en-de  Extending the genetic code - Adding new DNA letters make novel proteins possible Hard
Erweiterung des genetischen Codes - Durch das Hinzufügen von neuen DNA-Basen werden neue Proteine möglich.

Eines von ihnen, ein Krebsmedikament, wird jetzt entwickelt.

The Economist, Science and Technology, 17. Januar, 2019, La Jolla, Kalifornien.

THE FUZZY specks growing on discs of jelly in Floyd Romesberg’s lab at Scripps Research in La Jolla look much like any other culture of E. coli. Aber der Schein trügt - denn die DNA dieser Bakterien besteht aus einer Basensequenz, die sechs Buchstaben, anstatt der üblichen vier enthält.

Jeder andere irdische Organismus beruht auf einen Quartett genetischer Basen: A (Adenin), C (Cytosin), T (Thymin) und G (Guanin). These fit together in pairs inside a double-stranded DNA molecule, A matching T and C, G. But in 2014 Dr Romesberg announced that he had synthesised a new, unnatural, base pair, dubbed X and Y, and slipped them into the genome of E. coli as well.

Kept supplied with sufficient quantities of X and Y, the new cells faithfully replicated the enhanced DNA—and, crucially, their descendants continued to do so, too. Seitdem haben Dr. Romesberg und seine Kollegen ihre neuen "halbsynthetischen" Zellen ermutigt, das erweiterte Alphabet zu benutzen, um Proteine herzustellen, die es zuvor nicht hätte geben können, und die Eigenschaften besitzen könnten, die sowohl neu als auch nützlich sind. Jetzt denken sie, dass sie eines gefunden haben. In Zusammenarbeit mit einem Spin-off Unternehmen namens Synthorx, hoffen sie, eine weniger giftige und effektivere Version des Krebsmedikaments Interleukin-2 zu schaffen.

Life. But not as we know it.

In einer normalen Zelle ist die Herstellung von Proteinen ein einer Fabrik ähnlichem Verfahren. DNA wird zunächst in RNA transkribiert - auch eine Abfolge von Basen, aber ein einzelner, statt eines doppelten Strangs. The RNA’s bases are then read, in groups of three known as codons, by a molecular machine called a ribosome. Sixty-one of the 64 possible codons correspond to one of 20 versions of a type of molecule called an amino acid. Die anderen drei haben die Funktion eines "Stop" Signals. Wenn ein Ribosom ein Codon liest, verbindet sie es mit einem anderen Molekül, das die dazu passende Aminosäure trägt. The resulting string of amino acids is a protein.

This arrangement has long been exploited to make natural proteins for use as drugs. Das Potential einer semisynthetischen Zelle besteht darin, etwas ähnliches zu tun, aber mit dem Ergebnis, dass ein in der Natur nicht vorkommendes Protein entsteht. Das würde einen breiteren Bereich von Eigenschaften zulassen.

Others have tried to achieve this by repurposing superfluous “stop” codons to encode novel amino acids, and one firm, Ambrx, has succeeded in doing so industrially. But this approach can add a maximum of only two amino acids to the existing set. Dr. Romesbergs Verfahren hat bereits mehr als das erreicht, wobei zwei der erfolgreichen Verfahren schon veröffentlich wurden und acht weitere kurz vor der Veröffentlichung stehen. Im Prinzip würde sein System 152 extra Codons, zusätzlich zu den existierenden 64, ermöglichen.

Dr Romesberg and Laura Shawver, Synthorx’s boss, picked interleukin-2 in particular to work on because of the mismatch between its potential and its reality. Though it is useless at low doses—actually suppressing the immune response to tumours rather than enhancing it—at high doses it is extremely effective at promoting such an anti-tumour response. Unglücklicherweise besteht ein Nebeneffekt darin, das es die Wände der Blutgefäße schädigt, wodurch Plasma nach außen dringt. Wenn dies in den Lungen geschieht, kann ein Patient ertrinken. As Dr Shawver puts it, some people have been cured of their cancers thanks to interleukin-2, “but they have to live to tell the tale”.

