A few days ago, I wrote a brief sketch of the status and paths forward in the molecular approach to atomically precise fabrication. It offers a sampling, not a full picture:
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Unnatural amino acids compatible with ribosomes
(circled: azide, alkyne,
and biotin derivative)
From Neumann et al., 2010 and Dougherty, 2000.
All ribosomes read genetic data as three-letter words that encode 20 standard amino acids (give or take a few anomalies). This is equally true of the ribosomes in deep-sea bacteria living at 120°C, and the ones in your thumb. This universal code has been a wall that bounds the scope of biosynthetic polypeptide engineering — until now.
Recent developments have cracked the wall by tweaking the code, but Jason Chin’s group in the UK has blasted a wide hole by expanding the address space.
From the abstract of a paper soon to be published in Nature:
[E]very triplet codon in the universal genetic code is used in encoding the synthesis of the proteome….Here we synthetically evolve an orthogonal ribosome (ribo-Q1) that efficiently decodes a series of quadruplet codons…. By creating mutually orthogonal aminoacyl-tRNA synthetase–tRNA pairs and combining them with ribo-Q1 we direct the incorporation of distinct unnatural amino acids…. it will be possible to encode more than 200 unnatural amino acid combinations using this approach.
H Neumann et al., “Encoding multiple unnatural amino acids via evolution of a quadruplet-decoding ribosome”, Nature (early online publication).
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Students often ask me for advice on how to study for a career in nanotechnology, and as you might imagine, providing a good answer is challenging. “Nanotechnology” refers to a notoriously broad range of areas of science and technology, and progress during a student’s career will open new areas, and some are yet to be imagined. Choices within this complex and changing field should reflect a student’s areas of interest and ability, current background, level of ambition, and willingness to to accept risk — there is a trade-off between pioneering new directions and seeking a secure career path.
Here is an attempt to give a useful answer that takes account of these unknowns. My advice centers on fundamentals, outlining areas of knowledge are are universally important, and offering suggestions for how to approach both specialized choices and learning in general. It includes observations about the future of nanotechnology, the context for future careers.
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Chemists understood the atomic structure of molecules in the 1800s, yet many say that Einstein established the existence of atoms in a paper on Brownian motion, “Die von der Molekularkinetischen Theorie der Wärme Gefordete Bewegung von in ruhenden Flüssigkeiten Suspendierten Teilchen”, published in 1905.
This is perverse, and has seemed strange to me ever since I began reading the history of organic chemistry. Chemists often don’t get the credit they deserve, and this provides an outstanding example.
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Synthetic biology doesn’t require cells, and in several ways, cells are liabilities.
Cells can make engineering difficult. Cell membranes and bacterial walls stand between new genes and the machinery needed to transcribe and translate them. They are barriers to liberating gene products. They contain systems that are complex products of eons of evolutionary history, not systems streamlined to simplify engineering. They are easily poisoned by what would be, to us, useful raw materials and products.
The state of the art in cell-free synthetic biology is already advanced, and moving forward rapidly:
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Atomically precise self-assembly of complex structures can be engineered by providing for multiple binding interactions that
- Cooperate to stabilize the correct configuration, in a thermodynamic sense, and
- Do not stabilize any other configuration, in a kinetic sense
Roughly speaking, in the correct configuration, the parts fit together to allow all the binding interactions to operate simultaneously, and the system doesn’t get stuck in other configurations. It’s easy to see how weak interactions and cooperative binding can implement these conditions, but there are alternatives.
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A commenter on the previous post raised several important issues, and my reply grew into this post. The comment is here, and my reply follows:
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This post is prompted by a set of interrelated advances in chemistry that hold great promise for advancing the art of atomically precise fabrication. In this post, I’ll describe an emerging class of modular synthesis methods for making a diverse set of small, complex molecular building blocks.
The road to complex self-assembled nanosystems starts with stable molecular building blocks, and the more choices, the better. Self-assembly and the folding of foldamers are similar processes: They work when parts fit together well, and in just one way. Having building blocks to choose from at the design stage will typically make possible a better fit, resulting in a denser, more stable structure.
Building blocks for building blocks for building blocks
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