and our senses attuned, and those remote phenomena which ordinary standards fail to measure, in regions where there is no habitable city for the mind of man. (7)

Good thing we have scientists, amazing minds, capable of studying, visualising and even starting to understand the universe on all its scales…

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My mind might be boggled, but here’s a man that looks like his mind contains the universe. (D’Arcy in his 80s)

(1) Permutation city – Greg Egan, p. 67

(2) Wildeman

(3) On Growth and Form – p. 77

(4) On Growth and Form – p. 57

(5) Gulliver

(6) On Growth and Form – p. 24

(7) On Growth and Form – p. 21

(3-4, 6-7) from D’Arcy Thompson, On Growth and Form,  Cambridge university press, 1992 (unaltered from 1942 edition)

There’s plenty of room at the bottom to listen

If you are in any way familiar with the world of electronics, electrical engineering or anything with the catchword “nano” in it (except perhaps the ipod nano, though actually it is a prime example of my Moore’s law point later on), you’ve heard of Feynman’s famous words:

“There is plenty of room at the bottom”

If you’re not, here’s the jest of it:

In December 1959, Richard P. Feynman presented a talk to the American Physical Society in Pasadena,  California, commenting on the wondrous world of miniaturisation. He explains that even though they progressed so far by that time, there is so much more room to improve. Things can still be made so much smaller.

 It is a staggeringly small world that is below. In the year 2000, when they look back at this age, they will wonder why it was not until the year 1960 that anybody began seriously to move in this direction. Why cannot we write the entire 24 volumes of the Encyclopedia Brittanica on the head of a pin?

And we’ve done it. We can manipulate single atoms. And we can image single atoms. Isn’t science grand?

When I was doing a course in nanotechnology, Feynman was often quoted in one breath together with Moore. Moore’s law, which dates back to 1965, postulates that every two years, the amount of transistors (an semiconductor element that is very important in computing) that can fit on an integrated circuit will double every two years. This prediction has been surprisingly well met;  most direct consequence is that the size of computers and electronic components keep getting smaller (remember, ipod nano). But there is a limit, transistors can only be so small; single atom transistors are not impossible (and currently in research stage), but after that, we cannot go any smaller.

Has research reached it’s lower limit? As I’ve stated, we are able to manipulate single atoms, we can build single atom electronics, and in the field of optics we are pretty much at the lower limit as well with superresolution microscopy and single molecule imaging and with electron microscopy to unravel the world at an atomic scale.

What is left to improve?*

* I’m not claiming research in these areas are futile. Obviously there is so much more to do in optics, electronics, atomic force microscopy, … Obviously there is so much more to learn. I just want to point out that size-wise, we have pushed these fields pretty much to their (lower) limit. So maybe it is worth exploring other fields as well? 

There are different ways to study something. For example, let’s take cancer cells. We can look at them, through a microscope, and if we want at very high resolution, to unravel the differences between cancerous cells and their healthy counterpart. We can feel them, well not us directly but through techniques such as atomic force microscopy, which also can provide very high resolution, to investigate the effects of different mutations. Additionally we can listen. Well, not us directly, but by using ultrasound. Now there’s a field with plenty of room on the bottom.

Conventional ultrasound, for example the type that is used to look at babies in wombs, uses frequencies from over 20 kHz (which is the maximum frequency of sound that is audible to us, hence ultrasound) to a few MHz and provides a resolution usually no less than 100 µm. Compared to optics, this is nothing. However, ultrasound has quite some advantages over optics. Higher penetration depth, no lasers (pew pew pew), possibility of quantifying a lot of useful things like mechanical properties, just to name a few. And it has plenty of room at the bottom, we are now where near the limit yet!

We can increase the frequency up to 47 MHz (what I use routinely), or 150 MHz or even up to 1000 MHz. It’s called high-frequency ultrasound. Or super-high ultrasound. Things get really interesting then. You can image cells. You can do superresolution imaging.

There are really exciting things going on in the field of ultrasonics, and I’m not just saying that because I’m looking more into it for my own research at the moment. Researchers were recently able to image the rat brain at a previously unseen resolution (see the pretty picture below). Other groups are extracting information from single cells using ultrasound that can’t be obtained using optical techniques. And that is just mentioning a few of the many recent advances.

In any case, my point is that we might be plateauing with regards to improving resolution on optics or miniaturising our electronics, but there is still plenty of room at the bottom to listen !

 

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High resolution image of vessels in a rat brain. Red/blue shows directionality of the blood, brightness gives an indication of speed. Photo credit: ESPCI/INSERM/CNRS.

 

“All these autumn leaves are yours tonight” *

Lets just skip over the (slightly depressing) fact that we seem to have skipped over summer this year. I’m not really sure there was even a proper spring, though in Scotland’s defence, I wasn’t in the country for most of it, so maybe I just skipped over it personally. But I think it’s official now, the clocks have been turned back, petty colds have made their introduction, people have started to quote Game of Thrones and the trees have started painting a colourful palette. Autumn is here.

