One protein engineered by scientist to fight cancer and regenerate neurons.

June 10, 2020
Engineered Protein cell

A team led by Stanford bioengineer and department chair Jennifer Cochran has tweaked one protein messenger in slightly different ways to produce two startlingly different results.

One way our bodies keep us in good health is by using protein messengers which are also known as ligands that bind to receptors on the surfaces of cells to regulate our biological processes. If those messages get scrambled, it can make us ill with a host of different diseases.

Recently, a team led by Jennifer Cochran, who is a stanford bioengineer and department chair has made some changes to one ligand in slightly different ways to bring about two surprisingly different results. One set of alterations caused neuronal cells to regenerate, while different changes to the same protein constrained lung tumor growth.

The experiments the team of scientists explained in the Proceedings of the National Academy of Sciences were performed on both rat and human cells. However, the results shows how scientists are becoming increasingly proficient at tinkering with the body's protein-based control mechanisms to assist vital organs in healing themselves.

"These proteins can hopefully one day be used to treat neurodegenerative disease, as well as cancers and other disorders such as osteoporosis and atherosclerosis," Jennifer Cochran said.

In her lab, they studied how ligands and receptors work together to deliver messages to cells, and how these interactions can be engineered to create formidable therapeutic agents. Shape is actually the critical concept. Like all proteins, ligands and receptors are composed of many different amino acids linked together like pearls and folded into distinct three-dimensional shapes. A ligand with the propper shape fits its matching receptor just like the way a key fits a lock.

With the use of complex molecular engineering techniques, the scientists can change the lineup of amino acids in a ligand, basically making millions of keys that they then screen to know which might unlock its matching receptor in some pleasing way. A key that fits better and trips the lock more efficiently (scientists call this a superagonist) might broadcast messages directing cells to grow more robustly. Bioengineering can also be used to turn ligands into antagonists, keys that also fit the receptor lock, but in a way that blocks the signal and thus might retard a function like cell growth.

In 2019, Jennifer Cochran partnered with Alejandro Sweet-Cordero, a UC San Francisco cancer researcher, to publish a paper that shows how an engineered version of the receptor protein CNTFR, helped in the stop of lung tumor growth in rodents.

The new experiments build on that work as a research team led by Jun Kim, a graduate student, engineered the ligand known as CLCF1 which basically binds with the CNTFR receptor. By making one set of amino acid alterations in CLCF1, Kim transformed that ligand into a superagonist. When they added this superagonist to a tissue culture of injured neuronal cells, the engineered CLCF1 increased the messaging signals that promote the growth of axons, the fibers that transmit nerve impulses, suggesting that this modified ligand was encouraging wounded neurons to regenerate themselves.

Contrarily, Jun Kim and his fellow researchers brought to light that, by introducing a few additional amino acid alterations to CLCF1, they could turn the ligand into a potent antagonist that could suppress the growth of lung tumors in mice, suggesting a different possible medicinal use for this variant of the molecule.

Jennifer Cochran has spent her career developing novel engineered proteins as therapeutic candidates for oncology and regenerative medicine applications. Variety of the molecules discovered in her lab have moved forward into early through late stage pre-clinical development, with her most advanced therapeutic, a treatment for ovarian and kidney cancer, now in human trials. She is optimistic that engineered ligands and receptors will continue to prove to be a promising class of drugs to fight illness and maintain health.

"I have long been fascinated with how proteins function as nature's molecular machines, and how the tools of engineering allow us to shape protein structure and function with the creativity of an artist, in this case using amino acids as our palette."


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