mRNA Vaccines for the Win; But mRNA Therapies…?

Unclear road ahead for biotech behind COVID-19 immunization successes

4 min read
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Moderna, the company behind one of the best-selling COVID-19 vaccines in the world, is trying to prove that its messenger RNA (mRNA) platform is not a one-trick pony.

Earlier this month, the biotech firm announced that an experimental mRNA therapy, called AZD8601, was well tolerated and showed hints of efficacy when injected directly into the hearts of seven people undergoing coronary artery bypass surgery.

It was the first demonstration in Moderna's 11-year history that the company's mRNA molecules could safely produce functional proteins that directly exert a therapeutic effect inside the body.

"The results are very encouraging," says Lior Zangi, a heart regeneration researcher at the Icahn School of Medicine at Mount Sinai in New York whose 2013 paper formed the basis for AZD8601. "This is the right tool for this dreadful disease."

But according to Zangi, mRNA "is not an answer for everything." And in fact, the concept of using mRNA as a drug to treat established disease, rather than as a preventative measure to ward off viral infections, is probably not a viable approach in many disease settings.

In 2015, Moderna planned to move 100 mRNA drug candidates into clinical trials within a decade. Vaccines were hardly mentioned.

When only limited amounts of protein are needed for a short time to heal damaged tissue, mRNA can get the job done—think muscle repair following a heart attack, or neural recovery after a stroke. Genome-editing companies such as Intellia Therapeutics are also turning to mRNA to deliver components of the CRISPR-Cas9 machinery for one-and-done gene therapies in people with inherited DNA defects.

"It's a come-and-go technology," Zangi says.

For most everything else, mRNA technologies—at least in their current form, experts say—are not up to snuff. "There's a reason why [most companies] are only doing vaccines," says Robert Kruse, a physician-scientist and biotech entrepreneur at Harvard Medical School in Boston.

Those arguments run counter to Moderna's long-running narrative as a platform company capable of deploying its mRNA for almost any ailment.

When I first met the company's CEO Stéphane Bancel at his Kendall Square offices, back in April 2015, he laid out a boldly ambitious plan: to move 100 drug candidates into clinical testing within the next 10 years, using mRNA to treat everything from cancer to rare genetic diseases.

"We are developing an OS of mRNA," Bancel told me at the time. "This is a true platform"—but one he intended would fix rather than prevent disease. Vaccines were hardly mentioned in Moderna's earlypress and public presentations.

Fast-forward two-thirds of a decade and Bancel's brash plan has largely fallen through. Faced with the many challenges involved with transforming mRNA technologies into therapeutics, the company opted to pivot to vaccines instead.

Rather than developing mRNA drugs that could replace missing or deficient proteins to treat chronic diseases—as Bancel initially proposed—Moderna is now largely a vaccine maker, with most of its clinical pipeline devoted to prophylactic measures for respiratory and mosquito-borne viruses.

Moderna has now forged ahead with early-stage trials for autoimmunity, enzyme deficiency disorders, and cancer.

Industry insiders have traditionally seen such products as less transformative and lucrative.

And if it wasn't for a global pandemic yielding a megablockbuster vaccine, Moderna might still be struggling to convince investors of its platform's value. It definitely wouldn't be valued at more than $100 billion, the highest of any biotech company founded in recent decades (and far exceeding that of any other drugmaker with only a single marketed product generating revenue).

For companies like Moderna, the COVID-19 response showcased the speed, flexibility, and nimbleness of their mRNA platforms. With vaccines, just a few injections of low-dose mRNA yielded sufficient levels of viral protein to kick the immune system into gear.

To tackle a lifelong health condition, however, any mRNA drug would have to make bucketloads of protein. Yet, the short-lived nature of the molecule, along with its attendant side effects, currently precludes administering repeated doses of mRNA on any schedule capable of having a therapeutic effect.

New startups are in works to address these challenges. And Moderna, while mostly focused on vaccines, has forged ahead with early-stage trials involving a few product candidates for autoimmunity, enzyme deficiency disorders, and cancer.

But it has also quietly abandoned several other therapeutic programs—recently shelving, for example, mRNA-based drug candidates for Fabry's disease (a rare inherited disorder of fat metabolism) and chikungunya virus infections (spread by mosquitoes around the world).

