Source: The Conversation – Canada – By Suiyang Liao, Postdoctoral researcher in Nanomedicine, University of British Columbia
Canadians swallow millions of pills every day to treat common health issues like high blood pressure, high cholesterol and Type II diabetes, but scientists are working at the molecular level to turn patients’ cells into pharmacies.
Nanotechnology, where atoms and molecules are manipulated on a tiny scale — a billion times smaller than a metre — is already incorporated into everyday products like sunscreen, waterproof clothing and smartphones.
In nanomedicine, it’s being used to prompt RNA to make protein-based drugs to treat diseases. Now we can fine-tune protein production by dialling it up or down, creating personalized medicine on an invisible scale.
Protein production and health
The human body is a precision instrument, and its smooth operation relies on the balance of proteins like keratin, which creates structure for your hair and nails, and collagen, which gives your skin its strength and elasticity.
Factor VIII is a clotting protein that acts like molecular glue at wound sites, and if your body doesn’t make enough of it — like people with Hemophilia A — a seemingly small injury can cause dangerous bleeding. Conversely, if you make too much of apolipoprotein C3 (ApoC3), it blocks the breakdown of fats in the blood called triglycerides, and these high lipid levels increase the risk of pancreatitis, heart disease and stroke.
The body maintains this delicate protein balance through an elegant molecular system, one that nanomedicine is now learning to control.
Immunity and Society is a new series from The Conversation Canada that presents new vaccine discoveries and immune-based innovations that are changing how we understand and protect human health. Through a partnership with the Bridge Research Consortium, these articles — written by experts in Canada at the forefront of immunology, biomanufacturing, social science and humanities — explore the latest developments and their impacts.
RNA’s balancing act
How does your body make proteins? Think of your cells as factories, with DNA as the operating manual.
In order to make the proteins it needs, your body’s cells act as factories, with DNA as the operating manual. The blueprints are safely locked away in the nucleus, and cells can’t make anything directly from the precious original.
Instead, when the cell needs a specific protein, it makes a temporary copy of the blueprint, called messenger RNA (mRNA). This single strand of nucleic acids carries the instructions to the cytoplasm, or the factory floor. There, molecular machines called ribosomes read the instructions and build amino acids into a protein.
This is the central dogma of molecular biology: DNA → RNA → protein.
When the body needs proteins, it makes mRNA copies and transfers them to the cytoplasm. The factory foreman is a mechanism called RNA interference, which ensures proteins are not over-produced or under-produced.
For example, small interfering RNA (siRNA) or Antisense oligonucleotides (ASO) molecules can stop the production of proteins by silencing genetic instructions from DNA and cutting target mRNA apart. In both cases, the mRNA degrades and protein production stops, like hitting the emergency button on a conveyor belt.
Turning RNA into drugs
What does this mean for future disease treatment? Unlike small-molecule drugs such as antibiotics or protein-based drugs like insulin, RNA drugs work upstream, at the instruction level itself.
As scientists in nanomedicine, we harness cellular machinery to treat diseases with RNA drugs by dialing up or dialing down protein production. Want more of a beneficial protein? Deliver more mRNA. Want less of a harmful one? Use siRNA or ASO to silence the gene.
Teaching cells to make what’s missing
When the human body lacks an essential protein, disease follows. In hemophilia A, the problem lies in the blueprint. A mutation in the DNA means the gene for factor VIII contains errors, like a typo in a recipe that calls for salt instead of sugar. The cell follows this flawed instruction, and makes messenger RNA that produces either a broken protein or none at all.
Without functional factor VIII, a simple nosebleed can last for hours, not minutes and a little bump can lead to a big bruise that takes a long time to heal. Even a minor cut can lead to prolonged bleeding.
Scientists can now synthesize mRNA in the lab — for example, by making a correct, error-free copy of the instructions for factor VIII — and package it in lipid nanoparticles, which are little protective bubbles of fat.
As a materials scientist at UBC working with researchers Anna Blakney and Pieter Cullis, I design formulations of lipid nanoparticles. When these particles are infused intravenously, they deliver the synthetic mRNA to liver cells, which then read the instructions and manufacture fresh factor VIII protein. The cell becomes its own pharmacy.
Silencing the trouble-makers
Over-expression of some proteins can also cause disease, for example, in familial chylomicronemia syndrome where the messenger RNA makes too much apolipoprotein C3.
ApoC3 helps regulate fat metabolism, but too much of it blocks the body’s ability to clear triglycerides from the bloodstream. The instructions from the DNA manual may be correct, but small interfering RNA molecules are not doing their job to keep production in check. Like an out-of-control assembly line, fat accumulates in the blood. If it reaches dangerous levels it can cause acute pancreatitis — a painful and potentially fatal inflammation of the pancreas.
The U.S. Food and Drug Administration and Health Canada recently approved Plozasiran, an injectable drug that treats familial chylomicronemia syndrome by delivering small interfering RNA to liver cells.
This siRNA molecule is a short double strand of nucleic acids to be unzipped as two single strands, one of which complements ApoC3 mRNA, like a key fitting a lock. The binding event will be recognized by the cellular machinery to cut the mRNA apart. No mRNA means no protein production.
The same technology offers different levers: mRNA amplifies production of beneficial proteins like factor VIII; siRNA silences production of harmful proteins like ApoC3. Together, they represent medicine’s new ability to program biology, turning genes up or down as precisely as adjusting the volume on a stereo.
Suiyang Liao is affiliated with the University of British Columbia.
– ref. How nanomedicine gets inside your cells and treats you from the inside out – https://theconversation.com/how-nanomedicine-gets-inside-your-cells-and-treats-you-from-the-inside-out-270414