A new scanning technique delivers exquisitely detailed images—and could revolutionize the study of human anatomy.

BY MICHAEL GRESHKO

When Paul Tafforeau saw his first experimental scans of a COVID-19 victim’s lung, he thought he had failed. A paleontologist by training, Tafforeau had been laboring with a team strewn across Europe for months to turn a particle accelerator in the French Alps into a revolutionary medical scanning tool.

It was the end of May 2020, and scientists were anxious for a better view of the ways human organs were being ravaged by COVID-19. Tafforeau had been tasked with developing a technique that could make use of the powerful x-rays generated at the European Synchrotron Radiation Facility (ESRF) in Grenoble, France. He’d pushed boundaries on high-resolution x-rays of rock-hard fossils and desiccated mummies as an ESRF staff scientist. Now, he was dismayed by a lump of soft, squishy tissue.

But when his colleagues caught their first glimpse of the lung scans, they felt something else: awe.

The Beamline BM05 is the place where the first phase of the experiments for the Human Organ Atlas project has been carried out. Dr Paul Tafforeau, lead scientist at the ESRF for the Human Organ Atlas project, during experiments at the ESRF, imaging the complete brain of a Covid-19 victim using the HiP-CT (Hierarchical Phase-Contrast Tomography) technique, resolving cellular features (ca. one-micron resolution) in local areas.
The Human Organ Atlas project, an international team including ESRF staff scientist Paul Tafforeau, has used HiP-CT to scan the organs of COVID-19 victims, including their brains. HiP-CT scans can zoom in from a whole-organ scan to provide a cellular view of regions of interest.

An image shows feasibility results using the ESRF technique called HiP-CT to assess the complex vascular system of the whole lung lobe of a 54 year old male COVID-19 victim, in 3D, non destructively. The research team has seen how severe Covid-19 infection ‘shunts’ blood between the two separate systems – the capillaries which oxygenate the blood and those which feed the lung tissue itself.

The images presented them with richer detail than any medical CT scan they’d seen before, allowing them to bridge a stubborn gap in how scientists and doctors can visualize—and make sense of—human organs. “In anatomy textbooks, when you see, This is the large scale, and this is the smaller one, they’re all beautiful hand-drawn images for a reason: They’re artistic interpretations, because we have no images for it,” says Claire Walsh, a senior postdoctoral fellow at University College London (UCL). “For the first time, we can make the real thing.”

Tafforeau and Walsh are part of an international team of more than 30 researchers that has created a powerful new kind of x-ray scan called hierarchical phase-contrast tomography (HiP-CT). With it, they can finally go from a complete human organ to a zoomed-in view of the body’s tiniest blood vessels and even individual cells.

The technique is already providing fresh insights into how COVID-19 damages and reshapes the blood vessels of the lungs. And while its long-term promise is hard to define, because nothing quite like HiP-CT has ever existed before, researchers excited by its potential are enthusiastically dreaming up new ways to understand disease and more rigorously chart the terrains of human anatomy.

“What is perhaps a surprise to most people is we’ve been studying the heart anatomically since hundreds of years ago,” says UCL cardiac anatomist Andrew Cook, “but there isn’t a consensus about the normal structure of the heart, particularly the muscle cells, and how it changes as the heart beats.”

A technique with HiP-CT’s promise, he says, is something “I’ve been waiting for my whole career.”

Dr Claire Walsh in the BM05 control cabin, where the results of experiments of Human Organ Atlas project are collected and studies are carried out.
UCL senior postdoctoral fellow Claire Walsh, one of HiP-CT’s co-creators, monitors the control cabin of BM05, the ESRF facility where the Human Organ Atlas’s first scans were carried out.

As soon as news of unusual pneumonia cases began trickling out of China, Danny Jonigk—a thoracic diseases pathologist at Hannover Medical School—and Maximilian Ackermann, a pathologist at University Medical Center Mainz, were on high alert. Both had expertise in lung disease, and right away they knew COVID-19 was unusual. The two were especially concerned about reports of a “silent hypoxia” that left COVID-19 patients awake but caused their blood oxygen levels to plummet.

Ackermann and Jonigk suspected that SARS-CoV-2 was somehow attacking the lungs’ blood vessels. As the disease spread through Germany in March 2020, the duo began conducting autopsies of COVID-19 victims. They soon tested their blood-vessel hypothesis by injecting tissue samples with resin and then dissolving the tissues in acid, which left behind faithful casts of the original vasculature.

Using this technique, Ackermann and Jonigk compared the tissues of people who hadn’t died of COVID-19 with those who had. They immediately saw that among COVID-19 victims, the smallest blood vessels in the lungs were distorted and reshaped. These landmark results, published online in May 2020, showed that COVID-19 wasn’t strictly a respiratory disease but a vascular one—one that could affect organs across the entire body.