Autumn leave pallet as seen through PDMS drip lenses.
Autumn leave palette as seen through PDMS drip lenses.

You might have noticed I said autumn and not fall. I may sound very American (not that you can hear that by reading this), but let’s be fair, autumn is simply a much nicer word.

Let’s dig in a bit deeper. Until the 16th century, autumn was referred to as Harvest, from the Old Norse word haust meaning “to gather or pluck.” In those days, a lot of people were dependent on farming, and this was the time to harvest crops, so it makes sense. But as more people went to go live in towns and cities, the word wasn’t as relevant anymore. Two new words came into use then: Fall, which was probably short for “fall of the leaf” and Autumn from the Latin automnus. There were both used, as far as I understand, but at a certain point of time the colonies stuck to the word fall (maybe because it’s easier to spell?), while fall fell into disuse in the UK. It’t quite interesting how US english and UK english started to evolve differently, and this season’s name is just one example.

Etymology aside, what I have noticed most, is that here in Dundee, in the autumn, it’s like living in a cloud. No, I’m not being particularly dreamy, or aspire myself to be in the virtual datacloud. It’s literally in a cloud. It gets really really foggy, or misty, or hazy, and this results in feeling like your stuck in a The Gothic Archies song.

View from my office. (This is not actually a picture I’ve taken of the view, this is just a image of a white square, or the cover of an album with the band name omitted if you will. But that is the view we get a lot.)

Okay, turns out foggy is the best word. In ye olden days, it would have been hazy, but language has evolved since then (yes, were talking about the words again). In general, mist and fog both consist of tiny water droplets, a low hanging cloud if you will, and their difference is quite vague and depends a lot on who you ask. Let’s just say fog is thicker than mist and is what caused my plane yesterday to be cancelled, and the next one to be delayed (because they waited until it got foggy again!), causing me to finish 2,5 books over the whole day. Haze is used to refer to a particularly thick fog, but now means “a rather thin fog and other causes of reduced visibility”, for example heat haze, something that I have not seen occur here yet.

Just imagine a night out drinking: you might be hazy after a few beers, misty after a few more, and foggy would be the last step before a complete black out. Not that I would know.

There another mist/fog-phenomena occurs here quite often: haar. This is cold sea fog that occurs when warm air passes over the cold North Sea, causing it to condense locally. This haar seeps in over the Tay (the local river) and in some cases just stays confined right there. It feels a bit like a scene in where cursed pirates would use a cloak of mist to creep up on their victims, in this case the city of Dundee.

Well, I guess autumn in Dundee is not that bad. It’s occasionally eerie. But in the moments when there is no fog, the sunrises are absolutely stunning, and there is nothing better to wake you up than a morning stroll in the cold. Bring along a pocket microscope and have a blast.

Not always white views... The bottom left depicts why I have occasional urges to break into
Not always white views… The bottom left depicts why I have occasional urges to break into “Nants ingonyama bagithi Baba“. An example of haar can be seen on the right.
Just some more PDMS drip lens images, taken during a autumn stroll.
Just some more PDMS drip lens images, taken during a autumn stroll.

* From Autumn by Paolo Nutini.

Cheap is good, almost free is better!

Working in a research environment definitely changes your perspective on the meaning of “cheap” and “expensive”. If paying £194 to go to a festival seems like a lot of money, then consider that you need to pay at least half more to buy an antibody. “Cheap” purchases include most things under, say, £200. And I don’t even want to think about how much money gets spent on consumables like pipets and petridishes. If you want to really do something, you need to buy equipment like microscopes or PCR meters and you can probably buy a car with the same amount of money. Or a jet. Needless to say then, that conducting scientific research is quite an expensive endeavour and it’s no bit surprise that a lot of time goes into applying for grants.

Does it really have to be this expensive though?

The simple answer is: probably.

The fun answer, however, is NO!

I’ll give you an example (and let’s pretend to ignore the fact that I’m too lazy to find another example): easy-to-make, affordable, microscopy lenses. It is quite similar to the water drop hack, which is even cheaper than the method I am going to purpose, but not quite as versatile. I am talking about a lens made out of PDMS.

Bear with me, I am going to explain.

The idea was published last year. It makes use of polydimethylsiloxane (also known as PDMS), which is a elastomer used commonly for making microfluidic devices. The elastomer is made by mixing to reagents together and exposed to heat to allow it to polymerise and form a stable, flexible, clear, rubbery bit of stuff.

An example of a microfluidic device made of PDMS (as a result of a quick google search).

