A new scanning technique produces images with great detail that could revolutionize the study of human anatomy.
When Paul Taforo saw his first experimental images of COVID-19 light victims, he thought he had failed. A paleontologist by training, Taforo spent months working with teams across Europe to turn particle accelerators in the French Alps into revolutionary medical scanning tools.
It was at the end of May 2020, and scientists were eager to better understand how COVID-19 destroys human organs. Taforo was commissioned to develop a method that could use the high-power X-rays produced by the European Synchrotron Radiation Facility (ESRF) in Grenoble, France. As an ESRF scientist, he has pushed the boundaries of high-resolution x-rays of rock fossils and dried mummies. Now he was terrified of the soft, sticky mass of paper towels.
The images showed them more detail than any medical CT scan they had ever seen before, allowing them to overcome stubborn gaps in how scientists and doctors visualize and understand human organs. “In anatomy textbooks, when you see it, it’s large scale, it’s small scale, and they’re beautiful hand-drawn images for one reason: they’re artistic interpretations because we don’t have images,” University College London (UCL) said. . Senior Researcher Claire Walsh said. “For the first time we can do the real thing.”
Taforo and Walsh are part of an international team of more than 30 researchers who have created a powerful new X-ray scanning technique called Hierarchical Phase Contrast Tomography (HiP-CT). With it, they can finally go from a complete human organ to an enlarged view of the body’s tiniest blood vessels or even individual cells.
This method is already providing new insight into how COVID-19 damages and remodels blood vessels in the lungs. Although its long-term prospects are difficult to determine because nothing like HiP-CT has ever existed before, researchers excited by its potential are enthusiastically envisioning new ways to understand disease and map human anatomy with a more accurate topographic map.
UCL cardiologist Andrew Cooke said: “Most people may be surprised that we have been studying the anatomy of the heart for hundreds of years, but there is no consensus on the normal structure of the heart, especially the heart … Muscle cells and how it changes when the heart beats.”
“I’ve been waiting my whole career,” he said.
The HiP-CT technique began when two German pathologists competed to track the punitive effects of the SARS-CoV-2 virus on the human body.
Danny Jonigk, a thoracic pathologist at the Hannover Medical School, and Maximilian Ackermann, a pathologist at the University Medical Center Mainz, were on high alert as news of the unusual case of pneumonia began to spread in China. Both had experience treating lung conditions and knew right away that COVID-19 was unusual. The couple were particularly concerned about reports of “silent hypoxia” that kept COVID-19 patients awake but caused their blood oxygen levels to plummet.
Ackermann and Jonig suspect that SARS-CoV-2 somehow attacks the blood vessels in the lungs. When the disease spread to Germany in March 2020, the couple began autopsies on COVID-19 victims. They soon tested their vascular hypothesis by injecting resin into tissue samples and then dissolving the tissue in acid, leaving an accurate model of the original vasculature.
Using this technique, Ackermann and Jonigk compared tissues from people who did not die from COVID-19 to those from people who did. They immediately saw that in the victims of COVID-19, the smallest blood vessels in the lungs were twisted and reconstructed. These landmark results, published online in May 2020, show that COVID-19 is not strictly a respiratory disease, but rather a vascular disease that can affect organs throughout the body.
“If you go through the body and align all the blood vessels, you get 60,000 to 70,000 miles, which is twice the distance around the equator,” said Ackermann, a pathologist from Wuppertal, Germany. . He added that if only 1 percent of these blood vessels were attacked by the virus, blood flow and the ability to absorb oxygen would be compromised, which could lead to devastating consequences for the entire organ.
Once Jonigk and Ackermann realized the impact of COVID-19 on blood vessels, they realized they needed to better understand the damage.
Medical x-rays, such as CT scans, can provide views of entire organs, but they are not of high enough resolution. A biopsy allows scientists to examine tissue samples under a microscope, but the resulting images represent only a small part of the entire organ and cannot show how COVID-19 develops in the lungs. And the resin technique the team developed requires dissolving the tissue, which destroys the sample and limits further research.
