In a pioneering research project, for the first time, scientists at IBM and the University of Aberdeen have collaborated to "see" the structure of a marine compound from the deepest place on the Earth using an atomic force microscope (AFM). The results of the project open up new possibilities in biological research which could lead to the faster development of new medicines in the future.
Last year, scientists from the University's Marine Biodiscovery Centre began work on a species of bacterium from a mud sample* taken from the Mariana Trench - the deepest place on Earth located 10,916 meters (35,814 feet) beneath the Pacific Ocean. This pressure-tolerant bacterium – called Dermacoccus abyssi - produced a chemical compound which could not be recognized.
Using a technique called noncontact atomic force microscopy (AFM), scientists from IBM Research were able to image individual molecules with atomic resolution within one week. These images together with density functional theory calculations confirmed the identification as cephalandole A, which is actually known and originally isolated from a Taiwanese orchid.
"Sourcing unique chemical compounds from some of the Earth's most extreme regions and identifying the structure of these compounds can be an extremely time-consuming process," said Leo Gross, scientist, IBM Research - Zurich. "This technique demonstrates that scanning probe microscopes can add powerful functionality and speed in identifying the structure of molecules which are challenging to resolve with conventional techniques."
The experiment was the first successful use of an AFM in the determination of, what was at the time, an unknown molecular structure.
"The Earth's natural environment is rich with a diverse range of unique organisms from which a vast array of chemical compounds can be sourced, many of which are entirely unknown to science," said Professor Marcel Jaspars, Director of the Marine Biodiscovery Centre at the University of Aberdeen. "These compounds have the potential to be used in the development of pharmaceuticals and other novel biomedical products. But in order to harness this potential we must first understand these compounds in terms of their molecular structure in order to determine whether they are viable for use in medicine."
For hundreds of years scientists have understood that a wide-range of unique resources – in the form of chemical compounds - exist in the natural environment, such as in oceans and deserts, which have the potential to be used in the development of new medicines.
Motivated by this insight, scientists at the Marine Biodiscovery Centre at the University of Aberdeen are focusing, in particular, on harnessing the potential of marine organisms as a source for the discovery of chemical compounds, which could be used to develop new treatments for cancer, inflammation, infection, and parasitic diseases.
Using high-resolution mass spectrometry, scientists at the University of Aberdeen quickly identified the chemical composition of the compound, but determining its exact molecular structure was more challenging. Even the use of state-of-the-art nuclear magnetic resonance techniques would not allow them to determine the exact structure due to the small number of protons and the positioning of certain atoms in the compound.
The scientists were left with four potential structures, none of which could be ruled out by the nuclear magnetic resonance data alone. The only remaining possibility to find the correct structure would be to take a chemical synthesis of the proposed structures, which is a very complex task that can take several months.
"Determining the structure of an unknown compound is a time-consuming process which could take months, therefore the ability to immediately 'see' the structure of a chemical compound simply by looking through a microscope is a tremendous feat," said Professor Jaspars, "This new approach could lead to much faster identification of unknown compounds and ultimately speed up the process of the development of new medicines."
Novel Biomedicines from the Deep
Nature offers a huge variety of small molecules and compounds with potential pharmaceutical applications. Such natural products are the cornerstone of drug discovery as they exhibit novel chemical structures and potent biological properties. Studies of the National Cancer Institute in the U.S. have shown that the marine environment--and in particular also remote and largely untouched areas--is a significant source for novel, unstudied biologically active compounds.
Structure determination of organic molecules is normally achieved using spectroscopic techniques such as mass spectrometry, which defines the molecular formula, and nuclear magnetic resonance (NMR) spectroscopy which is the molecular cousin of MRI (magnetic resonance imaging). Each carbon and hydrogen atom in a molecule has a defined frequency in the NMR spectrum. Using sophisticated variants of this technique, one can determine how hydrogen and carbon atoms are connected together, thus mapping out the molecular structure. However, when there are few hydrogen atoms in the molecule, as occurred in this case, these techniques fail to come up with a unique solution, meaning that other methods are needed to solve the problem.
Imaging the "anatomy" of a molecule
The AFM uses a sharp tip attached to a small spring to measure the tiny forces between the tip and the sample, such as a molecule, to create an image. To image the chemical structure of a molecule with an AFM, it is necessary to operate in very close proximity to the molecule -- the range, where chemical interactions give significant contributions to the forces, is less than a nanometer. To achieve this, IBM scientists increased the sensitivity of the tip by deliberately picking up a carbon monoxide (CO) molecule. When close enough to the sample, the CO-terminated tip is able to sense tiny repulsive forces. In this way, the CO-terminated tip resolves the individual atoms within the investigated molecule, revealing its atomic-scale chemical structure.
IBM and nanotechnology
Scientists have been striving to "see" and manipulate atoms and molecules to extend human knowledge and push the frontiers of manufacturing capabilities to the nanometer regime. IBM has been a pioneer in nanoscience and nanotechnology ever since the development of the scanning tunneling microscope in 1981 by IBM Fellows Gerd Binnig and Heinrich Rohrer at IBM Research – Zurich. For this invention, which made it possible to image individual atoms, Binnig and Rohrer were awarded the Nobel Prize in Physics in 1986. The AFM, an offspring of the STM, was invented by Binnig in 1986. The STM is widely regarded as the instrument that opened the door to the nanoworld. A new facility for world-class collaborative nanoscale research will open in 2011 on the campus of IBM Research – Zurich. The new nanotech center is part of a strategic partnership in nanotechnology with ETH Zurich, one of Europe's premier technical universities.
The scientific paper entitled "Organic structure determination using atomic-resolution scanning probe microscopy" by L. Gross, F. Mohn, N. Moll, G. Meyer, R. Ebel, W. M. Abdel-Mageed and M. Jaspars, appeared online in Nature Chemistry, DOI: 10.1038/NCHEM.765 (1 August 2010).
* The original samples came from Prof. Koki Horikoshi at JAMSTEC in Japan - using the deep submersible, Kaiko.