“If you go through the human body and you take all the blood vessels in one line, you come up with [60,000] to 70,000 miles, double the distance around the Equator,” says Ackermann, who is also a pathologist at Wuppertal, Germany’s HELIO Clinics. If just one percent of these blood vessels gets attacked by a virus, he adds, the blood’s flow and ability to absorb oxygen can be impaired, with potentially devastating consequences across entire organs.

As soon as they recognized COVID-19’s vascular effects, Jonigk and Ackermann realized that they needed a much better view of the damage.

Medical x-rays such as CT scans can provide a view of an entire organ, but they weren’t high-resolution enough. Biopsies can let scientists study tissue samples under a microscope, but the resulting images are only small bits of a whole organ and can’t show how COVID-19 progresses across an entire lung. And the team’s resin technique required dissolving tissue, which destroys the sample and limits further study.

“At the end of the day, [the] lung is oxygen in, carbon dioxide out—but for that, it has thousands and thousands of miles of blood vessels and capillaries that are so finely and nicely arranged … it’s almost a miracle,” says Jonigk, the founding principal investigator of the German Center of Lung Research. “So how could we actually assess something as complex as COVID-19 … without destroying the organ?”

Jonigk and Ackermann needed the unprecedented: a series of x-rays, all done on the same organ, that would let researchers zoom into portions of the organ down to the cellular scale. In March 2020, the German duo reached out to a longtime collaborator of theirs, Peter Lee, a materials scientist and chair of emerging technologies at UCL. Lee‘s specialty is studying biological materials with powerful x-rays—so his mind immediately went to the French Alps.

A brain conserved in the biomedical sample preparation lab, where donated human organs are stored for research purposes part of Human Organ ATLAS.
A donated brain undergoes conservation in the ESRF’s biomedical sample preparation lab, where the Human Organ Atlas’s donated human organs are stored for research purposes.

Getting the scans to work
The European Synchrotron Radiation Facility sits in the northwestern corner of Grenoble on a triangular plot of land where two rivers meet. The facility is a particle accelerator that makes electrons travel at nearly the speed of light around a half-mile-long circular track. As these electrons careen round and round, powerful magnets along the track bend the particle stream, which causes the electrons to emit the world’s brightest x-rays.

This powerful radiation lets the ESRF peer into objects at the scale of micrometers, even nanometers. It is frequently used to study materials such as alloys and composites, check the molecular structures of proteins, and even reconstruct ancient fossils without having to separate rock from bone. Ackermann, Jonigk, and Lee wanted to use this huge instrument to perform the world’s most detailed x-ray scans of a human organ.

Enter Tafforeau, whose work at the ESRF has stretched the limits of what synchrotron scans can see. His impressive bag of tricks previously let scientists peer inside dinosaur eggs and virtually unwrap mummies, and almost immediately, Tafforeau confirmed that the synchrotron could, in theory, make a good scan of an entire lung lobe. But actually scanning a whole human organ posed a grand challenge.

For one, there’s the issue of contrast. Standard x-rays make images based on how much radiation gets absorbed by different materials, with heavier elements absorbing more than lighter ones. Soft tissues are mostly made of light elements—carbon, hydrogen, oxygen, and so on—which is why they don’t show up clearly in a classic medical x-ray.

One of the ESRF’s great benefits is that its x-ray beams are very coherent: Light moves in waves, and in the ESRF’s case, its x-rays all start out with the same frequency and alignment, undulating in unison like the marks left behind by a zen garden’s rake. But as these x-rays move through an object, subtle differences in density can cause each x-ray’s path to deviate slightly, a difference that gets more detectable the farther the x-rays propagate once they exit the object. These deviations can reveal the slight density differences within an object, even if it is made of light elements.

But stability is another challenge. To pull off a series of zoomed-in x-rays, a given organ would have to be immobilized in its natural shape so it wouldn’t flex and shift by more than a thousandth of a millimeter. Any more wiggle than that, and successive x-ray scans on the same organ wouldn’t align with each other. Needless to say, though, organs can be quite floppy.

Lee and his team at UCL rushed to devise containers that could withstand the synchrotron’s x-rays but also let through as many waves as possible. Lee also juggled the project’s overall organization—such as the finer points of shipping human organs between Germany and France—and recruited Walsh, who specializes in huge biomedical datasets, to help work out how to analyze the scans. Back in France, Tafforeau’s jobs included refining the scanning procedure and figuring out how to keep the organs still within the containers that Lee’s team was building.

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