So, there is a lot riding on AZD8601, Moderna's lead therapeutic asset—which is being co-developed with AstraZeneca under an agreement that dates back to 2013.

The mRNA therapy encodes the genetic recipe for making a growth factor, called VEGF-A, which helps promote blood vessel growth and is designed to regenerate damaged muscles in the heart.

Previously, scientists from AstraZeneca and Moderna, along with their academic collaborators, demonstrated that the treatment improved cardiac function following a heart attack in pigs, and that injections into the skin led to localized and temporary production of VEGF-A without severe side effects in people.

Now, a clinical team led by cardiac surgeon Vesa Anttila from Turku University Hospital in Finland has shown that injecting the mRNA directly into the sac surrounding the heart may be beneficial for people undergoing bypass surgery as well.

In the latest trial, seven participants received the active treatment and four got a placebo control. Although the study was likely too small to document statistically significant improvements in outcomes, the researchers did observe hints that AZD8601 improved heart-pumping capacity and reduced signs of heart failure.

Anttila presented the findings on November 15 at the Scientific Sessions annual meeting of the American Heart Association.

According to Zangi, the decision to focus on VEGF-A, rather than using mRNA to spur the production of some other heart regenerative factor, was largely an accident of history. Back when he started working on the project, in the early-2010s, it seemed like a good protein to prove the concept that mRNA-encoded therapeutics had potential.

But since then, Zangi and his colleagues have identified several other proteins that, in mice at least, have far greater heart-healing effects when delivered via mRNA. In fact, Zangi has examined more than two dozen different genes and their encoded proteins as putative agents of heart regeneration. By his estimation, VEGF-A ranks near the bottom of the list in terms of its ability to restore cardiac function.

So, if AZD8601 is showing promise in patients, Zangi says, "one can only imagine what kind of an effect you'll have if you use the right gene."

The Conversation (1)
Mark Milliman06 Dec, 2021
SM

It should be noted that the COVID mRNA therapies are not technically vaccines and are still under EUA in the U.S.. Their efficacy and safety are still unknown since long-term studies have not been completed. The hundreds of thousands of incidents in the VAERS database suggest the opposite.

The Inner Beauty of Basic Electronics

Open Circuits showcases the surprising complexity of passive components

5 min read
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A photo of a high-stability film resistor with the letters "MIS" in yellow.
All photos by Eric Schlaepfer & Windell H. Oskay
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Eric Schlaepfer was trying to fix a broken piece of test equipment when he came across the cause of the problem—a troubled tantalum capacitor. The component had somehow shorted out, and he wanted to know why. So he polished it down for a look inside. He never found the source of the short, but he and his collaborator, Windell H. Oskay, discovered something even better: a breathtaking hidden world inside electronics. What followed were hours and hours of polishing, cleaning, and photography that resulted in Open Circuits: The Inner Beauty of Electronic Components (No Starch Press, 2022), an excerpt of which follows. As the authors write, everything about these components is deliberately designed to meet specific technical needs, but that design leads to “accidental beauty: the emergent aesthetics of things you were never expected to see.”

From a book that spans the wide world of electronics, what we at IEEE Spectrum found surprisingly compelling were the insides of things we don’t spend much time thinking about, passive components. Transistors, LEDs, and other semiconductors may be where the action is, but the simple physics of resistors, capacitors, and inductors have their own sort of splendor.

High-Stability Film Resistor

A photo of a high-stability film resistor with the letters "MIS" in yellow.

All photos by Eric Schlaepfer & Windell H. Oskay

This high-stability film resistor, about 4 millimeters in diameter, is made in much the same way as its inexpensive carbon-film cousin, but with exacting precision. A ceramic rod is coated with a fine layer of resistive film (thin metal, metal oxide, or carbon) and then a perfectly uniform helical groove is machined into the film.

Instead of coating the resistor with an epoxy, it’s hermetically sealed in a lustrous little glass envelope. This makes the resistor more robust, ideal for specialized cases such as precision reference instrumentation, where long-term stability of the resistor is critical. The glass envelope provides better isolation against moisture and other environmental changes than standard coatings like epoxy.

15-Turn Trimmer Potentiometer

A photo of a blue chip
A photo of a blue chip on a circuit board.

It takes 15 rotations of an adjustment screw to move a 15-turn trimmer potentiometer from one end of its resistive range to the other. Circuits that need to be adjusted with fine resolution control use this type of trimmer pot instead of the single-turn variety.

