It’s a familiar story, told in elementary school science lessons.  In 1867, Alfred Nobel patented Dynamite–a ground-breaking technology if there ever was one–which exploded into uses in rock quarries, road projects and the on the battlefield.  The wealth yielded by the sale of dynamite allowed the famous Swede to finance the Prize, which today was awarded for the beautiful research that led to 3-D structural models of the ribosome.

It could be argued that the word “fundamental” could be applied to any number of molecular machines that are essential to the livelihood of practically every cell in our bodies.  But ribosomes are in the very middle of the dogmatic process of turning genes to proteins, and they are extremely well-conserved throughout evolution.  And, as I’ve written before, these revealing biological discoveries will be protected by patents for years.

The New York Times news update described ribosomes this way:

If the sequence of lettered nucleic acids in the DNA form the blueprint for life, ribosomes are the factory floor.

It was a kind of reverse-engineering of this “factory floor” that constitutes the Nobel-winning work.  The laureates first had to crystallize various parts of ribosomes, an extremely complicated task given the size and complexity of these molecular complexes.  These crystals were analyzed with a very sensitive X-ray device, yielding information that, when reconstructed by a computer, can be modeled into a three-dimensional diagram of the molecular structures.

Other than being extremely beautiful, these structures are vital for determining how ribosomes interact physically with other molecules.  These other molecules include ones that  ribosomes would normally commingle with in the cells, like RNA.  More usefully, perhaps, this information can be used to design small, artificial molecules–drugs–that could bind to a part of the ribosome to alter its function in some way, or perhaps to disrupt it completely.

Tetracycline, designed and manufactured by bacteria. (Wikimedia)

A particular bacteria, Streptomyces, has been doing this kind of “drug-design” work for a very, very long time.  Streptomyces evolved various small molecules that bind to ribosomes and disrupt their function. These natural, bacterial molecules–tetracycline, neomycin and others–are now found in pills and over-the counter ointments.  As antibiotics, they kill other cells by attaching to and rendering their ribosomes useless.

Using the Nobel-winning structures to design the types of molecules that these bacteria have long been producing is a practice now protected by a number of patents.  Some of these patents, held by Yale in the name of the prize-winner Thomas Steitz and others, cover not only the process for determining the structure of the molecules, but also the computation used to design new antibiotics.  The Yale patents are currently licensed to Rib-X pharmaceuticals, a Yale-spinoff biotech company based in the New Haven area.

As always, there is an argument that intellectual property must be fully patent-protected before major investments can be made towards developing commercial products.  The patent holders and licensees surely believe that these products will be life-saving, and profitable, and I hate to rain on the Nobel Prize parade.  But should research so fundamental to life, such as the ribosome structure, be locked up for commercial gain–like Dynamite?  Should a private institution, such as Yale, have the only say over how ribosomes may be developed into new biomedical technologies?

Update, October 7, 2009: The description of ribosome structure, including the work protected by these patents, was awarded the 2009 Nobel Prize in Chemistry, announced today.  A new post discusses the implications.

Patent 7,504,486 : Determination and uses of the atomic structures of the large ribosomal subunit and ribosomal subunits and their ligand complexes. Granted March 17, 2009. full text from USPTO.

This is the most recent from a set of similar Yale patents, most importantly: Patent 6,638,908: Crystals of the large ribosomal subunit. Granted October 28, 2003. full text from USPTO.

Inventors:  Thomas A. Steitz (Yale faculty), Peter B. Moore (Yale faculty), et al.

Background

Ribosomes translate messenger RNA into protein.  To accomplish this most basic biological task, at the very center of the “central dogma” of biology, requires a large molecular machine composed of both protein and RNA pieces.  The genes coding for these components are among the most evolutionarily conserved (i.e. sharing similar sequences), indicating the ribosome’s essential and highly optimized function.  Because of the absolute biological requirement of synthesizing proteins, the ribosome is an attractive target for antibiotics.  Designing drugs that inhibit the ribosomes of human pathogens efficiently and specifically is a major goal of ribosome biology.

Our modern understanding of molecular mechanism in the cell comes from x-ray crystallography.  This technique relies on x-rays, directed through highly-pure crystals of the molecule to be examined.  Based on the structure of the molecular components of the crystal, the x-rays are diffracted into a complex pattern.  This pattern may be deconvolved–computationally reconstructed–into a three-dimensional model of the molecule-of-interest, at atomic-scale resolution.

Acquiring these fascinating 3D molecular models is complicated by a number of factors, particularly the difficulty of procuring a sufficiently large, pure sample of the subject molecule.  This protein, nucleic acid, etc. must then self-assemble into a highly ordered crystal–a requirement for high-resolution crystallography.  RNA, a major component of the ribosome, is notoriously tricky to crystallize and diffract, and the crystallization of the large ribosomal subunit in 2000 (by Steitz and colleagues at Yale) represented a huge breakthrough in our understanding of not only the ribosome, but of the structure of RNA molecules generally–that is, how they interact physically with themselves and other molecules.

Patent implications

A key patent on the work of Steitz, et al., 6,638,908, claims the crystallization of the large ribosomal subunit, from any organism, with attached ligands (drugs), to a resolution of 5 angstroms.  Other patents (7,504,486, 6,952,650, 6,947,845, 6,947,844, 6,939,848, 6,631,329) deal with other details of crystallization and methods for identifying “modulators of ribosome function” and protein synthesis, such as antibiotic drugs.

These patents have been licensed by Yale to Rib-X pharmaceuticals, co-founded by Dr. Steitz and Dr. Moore and based in greater New Haven.

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