Here are just a few examples of our successes - see more at 4A Insights!

Unlocked an unexpected mode of molecular interaction in cancer that introduced an entirely new biotherapeutic modality for targeting the Wnt signaling pathway and catalyzed biotherapeutic efforts targeting Smoothened, a key membrane protein involved in oncogenesis. Read more here.


Developed a new approach to accelerate the functional characterization of disease-associated secreted proteins to reveal novel therapeutic targets as well as new insights in biology.
The strategy maps the evolutionarily conserved core of the human secretome (with an emphasis on gene associated with human disease) to orthologous genes with critically preserved functions in model organisms tractable to in vivo validation. Proof of principle for this approach was obtained with an intriguing cancer-associated protein, Jumping Translocation Breakpoint (JTB), which is preserved along the phylogenetic spectrum to plants, fungi and slime molds. JTB is of clinical interest because its structure suggests an intriguing relationship to a class of novel morphogens, associated with receptors that are active drug targets in cancer.


Discovered and christened the family of Toll-like receptors (TLRs) as reported in a highly cited 1998 publication in PNAS, and correctly predicted the structure of their binding ectodomains and signaling intracellular modules.  



© 4th & Aspen Life Sciences Consulting LLC 2013


Strong background in novel cytokine/receptor discovery and characterization.

Early work defined the structural nature of interacting cytokine and receptor families, and proposed a family classification scheme that has stood the test of time. As early as 1992, Dr. Bazan made the controversial prediction that the published crystal structure of interleukin-2 was seriously flawed, and instead was better defined by a model structure based on the deduced cytokine family fold. The resulting Science paper drove the reconsideration of the IL-2 X-ray data and showed that the model was correct.  

Subsequent achievements in the field included the highly-cited discoveries of IL-23, IL-27 and TSLP cytokines (and their respective signaling receptors) that sparked a number of new biotherapeutic programs, as well as drove the discovery of Th17 and other inflammatory cellular subsets that are now major areas of immunological study and therapeutic interest.

In 2005, Dr. Bazan's team discovered IL-33, the long-sought ligand for ST2 implicated in Th2 immune reactions and cardioprotection. Read more here
 
Most recently, Dr. Bazan led the discovery and structural characterization of the novel cytokine IL-34, and showed that it engages the same receptor as the cytokine CSF-1––in spite of almost complete lack of sequence similarity. 

Other notable cytokine families tackled include chemokines, including the discovery of the most divergent member, the membrane-bound chemokine CX3C/fractalkine, was as published in Nature.

Identified the structure and mechanism of action of a large class of proteases encoded in a large number of viral genomes including picornaviruses and flaviviruses. These enzymes, predicted to bear a trypsin-like fold, contain an unusual substitution of the catalytic serine normally found in trypsin-like enzymes for a cysteine, and have no sequence similarity to known mammalian enzymes. These proteases are now being avidly pursued as drug targets by several pharmaceutical companies.



Discovered the first new class of TIR domain adaptors (that engage TLR and IL-1 receptors) since 2003. These novel adaptors contain unique domains that allow molecular bridging of innate and adaptive immune receptor signaling complexes and have opened up a new perspective on how innate immunity shapes the development and activation of certain immune cells, as characterized in close collaboration with Dr. Chandra Pasare (UT-Southwestern).



Together with Maxence Nachury and Peter Jackson of Stanford University, helped define the molecular players in the key machinery involved in gating and shepherding of receptors and signaling molecules in primary cilia, specialized organelles with important signaling and sensory roles. These molecular machines likely play a role in other contexts as well, such as the function of immune and neural synapses.
The findings have been published in Cell and Developmental Cell.