“At the end of the day, [the lungs] get oxygen and carbon dioxide goes out, but for that, it has thousands of miles of blood vessels and capillaries, very thinly spaced… it’s almost a miracle,” Jonigk, founder, said principal investigator at the German Lung Research Center. “So how can we really evaluate something as complex as COVID-19 without destroying organs?”
Jonigk and Ackermann needed something unprecedented: a series of x-rays of the same organ that would allow the researchers to enlarge parts of the organ to cellular scale. In March 2020, the German duo contacted their longtime collaborator Peter Lee, a materials scientist and chair of emerging technologies at UCL. Lee’s specialty is the study of biological materials using powerful X-rays, so his thoughts immediately turned to the French Alps.
The European Synchrotron Radiation Center is located on a triangular patch of land in the northwestern part of Grenoble, where two rivers meet. The object is a particle accelerator that sends electrons in circular orbits half a mile long at nearly the speed of light. As these electrons spin in circles, powerful magnets in orbit warp the stream of particles, causing the electrons to emit some of the brightest X-rays in the world.
This powerful radiation allows the ESRF to spy on objects on the micrometer or even nanometer scale. It is often used to study materials such as alloys and composites, to study the molecular structure of proteins, and even to reconstruct ancient fossils without separating stone from bone. Ackermann, Jonigk and Lee wanted to use the giant instrument to take the world’s most detailed x-rays of human organs.
Enter Taforo, whose work at ESRF has pushed the boundaries of what synchrotron scanning can see. Its impressive array of tricks had previously allowed scientists to peer inside dinosaur eggs and nearly cut open mummies, and almost immediately Taforo confirmed that synchrotrons could theoretically scan entire lung lobes well. But in fact, scanning entire human organs is a huge challenge.
On the one hand, there is the problem of comparison. Standard x-rays create images based on how much radiation different materials absorb, with heavier elements absorbing more than lighter ones. Soft tissues are mostly made up of light elements—carbon, hydrogen, oxygen, etc.—so they don’t show up clearly on a classic medical x-ray.
One of the great things about ESRF is that its X-ray beam is very coherent: light travels in waves, and in the case of ESRF, all of its X-rays start at the same frequency and alignment, constantly oscillating, like footprints left by Reik through a zen garden. But as these X-rays pass through the object, subtle differences in density can cause each X-ray to deviate slightly from the path, and the difference becomes easier to detect as the X-rays move further away from the object. These deviations can reveal subtle density differences within an object, even if it is made up of light elements.
But stability is another issue. In order to take a series of enlarged x-rays, the organ must be fixed in its natural shape so that it does not bend or move more than a thousandth of a millimeter. Moreover, successive x-rays of the same organ will not match each other. Needless to say, however, the body can be very flexible.
Lee and his team at UCL aimed to design containers that could withstand synchrotron X-rays while still letting as many waves through as possible. Lee also handled the overall organization of the project—for example, the details of transporting human organs between Germany and France—and hired Walsh, who specializes in biomedical big data, to help figure out how to analyze the scans. Back in France, Taforo’s work included improving the scanning procedure and figuring out how to store the organ in the container Lee’s team was building.
Tafforo knew that in order for the organs not to decompose, and the images to be as clear as possible, they must be processed with several portions of aqueous ethanol. He also knew that he needed to stabilize the organ on something that exactly matched the density of the organ. His plan was to somehow place the organs in ethanol-rich agar, a jelly-like substance extracted from seaweed.
However, the devil is in the details – as in most of Europe, Taforo is stuck at home and locked up. So Taforo moved his research into a home lab: He spent years decorating a former middle-sized kitchen with 3D printers, basic chemistry equipment and tools used to prepare animal bones for anatomical research.
Taforo used products from the local grocery store to figure out how to make agar. He even collects stormwater from a roof he recently cleaned to make demineralized water, a standard ingredient in lab-grade agar formulas. To practice packing organs in agar, he took pig intestines from a local slaughterhouse.