The resistive element in this trimmer is a strip of cermet—a composite of ceramic and metal—silk-screened on a white ceramic substrate. Screen-printed metal links each end of the strip to the connecting wires. It’s a flattened, linear version of the horseshoe-shaped resistive element in single-turn trimmers.

Turning the adjustment screw moves a plastic slider along a track. The wiper is a spring finger, a spring-loaded metal contact, attached to the slider. It makes contact between a metal strip and the selected point on the strip of resistive film.

Ceramic Disc Capacitor

A cutaway of a Ceramic Disc Capacitor
A photo of a Ceramic Disc Capacitor

Capacitors are fundamental electronic components that store energy in the form of static electricity. They’re used in countless ways, including for bulk energy storage, to smooth out electronic signals, and as computer memory cells. The simplest capacitor consists of two parallel metal plates with a gap between them, but capacitors can take many forms so long as there are two conductive surfaces, called electrodes, separated by an insulator.

A ceramic disc capacitor is a low-cost capacitor that is frequently found in appliances and toys. Its insulator is a ceramic disc, and its two parallel plates are extremely thin metal coatings that are evaporated or sputtered onto the disc’s outer surfaces. Connecting wires are attached using solder, and the whole assembly is dipped into a porous coating material that dries hard and protects the capacitor from damage.

Film Capacitor

An image of a cut away of a capacitor
A photo of a green capacitor.

Film capacitors are frequently found in high-quality audio equipment, such as headphone amplifiers, record players, graphic equalizers, and radio tuners. Their key feature is that the dielectric material is a plastic film, such as polyester or polypropylene.

The metal electrodes of this film capacitor are vacuum-deposited on the surfaces of long strips of plastic film. After the leads are attached, the films are rolled up and dipped into an epoxy that binds the assembly together. Then the completed assembly is dipped in a tough outer coating and marked with its value.

Other types of film capacitors are made by stacking flat layers of metallized plastic film, rather than rolling up layers of film.

Dipped Tantalum Capacitor

A photo of a cutaway of a Dipped Tantalum Capacitor

At the core of this capacitor is a porous pellet of tantalum metal. The pellet is made from tantalum powder and sintered, or compressed at a high temperature, into a dense, spongelike solid.

Just like a kitchen sponge, the resulting pellet has a high surface area per unit volume. The pellet is then anodized, creating an insulating oxide layer with an equally high surface area. This process packs a lot of capacitance into a compact device, using spongelike geometry rather than the stacked or rolled layers that most other capacitors use.

The device’s positive terminal, or anode, is connected directly to the tantalum metal. The negative terminal, or cathode, is formed by a thin layer of conductive manganese dioxide coating the pellet.

Axial Inductor

An image of a cutaway of a Axial Inductor
A photo of a collection of cut wires

Inductors are fundamental electronic components that store energy in the form of a magnetic field. They’re used, for example, in some types of power supplies to convert between voltages by alternately storing and releasing energy. This energy-efficient design helps maximize the battery life of cellphones and other portable electronics.

Inductors typically consist of a coil of insulated wire wrapped around a core of magnetic material like iron or ferrite, a ceramic filled with iron oxide. Current flowing around the core produces a magnetic field that acts as a sort of flywheel for current, smoothing out changes in the current as it flows through the inductor.

This axial inductor has a number of turns of varnished copper wire wrapped around a ferrite form and soldered to copper leads on its two ends. It has several layers of protection: a clear varnish over the windings, a light-green coating around the solder joints, and a striking green outer coating to protect the whole component and provide a surface for the colorful stripes that indicate its inductance value.

Power Supply Transformer

A photo of a collection of cut wires
A photo of a yellow element on a circuit board.

This transformer has multiple sets of windings and is used in a power supply to create multiple output AC voltages from a single AC input such as a wall outlet.

The small wires nearer the center are “high impedance” turns of magnet wire. These windings carry a higher voltage but a lower current. They’re protected by several layers of tape, a copper-foil electrostatic shield, and more tape.

The outer “low impedance” windings are made with thicker insulated wire and fewer turns. They handle a lower voltage but a higher current.

All of the windings are wrapped around a black plastic bobbin. Two pieces of ferrite ceramic are bonded together to form the magnetic core at the heart of the transformer.

This article appears in the February 2023 print issue.

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