Ribonucleic acid, a key player in cellular protein production, is used, with increasing success, by biotechnologists bent on preventing and curing diseases.
March 12, 2021 - By Bruce Goldman
The new kid on the infectious-disease vaccine block, a molecule called ribonucleic acid or RNA, is not only revolutionizing the pharmaceutical industry but will also speed advances in treating cancer and genetic diseases, said Melissa Moore, PhD, of Moderna Therapeutics.
Moore, Moderna’s chief scientific officer for platform research, chronicled the creation of the company’s COVID-19 vaccine before a virtual audience of more than 600 during the 41st annual Katharine D. McCormick Distinguished Lecture on March 8.
The lecture, sponsored by Stanford Medicine’s Office of Faculty Development and Diversity, is held annually on International Women’s Day to honor McCormick, a celebrated biologist who on her death in 1967 left a bequest of $5 million (equivalent to $40 million in today’s money) to Stanford University.
“The Katharine D. McCormick Lecture Series not only showcases exceptional biomedical research, it preserves the courage and spirit of a transformative philanthropist and women’s rights activist,” said Lloyd Minor, MD, dean of the Stanford School of Medicine. “I’m delighted that Stanford Medicine hosts this informative and important annual event.”
The event was the first McCormick lecture to be presented virtually. Last year’s was canceled because of the newly burgeoning COVID-19 epidemic, before Zoom became a household utility.
A new way of making medicines
Since the advent of genetic engineering about four decades ago, Moore told her audience, the development of new medicines has expanded from the chemical chiseling of small molecules into medicinally useful shapes to the bulk production of proteins duplicating or closely mimicking those our own cells produce. Proteins are the workhorses in all cells and in the spaces surrounding them.
RNA plays a key intermediate role in protein production. The recipes for proteins — genes — dot the chromosomes ensconced in each cell’s nucleus. Chromosomes consist of DNA, a substance composed of long strings of chemical building blocks. An RNA molecule is a close copy of the DNA sequence representing an individual gene or small group of them. Unlike DNA, that RNA molecule can exit the nucleus and find its way to cellular machinery that reads its chemical sequence and, using this recipe, builds the specified protein.
Biotechnology has harnessed this natural process, generating huge quantities of desired proteins in commercial-scale bioreactors. Such proteins, generally known as biologicals, dominate the pharmaceutical industry, accounting for 10 of the 15 largest-selling drugs worldwide by sales in 2019, Moore said. Commercially available biological drugs run from insulin to monoclonal antibodies to anti-inflammatory substances.
RNA and vaccines
Most vaccines that are routinely injected into our arms contain proteins, or bits of them, derived from microbial pests. Vaccines train the immune system to recognize and get the jump on a viral or bacterial pathogen it has yet to encounter, thereby preventing the bug from gaining a foothold in the body.
But developing protein-based vaccines has been exacting, laborious and time-consuming because each new vaccine requires starting from scratch and plodding through extensive experiments and optimization steps that vary from one vaccine to the next.
Meanwhile, viruses and bacteria evolve very quickly, a result of random mutations that occur during their replication. While most of these mutations are inconsequential or even deleterious to the microbe, now and then they help it become more infectious, evade immune detection or render a formerly effective vaccine useless. Thus is a new strain born.
RNA is like software,” Moore said. “Once you find a way to deliver it, you can just change the sequence.
Scientists have found a workaround: The recipes for all these proteinaceous vaccine components — no matter how much they might vary in their composition, chemistry and function — are made of a single substance: RNA. If you can just get an RNA molecule directing production of a chosen protein into a cell, the cell will do the rest of the work.
“RNA is like software,” Moore said. “Once you find a way to deliver it, you can just change the sequence” to the one coding for any protein you want the body to produce. The delivery vehicle remains essentially unchanged. In theory, it should be possible to make massive numbers of RNA molecules coding for any protein, encase the RNA molecules in the delivery vehicle, and target them to desired tissues for uptake by cells that will generate the proteins.
Moderna, she said, had been working on perfecting just such an RNA delivery vehicle for well over a decade when the coronavirus pandemic began. It took the company less than two months from the day the virus’s sequence was published to formulate a candidate vaccine targeting that virus.
The vaccine contains the RNA recipe for the “spike protein” — a key immune-response-prompting feature of SARS-CoV-2’s viral surface — wrapped in a nanoscale fat globule. The minuscule fat droplet serves three purposes: First, it prevents the RNA — which is inherently unstable and short-lived — from decomposing before its work is done. Second, it keeps the immune system from overreacting with a dangerous inflammatory response to the RNA molecule, which could cause extensive collateral damage to healthy tissues. And third, it attracts the attention of specific immune sentry cells that delight in ingesting small, fat-enclosed nucleic-acid particles (which, these sentry cells surmise, just might be invading bacteria). Activated by the encounter, these immune cells hasten to “describe” the spike protein to other immune cells, which seek out and disable the virus while leaving the body’s uninfected tissues intact.
RNA versus cancer, genetic diseases
A similar approach can be applied to cancer vaccines, Moore said: Identify proteinaceous features exclusive to a patient’s tumor; generate RNA coding for them; and inject the RNA into the patient’s tumor, or into the bloodstream, to arouse an immune response to tumor cells but not to healthy cells. It’s possible to package RNA molecules coding for up to a dozen different proteins in the same nanoscale fat globule, Moore said. A whole battery of proteins can be injected at once.
Likewise, genetic diseases characterized by a missing or defective enzyme, such as cystic fibrosis, may be treatable by injecting RNA coding for that enzyme into lung tissue. Or, delivering RNA coding for blood-vessel growth factor to an oxygen-compromised heart muscle could allow capillaries to permeate the heart, supplying a heart failure patient with much-needed oxygen.
RNA-encasing fat-globule surfaces can be coated with small antibody-like constructs that bind to specific molecules found exclusively on one or another cell type. This makes it possible to direct medicinal RNA to tissues in which those cell types are found, Moore said.
The versatility of RNA-based technology is already speeding up drug development to a red-hot pace. Marching to the fast-moving metronome of RNA-based technology, “Moderna has produced 25 publicly announced medicines in the last five years,” Moore said. There will be more to come.
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