Nanotechnology Now

Our NanoNews Digest Sponsors

Heifer International

Wikipedia Affiliate Button

Home > Press > Scripps Research Institute Study Suggests Expanding the Genetic Alphabet May Be Easier than Previously Thought

Scripps Research Institute Associate Professor Floyd Romesberg
Scripps Research Institute Associate Professor Floyd Romesberg

Abstract:
A new study led by scientists at The Scripps Research Institute suggests that the replication process for DNA—the genetic instructions for living organisms that is composed of four bases (C, G, A and T)—is more open to unnatural letters than had previously been thought. An expanded "DNA alphabet" could carry more information than natural DNA, potentially coding for a much wider range of molecules and enabling a variety of powerful applications, from precise molecular probes and nanomachines to useful new life forms.

Scripps Research Institute Study Suggests Expanding the Genetic Alphabet May Be Easier than Previously Thought

La Jolla, CA | Posted on June 3rd, 2012

The new study, which appears in the June 3, 2012 issue of Nature Chemical Biology, solves the mystery of how a previously identified pair of artificial DNA bases can go through the DNA replication process almost as efficiently as the four natural bases.

"We now know that the efficient replication of our unnatural base pair isn't a fluke, and also that the replication process is more flexible than had been assumed," said Floyd E. Romesberg, associate professor at Scripps Research, principal developer of the new DNA bases, and a senior author of the new study. The Romesberg laboratory collaborated on the new study with the laboratory of co-senior author Andreas Marx at the University of Konstanz in Germany, and the laboratory of Tammy J. Dwyer at the University of San Diego.

Adding to the DNA Alphabet

Romesberg and his lab have been trying to find a way to extend the DNA alphabet since the late 1990s. In 2008, they developed the efficiently replicating bases NaM and 5SICS, which come together as a complementary base pair within the DNA helix, much as, in normal DNA, the base adenine (A) pairs with thymine (T), and cytosine (C) pairs with guanine (G).

The following year, Romesberg and colleagues showed that NaM and 5SICS could be efficiently transcribed into RNA in the lab dish. But these bases' success in mimicking the functionality of natural bases was a bit mysterious. They had been found simply by screening thousands of synthetic nucleotide-like molecules for the ones that were replicated most efficiently. And it had been clear immediately that their chemical structures lack the ability to form the hydrogen bonds that join natural base pairs in DNA. Such bonds had been thought to be an absolute requirement for successful DNA replication‑—a process in which a large enzyme, DNA polymerase, moves along a single, unwrapped DNA strand and stitches together the opposing strand, one complementary base at a time.

An early structural study of a very similar base pair in double-helix DNA added to Romesberg's concerns. The data strongly suggested that NaM and 5SICS do not even approximate the edge-to-edge geometry of natural base pairs—termed the Watson-Crick geometry, after the co-discoverers of the DNA double-helix. Instead, they join in a looser, overlapping, "intercalated" fashion. "Their pairing resembles a ‘mispair,' such as two identical bases together, which normally wouldn't be recognized as a valid base pair by the DNA polymerase," said Denis Malyshev, a graduate student in Romesberg's lab who was lead author along with Karin Betz of Marx's lab.

Yet in test after test, the NaM-5SICS pair was efficiently replicable. "We wondered whether we were somehow tricking the DNA polymerase into recognizing it," said Romesberg. "I didn't want to pursue the development of applications until we had a clearer picture of what was going on during replication."

Edge to Edge

To get that clearer picture, Romesberg and his lab turned to Dwyer's and Marx's laboratories, which have expertise in finding the atomic structures of DNA in complex with DNA polymerase. Their structural data showed plainly that the NaM-5SICS pair maintain an abnormal, intercalated structure within double-helix DNA—but remarkably adopt the normal, edge-to-edge, "Watson-Crick" positioning when gripped by the polymerase during the crucial moments of DNA replication.