Taforo was cleared to return to the ESRF in mid-May for the first test lung scan of pigs. From May to June, he prepared and scanned the left lung lobe of a 54-year-old man who died of COVID-19, which Ackermann and Jonig took from Germany to Grenoble.
“When I saw the first image, there was an apology letter in my email to everyone involved in the project: we failed and I couldn’t get a high-quality scan,” he said. “I just sent them two pictures that were terrible for me but great for them.”
For Lee of the University of California, Los Angeles, the images are stunning: whole-organ images are similar to standard medical CT scans, but “a million times more informative.” It is as if the explorer has been studying the forest all his life, either flying over the forest in a giant jet plane, or traveling along the trail. Now they soar above the canopy like birds on wings.
The team published their first full description of the HiP-CT approach in November 2021, and the researchers also released details on how COVID-19 affects certain types of circulation in the lungs.
The scan also had an unexpected benefit: it helped the researchers convince friends and family to get vaccinated. In severe cases of COVID-19, many blood vessels in the lungs appear dilated and swollen, and to a lesser extent, abnormal bundles of tiny blood vessels may form.
“When you look at the structure of a lung from a person who died from COVID, it doesn’t look like a lung — it’s a mess,” Tafolo said.
He added that even in healthy organs, the scans revealed subtle anatomical features that were never recorded because no human organ had ever been examined in such detail. With over $1 million in funding from the Chan Zuckerberg Initiative (a non-profit organization founded by Facebook CEO Mark Zuckerberg and Zuckerberg’s wife, physician Priscilla Chan), the HiP-CT team is currently creating what is called an atlas of human organs.
So far, the team has released scans of five organs — the heart, brain, kidneys, lungs, and spleen — based on the organs donated by Ackermann and Jonigk during their COVID-19 autopsy in Germany and the health “control” organ LADAF. Anatomical laboratory of Grenoble. The team produced the data, as well as flight films, based on data that is freely available on the Internet. The Atlas of Human Organs is rapidly expanding: another 30 organs have been scanned, and another 80 are at various stages of preparation. Nearly 40 different research groups contacted the team to learn more about the approach, Li said.
UCL cardiologist Cook sees great potential in using HiP-CT to understand basic anatomy. UCL radiologist Joe Jacob, who specializes in lung disease, said HiP-CT will be “invaluable for understanding disease,” especially in three-dimensional structures such as blood vessels.
Even the artists got into the fray. Barney Steele of London-based experiential art collective Marshmallow Laser Feast says he is actively investigating how HiP-CT data can be explored in immersive virtual reality. “Essentially, we are creating a journey through the human body,” he said.
But despite all the promises of HiP-CT, there are serious problems. First, says Walsh, a HiP-CT scan generates a “staggering amount of data,” easily a terabyte per organ. To allow clinicians to use these scans in the real world, the researchers hope to develop a cloud-based interface for navigating them, such as Google Maps for the human body.
They also needed to make it easier to convert scans into workable 3D models. Like all CT scan methods, HiP-CT works by taking many 2D slices of a given object and stacking them together. Even today, much of this process is done manually, especially when scanning abnormal or diseased tissue. Lee and Walsh say the HiP-CT team’s priority is to develop machine learning methods that can make this task easier.
These challenges will expand as the atlas of human organs expands and researchers become more ambitious. The HiP-CT team is using the latest ESRF beam device, named BM18, to continue scanning the project’s organs. The BM18 produces a larger X-ray beam, which means scanning takes less time, and the BM18 X-ray detector can be placed up to 125 feet (38 meters) away from the object being scanned, making it scan clearer. The BM18 results are already very good, says Taforo, who has rescanned some of the original Human Organ Atlas samples on the new system.
The BM18 can also scan very large objects. With the new facility, the team plans to scan the entire torso of the human body in one fell swoop by the end of 2023.
Exploring the enormous potential of the technology, Taforo said, “We are really just at the beginning.”
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