More great new science at the observable cellular level. As described below, scientists used tools to observe cellular level shapes, and then figured out a way to “staple” some proteins to better take on the needed shape to fit cellular receptors. How cool and important is this discovery? Very – the science is so good it was published in Nature this month. Go here to Science Daily for the broader whole story; excerpts are below.

Why does this relate to law? As these techniques are used to actually implement ways to “turn off” cancer, they will become the remedies sought by persons facing cancer allegedly or actually caused by particular substances.

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ScienceDaily (Nov. 12, 2009) — Scientists have devised an innovative way to disarm a key protein considered to be “undruggable,” meaning that all previous efforts to develop a drug against it have failed. Their discovery, published in the November 12 issue of Nature, lays the foundation for a new kind of therapy aimed directly at a critical human protein — one of a few thousand so-called transcription factors — that could someday be used to treat a variety of diseases, especially multiple types of cancer.

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Based on his work as an oncologist, Bradner became deeply interested in a human protein called NOTCH. The gene encoding this protein is often damaged, or mutated, in patients with a form of blood cancer, known as T-ALL or T-cell acute lymphoblastic leukemia.

Abnormal NOTCH genes found in cancer patients remain in a state of constant activity, switched on all the time, which helps to drive the uncontrolled cell growth that fuels tumors. Similar abnormalities in NOTCH also underlie a variety of other cancers, including lung, ovarian, pancreatic and gastrointestinal cancers.

Even with this deep scientific knowledge, drugs against NOTCH — or any other transcription factor — have traditionally been extremely difficult, if not impossible, to develop. Most current drugs take the form of small chemicals (known as “small molecules”) or larger-sized proteins, both of which have proven impractical to date for disabling transcription factors.

A few years ago, Bradner and his colleagues hatched a different idea about how to tame the runaway NOTCH protein. Looking closely at its structure as well as the structures of its partner proteins, they noticed a key protein-to-protein junction that featured a helical shape.

“We figured if we could generate a set of tiny little helices we might be able to find one that would hit the sweet spot and shut down NOTCH function,” said Bradner.

Creating and testing these helices involved a team of interdisciplinary researchers, including Greg Verdine, Erving Professor of Chemistry at Harvard University and director of the Chemical Biology Initiative at Dana-Farber Cancer Institute, as well as scientists at Brigham and Women’s Hospital and the Broad Institute’s Chemical Biology Program, which is directed by Stuart Schreiber.

Verdine invented a drug discovery technology that uses chemical braces or “staples” to hold the shapes of different protein snippets. Without these braces, the snippets (called “peptides”) would flop around, losing their three-dimensional structure and thus their biological activity. Importantly, cells can readily absorb stapled peptides, which are significantly smaller than proteins. That means the peptides can get to the right locations inside cells to alter gene regulation.”

Wondering what the Daubert case law will look like in a few years as great new science pushes past epidemiology as new machines and techniques make cause and effect more or less directly observable ? Worried about Alzheimer’s perhaps being part of your future and wondering what’s ahead? Wondering why nations need to invest more n fundamental science at national laboratories such as Brookhaven and Argonne ? If any of those topics are in mind, consider reading a short article that reports on a new molecular level discovery made by scientists at the storied Cold Springs Harbor Laboratory using the National Synchrotron Light Source at Brookhaven National Laboratory. For the article online, go to ScienceDaily (Nov. 13, 2009). Key excerpts are below:

“A team of scientists at Cold Spring Harbor Laboratory (CSHL) reports on Thursday their success in solving the molecular structure of a key portion of a cellular receptor implicated in Alzheimer’s, Parkinson’s, and other serious illnesses

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“Without a highly detailed molecular picture of the ATD, however, efforts to rationally design inhibitors cannot proceed. Hence the importance of Furukawa’s achievement: a crystal structure revealed by the powerful light source at Brookhaven National Laboratory, that shows the ATD to have a “clamshell”-like appearance that is important for its function. The results are published in a paper appearing online Thursday ahead of print in The EMBO Journal, the publication of the European Molecular Biology Organization. (emphasis added)

The team obtained structures of the ATD domain with and without zinc binding to it. Zinc is a natural ligand that docks at a spot within the “clamshell” in routine functioning of the NMDA receptor. Of much greater interest is the location and nature of a suspected binding site of a small molecule type that is known to bind the ATD and inhibit the action of the NMDA receptor.

These inhibitor molecules are members of a class of compounds called phenylethanolamines which “have high efficacy and specificity and show some promise as neuroprotective agents without side effects seen in compounds that bind at the extracellular domain of other receptors,” Furukawa explains. Now that his team has solved the structure of the ATD domain of the NR2B subunit, it becomes possible to proceed with rational design of a phenylethanolamine-like compound that can precisely bind the ATD within what Furukawa and colleagues call its “clamshell cleft,” based on the crystal structure they have obtained.”