Interleukin-2 funktioniert, indem es an Zellen des Immunsystems, sogenannten Lymphozyten, andockt und ihre Aktivität stimuliert. Der Rezeptor, an dem es sich an der Oberfläche der Lymphozyte festsetzt, besteht aus drei Einheiten: Alpha, Beta und Gamma. Immunzellen mit allen dreien bilden mit Interleukin-2 ein starkes Band, und das ist es, was den toxischen Effekt triggert. Wenn allerdings Interleukin-2 dazu veranlasst werden kann, sich nur an die Beta- und Gamma-Einheiten zu binden, bleibt die Toxizität aus. And that, experiments have shown, can be done by attaching polyethylene glycol (PEG) molecules to it.

The trick is to make the PEGs stick. Hier ist es, wo das erweiterte genetische Alphabet wichtig wird. Using it, Synthorx has created versions of interleukin-2 to which PEGs attach themselves spontaneously in just the right place to stop them linking to the alpha unit. An Mäusen getestet, hat das veränderte Molekül genau die gewünschte Anti-Tumor-Wirkung. Synthorx plant später in diesem Jahr die Genehmigung für Studien an Menschen zu beantragen.

Dr. Shawver betrachtet THOR-707, der Name des neuen Interleukins, erst als einen Anfang. Synthorx hat schon synthetische Versionen verschiedener anderer Medikamente in der Mache. And the wider possibilities are endless. Das Schöne an Dr. Romesbergs System ist, dass es funktioniert, ohne die normale Zellfunktionen zu stören, wodurch es möglich wird, die fabrikähnlichen Zellbestandteile zu benutzen, um fast jedes "Designer"-Protein zu erzeugen. Diese könnten Eigenschaften haben, die man normalerweise bei organischen Molekülen nicht findet - vielleicht Halbleiter-Proteine, die in weiche Materialien eingewebt werden können.

Auch diejenigen, die Befürchtungen haben, dass genetisch veränderte Organismen aus dem Labor entweichen könnten, brauchen sich bei diesem speziellen System keine Sorgen zu machen. Ohne einen ständigen Nachschub von X und Y, würde jedes entwischene Molekül, in der Wildnis nicht weit kommen.

Dieser Artikel erschien in der Sparte "Wissenschaft und Technology" der gedruckten Version unter der Überschrift "New tricks".

https://www.economist.com/science-and-technology/2019/01/19/adding-new-dna-letters-make-novel-proteins-possible
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Extending the genetic code - Adding new DNA letters make novel proteins possible.
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One such, a cancer drug, is now in development.
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The Economist, Science and Technology, January 17, 2019, La Jolla, California.
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Now they think they have found one.
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Life.
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But not as we know it.
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In a normal cell, protein-making is a factory-like operation.
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The other three act as “stop” signals.
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The resulting string of amino acids is a protein.
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That would permit a wider range of properties.
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His system could, in principle, provide 152 extra codons on top of the existing 64.
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When this happens in the lungs, the patient may drown.
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The trick is to make the PEGs stick.
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This is where the extended genetic alphabet comes in.
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Tested on mice, the modified molecule has exactly the desired anti-tumour effects.
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Synthorx plans to ask permission for human trials later this year.
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Dr Shawver sees THOR-707, as the new interleukin is known, as just the beginning.
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Synthorx already has synthetic versions of several others in the pipeline.
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And the wider possibilities are endless.
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Without a steady supply of X and Y, any escapee would not get far in the wild.
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Extending the genetic code - Adding new DNA letters make novel proteins possible.

One such, a cancer drug, is now in development.

The Economist, Science and Technology, January 17, 2019, La Jolla, California.

THE FUZZY specks growing on discs of jelly in Floyd Romesberg’s lab at Scripps Research in La Jolla look much like any other culture of E. coli. But appearances deceive—for the DNA of these bacteria is written in an alphabet that has six chemical letters instead of the usual four.

