A protein in a box

Exactly one year ago today I defended my doctoral thesis in Delft. Fast-forward one year, and I find myself writing these words in the California sun. How different life has become! Having embarked on an exciting new project, I am now challenged to think about a whole new universe of fascinating problems. Yet I do enjoy looking back every now and then to remember the good times of grad school. The good times of a protein in a box.


What is life? At the very least it is a concept that we humans find surprisingly difficult to define. Though generally wet and dynamic1, arguments about what defines life inevitably involve terms like ‘reproduction’, ‘growth’, and ‘adaptation’ – matters very common to cells and viruses alike, yet whether the latter belong to the category of living things is a matter of ongoing debate. For the purpose of this thesis (as well as for my own understanding), I adopt a less materialistic and more conceptual definition of life:

Life is a process brought forward by the self-organization of molecules, a process that seemingly violates the second law of thermodynamics2 as it increasingly acquires and maintains information over timescales that vastly exceed the lifetime of the molecules holding this information.

In this manner the distinction between a virus and a cell becomes rather meaningless: viruses are just as much part of the process that we know as ‘life’ as a homo sapiens like you or me is.3 In addition, it allows me to conveniently classify my thesis work as “an effort to gain better understanding of the molecular processes and building blocks of life”. Though this classification is rather broad – as myriads of doctoral theses written over the past century or so belong to this category – my thesis belongs to a relatively small and novel subcategory of the ‘gaining insight into the building blocks of life’ class by making use of two concepts: single-molecule and bottom-up approach.

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Tus fuss (1)

 

The main actors.

My Tus paper in the news, those interested can start reading up. Again, more to follow

 

Today’s headlines

Is it a bird? Is it a plane? No: It’s my project on the cover of Nature Chemical Biology!

Tussle stories.

More will follow soon, for the time being I’ll quote the Journal:

“A single-molecule approach using magnetic tweezers shows that DNA strand separation alone can trigger a lock at Tus–Ter sites where oppositely moving replisomes on circular bacterial chromosomes must avoid crashing. The results support a ‘mousetrap’ model in which replication-related proteins are not necessary and strand separation is followed by an interaction between Tus and C6 of the Ter site that sets up a hierarchy of interactions to allow the Tus–Ter complex to progressively strengthen. Cover art by Erin Dewalt, based on an image provided by TU Delft/Tremani.”

Will work for food.

Like all nationalities, the Dutch have something with food. However, unlike quite a few other nationalities, for the Dutch ‘having something with food’ does not mean ‘having a sophisticated cuisine’. The Dutch approach to life – sober, functional, yet efficient – also holds for their eating habits. Though sliced bread is officially an American invention, the Dutch deserve a prize for so eagerly embracing this concept. Indeed, with their endless plain cheese or peanut butter sandwiches, the Dutch are often ridiculed as being prepared to eat anything. Having grown up in Belgium – the culinary buffer zone between France and The Netherlands – I definitely also sensed a gradient (a step function, actually) of culinary complexity when crossing the border.

From those new to The Netherlands, I have heard personal accounts of going through various stages of surprise, to astonishment, disbelief, disgust, rebellion, and finally to acceptance by sticking with home cooking. While home cooking might be a good alternative meaning for ‘going Dutch’, it is only then that people realize that the supermarkets do not offer what could be bought abroad.

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Let’s talk Tweezers

Let’s talk tweezers. Magnetic Tweezers, that is – de lekenversie. Toegegeven niet het meest spannende verhaal op deze site, ondanks dat interessant en momenteel niet weg te denken uit mijn dagelijks bestaan. Voor het nageslacht zullen we maar zeggen. De techniek bestaat inmiddels al een aantal decennia, en het woord ‘magnetic’ verraadt al een goed deel van het verhaal. De kracht van deze truc schult in het feit dat het concept zelf – alsmede het opzetten van een experiment – vrij eenvoudig is, terwijl er toch gecompliceerde systemen op het niveau van een enkel molecuul mee onderzocht kunnen worden.

Eureka.

Zoals eerder beschreven voer je je experiment uit in een vloeistofcel ter grootte van een microscooppreparaatplaatje. Deze zogenaamde flow cell bevindt zich in een microscoop-opstelling, met bijbehorende lichtbron, objectief en camera voor beeldregistratie. Verder komt er nog één attribuut bij kijken: de magneet natuurlijk.

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Enkel-molecuul en centrale dogma’s

Single-molecule techniek, wat is dat eigenlijk? Welnu, een korte inleiding. In de wereld van het hele kleine, het onderzoek naar (de werkingsmechanismen van) het leven, cellen of onderdelen hiervan, loop je vaak tegen zeer moeilijk achterhaalbare vraagstukken aan. Nu zijn er grofweg twee manieren om tegen dit soort vraagstukken aan te kijken.

Berend botje ging uit varen.

Me volledig bewust van het feit dat ik nu generaliseer – daarnaast ook absoluut niet de eerste die hier woorden aan vuil maakt – maar voor het gemak bestaat er de biologen- en de fysici-aanpak. Eerstgenoemden worden

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