"The DNA polymerase apparently induces this unnatural base pair to form a structure that's virtually indistinguishable from that of a natural base pair," said Malyshev.

NaM and 5SICS, lacking hydrogen bonds, are held together in the DNA double-helix by "hydrophobic" forces, which cause certain molecular structures (like those found in oil) to be repelled by water molecules, and thus to cling together in a watery medium. "It's very possible that these hydrophobic forces have characteristics that enable the flexibility and thus the replicability of the NaM-5SICS base pair," said Romesberg. "Certainly if their aberrant structure in the double helix were held together by more rigid covalent bonds, they wouldn't have been able to pop into the correct structure during DNA replication."

An Arbitrary Choice?

The finding suggests that NaM-5SICS and potentially other, hydrophobically bound base pairs could some day be used to extend the DNA alphabet. It also hints that Evolution's choice of the existing four-letter DNA alphabet—on this planet—may have been somewhat arbitrary. "It seems that life could have been based on many other genetic systems," said Romesberg.

He and his laboratory colleagues are now trying to optimize the basic functionality of NaM and 5SICS, and to show that these new bases can work alongside natural bases in the DNA of a living cell.

"If we can get this new base pair to replicate with high efficiency and fidelity in vivo, we'll have a semi-synthetic organism," Romesberg said. "The things that one could do with that are pretty mind blowing."

The other contributors to the paper, "KlenTaq polymerase replicates unnatural base pairs by inducing a Watson-Crick geometry," are Thomas Lavergne of the Romesberg lab, Wolfram Welte and Kay Diederichs of the Marx lab, and Phillip Ordoukhanian of the Center for Protein and Nucleic Acid Research at The Scripps Research Institute.

The study was supported in part by a grant from the National Institutes of Health.

####

About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. Over the past decades, Scripps Research has developed a lengthy track record of major contributions to science and health, including laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. The institute employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, ranks among the top ten of its kind in the nation.

For more information, please click here

Contacts:
Mika Ono
858-784-2052

Copyright © AlphaGalileo

If you have a comment, please Contact us.

Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.

Bookmark:
Delicious Digg Newsvine Google Yahoo Reddit Magnoliacom Furl Facebook

Related News Press

News and information

A new product to help combat mouldy walls, thanks to technology developed at the ICN2 December 14th, 2017

Sandia researchers make solid ground toward better lithium-ion battery interfaces: Reducing the traffic jam in batteries December 13th, 2017

Perking up and crimping the 'bristles' of polyelectrolyte brushes December 13th, 2017

Columbia engineers create artificial graphene in a nanofabricated semiconductor structure: Researchers are the first to observe the electronic structure of graphene in an engineered semiconductor; finding could lead to progress in advanced optoelectronics and data processing December 13th, 2017

Govt.-Legislation/Regulation/Funding/Policy

Sandia researchers make solid ground toward better lithium-ion battery interfaces: Reducing the traffic jam in batteries December 13th, 2017

Perking up and crimping the 'bristles' of polyelectrolyte brushes December 13th, 2017

Columbia engineers create artificial graphene in a nanofabricated semiconductor structure: Researchers are the first to observe the electronic structure of graphene in an engineered semiconductor; finding could lead to progress in advanced optoelectronics and data processing December 13th, 2017

Wheat gets boost from purified nanotubes: Rice University toxicity study shows plant growth enhanced by -- but only by -- purified nanotubes December 6th, 2017

Molecular Machines

Going swimmingly: Biotemplates breakthrough paves way for cheaper nanobots: By using bacterial flagella as a template for silica, researchers have demonstrated an easier way to make propulsion systems for nanoscale swimming robots November 30th, 2017

How to draw electricity from the bloodstream: A one-dimensional fluidic nanogenerator with a high power-conversion efficiency September 11th, 2017

First 3-D observation of nanomachines working inside cells: Researchers headed by IRB Barcelona combine genetic engineering, super-resolution microscopy and biocomputation to allow them to see in 3-D the protein machinery inside living cells January 27th, 2017

