Scientists 3D-Printed a Human Immune System to Battle Covid-19

A completely artificial immune system quickly pumps out much-needed antibodies

Antibodies (Y-shaped) respond to a SARS-CoV-2 infection. Image: Kateryna Kon/Science Photo Library/Getty Images

In the early stages of the Covid-19 outbreak, Maker communities around the globe fired up their 3D printers to come to the aid of overburdened hospitals and first responders. Individuals and groups of amateurs and experts alike created 3D-printed face shields, masks, and ventilators. In labs, tissue engineers printed organs like lungs and blood vessels to study the devastating effects of the disease.

Meanwhile, in San Francisco, one group of scientists pushed 3D printing technology to the limit: They synthesized an entire functional immune system. Researchers at the biotech company Prellis Biologics have developed a fully synthetic system of 3D-printed lymph nodes — the small but mighty organs at the front lines of your immune system that generate antibodies in response to infection — that can pump out large numbers of antibodies to SARS-CoV2 within just a few weeks. And they were able to do it all without the need for a living host.

Research on Covid-19 has underscored the critical role of the immune system in treating and preventing the disease — in particular, the ability of the immune system to churn out hosts of the molecular sentinels known as antibodies. Infusions of antibodies against a variety of different pathogens have the potential to help fight off active infection and prevent it in the future.

But acquiring antibodies is tricky. While they can be grown in a lab, doing so is a labor-intensive process that involves finding the genes that code for the antibodies, then co-opting cells to mass-produce them. Most of the time, antibodies come from the blood plasma of people who have recovered from an infection, but this is a slow process that relies on the generosity of healthy human donors. Even then, the antibodies harvested may not be the right type. In the case of the Covid-19 pandemic, time isn’t a luxury that science can afford.

The immune system is an umbrella term for the variety of cell types and organs, like the spleen, tonsils, and bone marrow, involved in fighting off pathogens. By harnessing recent advances in 3D printing, Prellis found a way to strip this system down to a few essential elements that could be pulled out of the body and onto the lab bench. If it can be used to produce a variety of antibodies at scale, it could provide an invaluable tool for keeping the current pandemic — and the next one — at bay.

You probably don’t think about your lymph nodes until you’re sick, and they become so painful and swollen that you can’t think of anything else. These humble, bean-shaped organs are powerhouses of immunity, stationed strategically all over your body to deliver the antibodies needed to fight infection. Synthetic versions that could emulate their abilities would be a powerful tool, but because of their spatial separation and dependence on inputs from so many other parts of the body, they’re very challenging to make in a lab.

Most tissues are grown in only two dimensions and have been for decades. In 1975, MIT biologists James Rheinwald, PhD, and Howard Green, PhD, seeded an ordinary glass petri dish with a living soup of growth factors and some cells taken from a human skin biopsy. In the following weeks, these ingredients gradually coalesced into delicate sheets of fully developed skin. This was the birth of modern tissue culture. Over the years, the process has hopped out of the dish and into sophisticated incubators. Today, bioengineers are starting to discover exciting new potential in the stem cell-derived inks and intricate machinery of 3D printers. Culturing cells in the 2D space of a dish, however, is still standard practice in most early pharmaceutical and biomedical research.

If the goal is to synthesize an organ, like a lymph node, a dish won’t suffice. Any skilled gardener can tell you that if you plant a vine in a pot, no combination of soil, sunlight, and water will make it climb. For that to happen, it needs support. Our organs work in the same way: They not only need good cellular soil but also room to branch out in all directions to reach their full potential — they need a trellis and space; they need to climb.

Similarly, a small amount of extra room can have a major impact on therapeutic efficacy. “This is critical when we are talking about drug discovery and toxicity studies,” says Deepak Lamba, PhD, an associate professor of ophthalmology at the University of California, San Francisco School of Medicine, whose lab is developing 3D models of the retina to study rare diseases of the eye. “A number of stellar drugs from classical cell line-based 2D screens and animal studies have failed in clinical trials due to these differences.”

Melanie Matheu, PhD, who was not available for comment, was well acquainted with these challenges when she co-founded Prellis Biologics in 2016, with the goal of printing human tissues for research and transplantable organs for human patients. As she explained in April to IndieBio, the San Francisco-based biotech accelerator that helped initially fund the venture, she spent years researching the lymphatic system and the way its structure and function intersect to produce an optimal immune response.

