Multidisciplinary Efforts Leverage Computation in Biological Discovery to Enable New Treatments from Cellular Engineering
Multidisciplinary teams of biologists and engineers at the National Science Foundation (NSF)-sponsored Engineering Research Center (ERC) for Cell Manufacturing Technologies (CMaT), headquartered at the Georgia Institute of Technology, have introduced a new application of computer science and engineering in cell biology that enables scientists to re-engineer the functional applications of specific cells. The Center’s findings on computation-facilitated cell biology have been highlighted in Naturemagazine.
New cell therapies, such as CAR T-cell therapy, can identify and attack antigens with common traits on a healthy cell, effectively enabling patients to leverage their own healthy immune systems to heal from illnesses as serious as cancer. With computation-facilitated cell biology, researchers can dramatically address key barriers to the manufacture of these living cell therapies. Studies that examine, copy or combine DNA transcription data, can create complex data sets of between 20,000–30,000 variables, spanning thousands of individual cells. The capabilities emerging from these methods include more targeted genetic editing of DNA via CRISPR-Cas9 technology and the use of viruses and proteins in therapeutic cell treatments. Given the data complexity, computer modelling and machine learning can also be employed to better manage and direct future applications, fostering insights that span cell biology, molecular biology, healthcare bioinformatics, chemical engineering, industrial engineering, and data science.
Treatments such as Car T-cell therapy are known as “living drugs” or “living cell” therapies, as they are derived directly from the patient’s own blood. T-cells extracted and separated from the patient’s blood are genetically altered to carry synthetic molecules known as chimeric antigen receptors (CARs) that are capable of attaching to proteins, tumors, or other antigens to enable treatment. In the case of OR-gate CAR T-cell therapy, Boolean operators are written into the altered cells, allowing the modified T-cells to recognize and attach to one or another antigen in killing cancer.
Other logical functions borrowed from computational models – such as AND logic and NOT logic—enable advanced functionality of genetically engineered cells used in living therapies. With these methods, researchers can develop therapies that respond more directly to a patient’s unique cellular needs. Other examples of computation-facilitated cell therapies include the creation of ‘smart cells’ capable of in-body monitoring for disease or malfunction; stem cell conversion treatments that leverage CRISPR to change factors either individually or in combination; and the use of large data sets to manipulate DNA factors for the purposes of better understanding genetic behavior.
While early work focuses on regenerative medicine and cell therapy applications, researchers remain cautious as they look to gain greater understanding of how cell editing affects cell behavior over time. As CMaT Director, Krishnendu Roy, remarks, “For the first time probably in human history, we are trying to do industrial-scale manufacturing of a living product.”
As new fields evolve through cellular engineering advances, ethics and policy issues will remain at the forefront. And, says Roy, “the whole paradigm of manufacturing needs to change.” Because living cells are highly dependent on their environmental conditions, CMaT argues that work needs to proceed in a multidisciplinary, cross-functional manner. “We have a very sensitive product that changes with slight manipulation. Whether those changes are important or not important is something we still need to figure out,” says Roy.
