Making Sure Cells Don't Get the Short End of the Stick

The cell is the foundation of life. It makes up tissues, which make up organs, which make up organisms. Pulitzer Prize-winning novelist and physician Siddhartha Mukherjee, MD, who has written entire books about genes, cancer and the laws of medicine, thought the cell should get one, too. His book The Song of the Cell is an ode to cells and all of their wonders.

"Without the cell to enliven genetics, without the cell to create ourselves, we would be nothing. There would be nothing," contended Mukherjee told Cure. "It is the single least autonomous unit of life, and every other unit of life is made out of cells."

A Symphony of Cells

Mukherjee likens cells to music. A musical score is made of the same notes, but it can sound different depending on who is playing it.

"The cell is incredibly diverse. A neuron looks nothing like a blood cell. A blood cell looks nothing like a skin cell, which looks nothing like a muscle cell," he explained. "And yet they're all playing out the genome, just as you play out a musical score."

His book is a series of linked short stories with cells as the central players. "Once the cell was discovered, a thousand flowers bloomed," he said. "There were neuroscientists who started looking at neurons. There were muscle scientists who started looking at muscles. There were cancer biologists who started looking at cancer cells, and so forth."

The Advent of Cellular Therapies

In recent years, scientists have created cellular therapies for cancer (primarily blood cancers). Examples include CAR T-cell therapies, in which some of a patient's own T cells are removed, modified to recognize a protein on their cancer cells, multiplied to much larger numbers and returned to the patient to fight cancer cells. This treatment has been hailed as a "living therapy" because the modified T cells continue to detect and destroy cancer cells long after the treatment has been given.

CAR T-cell therapies have cured many patients of cancer — from a girl with acute lymphocytic leukemia (ALL) treated at age 7 who is now applying to college, to a 70 percent cure rate for patients in India treated with CAR T-cell therapies from one of Mukherjee's companies. Multiple FDA-approved CAR T-cell products are available to treat people with ALL, non-Hodgkin lymphoma and multiple myeloma, and others are under investigation for acute myeloid leukemia (AML) and solid tumors.

Mukherjee's company Vor is at the forefront of cellular innovation with the development of therapies for AML designed to have fewer side effects than conventional treatments. They work by altering cells donated by a healthy donor which, when given to the patient, grow into healthy blood cells that are resistant to anti-cancer drugs. The patient's AML cells remain vulnerable to gemtuzumab ozogamicin (Mylotarg™), a standard treatment, leaving the altered healthy cells unscathed during therapy.

Mukherjee said his idea for the treatment came when drawing inverted designs while on vacation with his children.

"I thought, what if we turn this whole thing around and change the biology of normal cells so that they become resistant to a drug, and the cancer cells would be sensitive to the drug? That is now possible with gene editing tools such as CRISPR," he explained. These therapies are being evaluated in early-stage clinical trials.

Storytelling in Science

Writing narratives is a natural part of being a scientist for Mukherjee. Science is an act of storytelling, he maintained, and he encourages scientists to practice explaining their work to people outside of their field.

"The idea is that we tell each other's stories constantly. By trading stories, we're trading narratives," he said. "There's so much jargon in science that we sometimes forget there's a through line and a plot."

Getting to a Cure

When asked how we ultimately achieve cures, Mukherjee believes that "prevention is the cure." In the meantime, we are seeing progress. Diseases like ALL that were once incurable are now curable. Some lung cancer variants are now curable. Breast cancer mortality is down and women with metastatic breast cancer are living longer. Ditto for people with multiple myeloma, whose remissions are lasting longer.

Other cancers, however, such as pancreatic cancer and brain tumors, remain a conundrum. Enhancing our understanding of cells is pivotal to making progress against the most challenging diseases.

"Our understanding of the components of the cell — the cytoskeleton, nucleus, mitochondria, lysosomes and so forth — is increasing day by day. A cell and an organism cannot be explained by the sum of their parts. Just as a car cannot be explained by adding a carburetor to a mechanical engine, you need to assemble these parts in ways that we still don't understand and may not understand for a while," Mukherjee concluded. "I don't think we're anywhere close to a bottom-up understanding or a top-down understanding of cells, but the enrichment of both of these arenas will bring us closer to a real understanding of physiology."