To solve the structure problem when building an organ in 3D, it’s essential to start with a good scaffold. Think of it as the simple wireframe skeleton a sculptor might use to hold their clay on while it is the process of becoming, say, an elephant and not a soggy gray blob. The more detailed the scaffold, the more closely you can mimic an organ’s native shape, together with its connections to other tissues and organs. Prellis’s attention to these details gives it a leg up on past attempts to recreate lymph nodes in other labs.

“People usually say, ‘Oh, you’re antibody positive so you must be immune.’ This may or may not be true.”

A handful of scientists have already published proof-of-concept studies that show it’s possible to imitate lymph nodes in the lab — often by growing immune cells on gelatinous polymers that roughly approximate actual lymph nodes — but this isn’t the same as 3D-printing lymph nodes. Most of these imitations aren’t capable of generating functional antibodies in the kinds of numbers that would be useful in the clinic.

Prellis’s approach, with its emphasis on finely detailed scaffolds, allows the growth of organs that are richly supplied with blood vessels. The ability to recreate complicated structures like veins and capillaries was the key ingredient in building better synthetic lymph nodes, which consist of delicate meshes of vessels and ducts that deliver the pathogens that elicit antibody production. In 2017, Prellis printed a network of hundreds of these lymph nodes, supplied with blood from a healthy donor, to produce antibodies against the human Zika virus.

They had similar success with this same synthetic immune system when they exposed the lymph nodes to SARS-CoV-2, generating hundreds of potential antibodies in a matter of weeks. The process, in theory, could also be quickly scaled up to make antibodies to use directly for therapy or for research.

In May, Prellis was gearing up to see how their newly discovered antibodies performed in cell culture, a step along the way to phase 1 clinical trials. The company has demonstrated that these synthetic lymph nodes can make large numbers of antibodies, but before these antibodies are tested in animals and humans, Prellis will next need to show that the antibodies can bind to the virus effectively in cells. They’ll also have to pinpoint any potential side effects.

Having large numbers of antibodies on hand could rapidly accelerate the development of therapies that would benefit the largest number of patients. But the immune response doesn’t end at antibody production, which might help explain why some people get sicker than others or show no symptoms at all. Antibodies come in a few different flavors, and the presence of each type in your blood can tell a doctor something different about your infection, including whether you’ve recovered or your immune system is still in the throes of battle.

Prellis’ system has generated hundreds of one of these antibody types, called IgG. Most antibody tests and therapies center on this type of antibody, but scientists are starting to appreciate a larger role for other kinds of antibodies in the overall immune response, especially in the wide variation between different patient groups in the severity of their symptoms.

The key lies not just in antibody numbers, but in what’s known as neutralization capacity — the ability of a person’s antibodies to stave off viral infection. Preliminary work by microbiologist Kenneth Stapleford, PhD, and his team at New York University suggests that neutralization capacity could vary widely from person to person, impacting not only the immediate response to viral infection but also long-term immunity. “People usually say, ‘Oh, you’re antibody positive so you must be immune.’” Stapleford tells Future Human. “This may or may not be true.”

Immunity is complex, he says. “It could be that you only need a small amount of antibody to do the trick or maybe you need a ton. However, there are many things that go into this including the amount, kind, and where the antibody binds on the virus.”

IgG is usually singled out for antibody therapies because it’s the most abundant component of the immune response and attacks its targets the most aggressively. Immunity is more than just a numbers game, though. “We and others are finding that it’s not only IgG that provides protection,” Stapleford points out. In early research on a group of people who had recently recovered from Covid-19, his team found that the people with the highest neutralization capacity were those who had a wide variety of antibodies.

This will be a delicate balance to strike in the lab, but an important one if variety really is the key to recovery and long term immunity. Prellis’s lymph nodes could offer just the kind of versatility needed to explore these subtle variations.

While most therapies are developed from a few isolated antibodies, Prellis’s system captures the whole immune response, leaving it up to the researchers which elements they want to focus on further. The starting material for the lymph nodes themselves can come from any patient, giving researchers expanded insight into the immune responses of those who were asymptomatic or even infected with different strains of the virus.

While the antibodies to SARS-CoV-2 have yet to reach the clinic, the technology itself could be an invaluable bridge between the lab and the clinic as both scientists and medical professionals work to reign in the current pandemic and prepare for the next one.

Neuroscientist & cellist. Explorer of the weird wonders of the human brain.

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