Stanford Bioengineers Manipulated Molecules to Create Proteins That Fight Off Cancer and Recreate Neurons

In a new study, a team of researchers led by Stanford bioengineer and department chair Jennifer Cochran adjusted a single molecule in slightly different ways to produce two amazing yet varying results. One set of modifications caused neuronal cells to regenerate, while various tweaks to the same protein restricted lung tumor growth.

The experiments were conducted on rats, human cells, or mice cells that act as models for actual disease processes. Although the researchers say that it would take a while before tests could be conducted on humans, encouraging results from animal studies show potential for human trials. Furthermore, it shows how scientists are increasingly becoming capable of manipulating the body's protein-based control systems to aid vital organs in healing themselves.

Cochran is hopeful that engineered ligands and receptors will continue in proving that the promising class of drugs can combat diseases and maintain health. The full findings of the study were published in the journal Proceedings of the National Academy of Sciences.

What are Ligands?

Cells are what compose major body organs. Protein messengers known as ligands bind to receptors on the surfaces of cells to manage biological processes and keep the body healthy. When those messages get mixed up, it can make the body ill with a variety of diseases.

Cochran's lab analyzes how ligands and receptors work together to deliver messages to cells. Moreover, they study how these interactions can be engineered to create potent therapeutic agents.

Shape is the vital concept, Cochran says. Just like all proteins, ligands and receptors are made up of many different amino acids strung together and folded into definite three-dimensional shapes. A ligand possessing the right form fits its matching receptor similar to how a key fits a lock.

Researchers are hopeful that one day, the proteins could be used in treating cancers, neurodegenerative conditions, and other diseases such as atherosclerosis and osteoporosis.

Bioengineering Proteins for Cancer Treatment

By using complex molecular engineering approaches, the researchers are able to alter the lineup of amino acids in a ligand. This process allows them to make millions of keys which they can screen to determine which might unlock its matching receptor.

Furthermore, bioengineering can also be used to convert ligands into antagonists. These antagonists also fit the receptor lock, but somehow blocks the signal and therefore might hinder a function like cell growth.

In a collaboration last year with the University of California - San Francisco cancer researcher Alejandro Sweet-Cordero, Cochran published a paper demonstrating how an altered version of the receptor protein CNTFR, helped stop lung tumor growth in rodents.

The new experiments bank on that work as a research team led by graduate student Jun Kim engineered the ligand known as CLCF1. Moreover, the altered ligand was made to bind with the CNTFR receptor. By making a single set of amino acid adjustments in CLCF1, Kim made that ligand into a superagonist.

When the team added the new superagonist to a tissue culture of damaged neuronal cells, the engineered CLCF1 increased the messaging signals that promote the growth of axons. The results suggest that the engineered ligand was promoting wounded neurons to reconstruct themselves.

Reciprocally, Jun Kim and his team showed that, by introducing a few additional amino acid alterations to CLCF1, the ligand could be turned into a potent antagonist that could inhibit the growth of lung tumors in mice. This mechanism then suggests a different possible medicinal use for this variation of the molecule.