As it is clear and has a high refractive index, making a droplet-shaped bit of this PDMS might very well be used as a lens in combination with a smartphone. And it is cheap, a 1.1 kg bottle of this PDMS might cost a little bit (around £100, but I have already that this is cheap in scientific consumables terms), but you can make so many lenses out of this, it results in about £0,05 per lens. Cheap huh.

So yesterday evening, we spent some time trying to make some of these lenses, which worked quite well. It is very easy to make (we are going to try this as an outreach workshop) and it is also absolutely cool. From just a few hours of messing around – and it is quite a sticky substance to work with – with cover slips, the PDMS, a syringe and a lamp to provide the heat, we made quite some lenses and took quite some pictures.

Wait, I’ll give you another example (it isn’t really though): so using these lenses, you can make a simple (and cheap!) optical trap. An optical trap uses a laser to trap, for example, a bead*. This can be used to measure the viscosity of fluids, measure forces involved in cellular processes (protein folding, motor proteins, adhesion, cytosol viscosity, motility forces, …) or to play a game of tetris. It’s quite a cool technique, and now you can save on costs by making your own lens! (I’m sure the paper will be accessible soon.)

Anyway, this is just to say that research doesn’t always have to be expensive. And obviously it was already fun, but it can be even more fun (who knew)?

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The result of mucking around. Top left: a PDMS drip lens. Top right and bottom left: pixels from some text on a paper. Bottom right: some of my finger print lines.
Another example: the fabric of my watch. Left is taken in macro mode without the lens (even a bit out of focus), right is with the PDMS lens.
Another example: the fabric of my watch. Left is taken in macro mode without the lens (even a bit out of focus), right is with the PDMS lens.

We live in exciting times. Nostalgia-drenched movies are out now or being released soon. Our childhood hero is returning in the form of theatre. Certain fantasy characters might have actually existed**. Advances that we could only dream of (or write Sci-Fi novels about) seem within reach. And new awesome ways are being developed to make science cheap and accessible for anyone.

Finally, I’ll end with a teaser:

We are currently setting up an outreach project bringing these things together:

I-Heard-The-Cutest-Conversations-Between-Everydays-Objects43__605
But I enjoy the far away things too! (source)

And it’s already been so much fun! Learn more on twitter or wait until I dedicate a post on the subject (sometime I will!)

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*Yes, this is in no way an adequate explanation of optical trapping. I could say it uses “magic” to trap beads, though I’m sure you won’t believe me.

** Yes, I just rushed over multiple topics that I not-so-secretly wanted to mention in one way or another.

I spent another day behind a microscope.

2D MDCK layer
Image taken on a Zeiss 710 Confocal microscope at the University of Dundee.
MDCK spheroid and 2D layer
Image taken on a Zeiss 710 Confocal microscope at the University of Dundee.
3D MDCK spheroids
Image taken on a Zeiss 710 Confocal microscope at the University of Dundee.
Glowing edges filter
Image taken on a Zeiss 710 Confocal microscope at the University of Dundee, but then put through a filter.

The last images are put though the very professional “Glowing edges” filter found in Microsoft Office Powerpoint.

Pretty Pictures

Originally posted on 29 Aug 2014

After two weeks of a semi-intensive microscopy workshop, I have learned several interesting things. Additionally, I have also learned some valuable life lessons.

  1. You’re never too old to be a crazy scientist. I know this because putting dry ice into a glass of lemonade is completely irrelevant but totally cool. Never grow up.
  2. The whole point of microscopy is to make pretty pictures². There are multiple ways of achieving this – obviously I am now an expert after this course – but if you want to be published, the end result just has to look amazing.

Exhibit A:

image
Octopus bimaculoides. Light Sheet Fluorescence Microscopy with a Zeiss light sheet microscope (www.zeiss.com/lightsheet). Image courtesy of Eric Edsinger & Daniel S. Rokhsar, Okinawa Institute of Science and Technology.

This looks absolutely incredible, right? It is a tiny embryo octopus, but don’t you just want to own it and train it and use it to be the very best? Of course you do!

Exhibit B:

image
Image published in Nature Nanotechnology. “Protein-inorganic hybrid nanoflowers”, J. Ge, J. Lei and R.N. Zare. DOI: 10.1038/NNANO.2012.80

Sometimes not only the imaging technique, but the whole point of creating a structure is just to have something pretty, like this nanoflower. I’ve got to admit, giving me that on a first date would definitely work in your favour.

However, at this very moment; all I’m able to image are things like this:

image
Image taken on a Nikon eclipse TS100 at the University of Dundee.

Just look at those phase rings! And the bad resolution! Awful!

But at least this collection of cells looks pretty peaceful, so that’s something.

² Footnote (it is number two because of simplicity, ² is on my keyboard): this obviously isn’t true. The point is to make images that have the right quality to show what you want to know. It’s just more fun if they turn out to be pretty (and) awesome.