Micro-bubbles make big impact: Research team develops new ultrasound-powered actuator to develop micro robot November 25th, 2016

Molecular Nanotechnology

Going swimmingly: Biotemplates breakthrough paves way for cheaper nanobots: By using bacterial flagella as a template for silica, researchers have demonstrated an easier way to make propulsion systems for nanoscale swimming robots November 30th, 2017

Spinning strands hint at folding dynamics: Rice University lab uses magnetic beads to model microscopic proteins, polymers October 17th, 2017

Assembly of nanoparticles proceeds like a zipper: Viruses and nanoparticles can be assembled into processable superlattice wires according to scientists from Aalto University Finland September 25th, 2017

First 3-D observation of nanomachines working inside cells: Researchers headed by IRB Barcelona combine genetic engineering, super-resolution microscopy and biocomputation to allow them to see in 3-D the protein machinery inside living cells January 27th, 2017

Nanomedicine

Perking up and crimping the 'bristles' of polyelectrolyte brushes December 13th, 2017

Leti to Demo Wristband with Embedded Sensors to Diagnose Sleep Apnea: APNEAband, Which Will Be Demonstrated at CES 2018, Also Monitors Mountain Sickness, Dehydration, Dialysis Treatment Response and Epileptic Seizures December 12th, 2017

Untangling DNA: Researchers filter the entropy out of nanopore measurements December 8th, 2017

Arrowhead Presents New Clinical Data Demonstrating a Sustained Host Response in Hepatitis B Patients Following RNAi Therapy — Up to 5.0 log10 reduction in HBsAg observed; data presented at HEP DART 2017 — December 6th, 2017

Discoveries

Sandia researchers make solid ground toward better lithium-ion battery interfaces: Reducing the traffic jam in batteries December 13th, 2017

Perking up and crimping the 'bristles' of polyelectrolyte brushes December 13th, 2017

Columbia engineers create artificial graphene in a nanofabricated semiconductor structure: Researchers are the first to observe the electronic structure of graphene in an engineered semiconductor; finding could lead to progress in advanced optoelectronics and data processing December 13th, 2017

Untangling DNA: Researchers filter the entropy out of nanopore measurements December 8th, 2017

Announcements

A new product to help combat mouldy walls, thanks to technology developed at the ICN2 December 14th, 2017

Sandia researchers make solid ground toward better lithium-ion battery interfaces: Reducing the traffic jam in batteries December 13th, 2017

Perking up and crimping the 'bristles' of polyelectrolyte brushes December 13th, 2017

Columbia engineers create artificial graphene in a nanofabricated semiconductor structure: Researchers are the first to observe the electronic structure of graphene in an engineered semiconductor; finding could lead to progress in advanced optoelectronics and data processing December 13th, 2017

Nanobiotechnology

Perking up and crimping the 'bristles' of polyelectrolyte brushes December 13th, 2017

Arrowhead Presents New Clinical Data Demonstrating a Sustained Host Response in Hepatitis B Patients Following RNAi Therapy — Up to 5.0 log10 reduction in HBsAg observed; data presented at HEP DART 2017 — December 6th, 2017

Going swimmingly: Biotemplates breakthrough paves way for cheaper nanobots: By using bacterial flagella as a template for silica, researchers have demonstrated an easier way to make propulsion systems for nanoscale swimming robots November 30th, 2017

Drug-delivering nanoparticles seek and destroy elusive cancer stem cells November 28th, 2017

NanoNews-Digest
The latest news from around the world, FREE



  Premium Products
NanoNews-Custom
Only the news you want to read!
 Learn More
NanoTech-Transfer
University Technology Transfer & Patents
 Learn More
NanoStrategies
Full-service, expert consulting
 Learn More











ASP
Nanotechnology Now Featured Books




NNN

The Hunger Project