Every other organism on Earth relies on a quartet of genetic bases: A (adenine), C (cytosine), T (thymine) and G (guanine). These fit together in pairs inside a double-stranded DNA molecule, A matching T and C, G. But in 2014 Dr Romesberg announced that he had synthesised a new, unnatural, base pair, dubbed X and Y, and slipped them into the genome of E. coli as well.

Kept supplied with sufficient quantities of X and Y, the new cells faithfully replicated the enhanced DNA—and, crucially, their descendants continued to do so, too. Since then, Dr Romesberg and his colleagues have been encouraging their new, “semisynthetic” cells to use the expanded alphabet to make proteins that could not previously have existed, and which might have properties that are both novel and useful. Now they think they have found one. In collaboration with a spin-off firm called Synthorx, they hope to create a less toxic and more effective version of a cancer drug called interleukin-2.

Life. But not as we know it.

In a normal cell, protein-making is a factory-like operation. DNA is first transcribed into RNA—also a string of bases, but a single, rather than a double strand. The RNA’s bases are then read, in groups of three known as codons, by a molecular machine called a ribosome. Sixty-one of the 64 possible codons correspond to one of 20 versions of a type of molecule called an amino acid. The other three act as “stop” signals. When a ribosome reads a codon, it links it with another molecule that carries the appropriate amino acid. The resulting string of amino acids is a protein.

This arrangement has long been exploited to make natural proteins for use as drugs. The potential of semisynthetic cells is to do something similar, but with an un-natural protein as the result. That would permit a wider range of properties.

Others have tried to achieve this by repurposing superfluous “stop” codons to encode novel amino acids, and one firm, Ambrx, has succeeded in doing so industrially. But this approach can add a maximum of only two amino acids to the existing set. Dr Romesberg’s process has already beaten that, with two published successes and another eight awaiting publication. His system could, in principle, provide 152 extra codons on top of the existing 64.

Dr Romesberg and Laura Shawver, Synthorx’s boss, picked interleukin-2 in particular to work on because of the mismatch between its potential and its reality. Though it is useless at low doses—actually suppressing the immune response to tumours rather than enhancing it—at high doses it is extremely effective at promoting such an anti-tumour response. Unfortunately, a side-effect is that it damages the walls of blood vessels, causing plasma to leak out. When this happens in the lungs, the patient may drown. As Dr Shawver puts it, some people have been cured of their cancers thanks to interleukin-2, “but they have to live to tell the tale”.

Interleukin-2 works by binding to, and stimulating the activity of, immune-system cells called lymphocytes. The receptor it attaches itself to on a lymphocyte’s surface is made of three units: alpha, beta and gamma. Immune cells with all three form a strong bond to interleukin-2, and it is this which triggers the toxic effect. If interleukin-2 can be induced to bind only to the beta and gamma units, however, the toxicity goes away. And that, experiments have shown, can be done by attaching polyethylene glycol (PEG) molecules to it.

The trick is to make the PEGs stick. This is where the extended genetic alphabet comes in. Using it, Synthorx has created versions of interleukin-2 to which PEGs attach themselves spontaneously in just the right place to stop them linking to the alpha unit. Tested on mice, the modified molecule has exactly the desired anti-tumour effects. Synthorx plans to ask permission for human trials later this year.

Dr Shawver sees THOR-707, as the new interleukin is known, as just the beginning. Synthorx already has synthetic versions of several others in the pipeline. And the wider possibilities are endless. The beauty of Dr Romesberg’s system is that it works without disrupting a cell’s normal function, making it possible to hijack cells’ factory-like properties to produce almost any “designer” protein. These might have properties not normally seen in organic molecules—semi-conductor proteins that can be woven into soft materials, perhaps.

Nor need those who worry about genetically modified organisms escaping from the lab fret about this particular system. Without a steady supply of X and Y, any escapee would not get far in the wild.

This article appeared in the Science and technology section of the print edition under the headline "New tricks".

https://www.economist.com/science-and-technology/2019/01/19/adding-new-dna-letters-make-novel-proteins-possible