This Resistance Fighter Invented Dialysis in Nazi-Occupied Holland
One of the Netherlands’ most famous pieces of pop culture is “Soldier of Orange.” It’s the title of the country’s most celebrated war memoir, movie and epic stage musical, all of which detail the exploits of the nation’s resistance fighters during World War II.
Willem Johan Kolff was a member of the Dutch resistance, but he doesn’t rate a mention in the “Solider of Orange” canon. Yet his wartime toils in a rural backwater not only changed medicine, but the world.
Kolff had been a physician less than two years before Germany invaded the Netherlands in May 1940. He had been engaged in post-graduate studies at the University of Gronigen but withdrew because he refused to accommodate the demands of the Nazi occupiers. Kolff’s Jewish supervisor made an even starker choice: He committed suicide.
After his departure from the university, Kolff took a job managing a small hospital in Kampen. Located 50 miles from the heavily populated coastal region, the facility was far enough away from the prying eyes of Germans that not only could Kolff care for patients, he could hide fellow resistance fighters and even Jewish refugees in relative safety. Kolff coached many of them to feign convincing terminal illnesses so the Nazis would allow them to remain in the hospital.
Despite the demands of practicing medicine and resistance work, Kolff still found time to conduct research. He had been haunted and inspired when, not long before the Nazi invasion, one of his patients died in agony from kidney disease. Kolff wanted to find a way to save future patients.
He broke his problem down to a simple task: If he could remove 20 grams of urea from a patient’s blood in 24 hours, they would survive. He began experimenting with ways to filter blood and return it to a patient’s body. Since the war had ground all non-military manufacturing to a halt, he was mostly forced to make do with material he could find at the hospital and around Kampen. Kolff eventually built a device from a washing machine parts, juice cans, sausage casings, a valve from an old Ford automobile radiator, and even scrap from a downed German aircraft.
The world’s first dialysis machine was hardly imposing; it resembled a rotating drum for a bingo game or raffle. Yet it carried on the highly sophisticated task of moving a patient’s blood through a semi-permeable membrane (about a 50-foot length of sausage casings) into a saline solution that drew out urea while leaving the blood cells untouched.
In emigrating to the U.S. to practice medicine, Kolff's intent was twofold: Advocate for a wider adoption of dialysis, and work on new projects. He wildly succeeded at both.
Kolff began using the machine to treat patients in 1943, most of whom had lapsed into comas due to their kidney failure. But like most groundbreaking medical devices, it was not an immediate success. By the end of the war, Kolff had dialyzed more than a dozen patients, but all had died. He briefly suspended use of the device after the Allied invasion of Europe, but he continued to refine its operation and the administration of blood thinners to patients.
In September 1945, Kolff dialyzed another comatose patient, 67-year-old Sofia Maria Schafstadt. She regained consciousness after 11 hours, and would live well into the 1950s with Kolff’s assistance. Yet this triumph contained a dark irony: At the time of her treatment, Schafstadt had been imprisoned for collaborating with the Germans.
With a tattered Europe struggling to overcome the destruction of the war, Kolff and his family emigrated to the U.S. in 1950, where he began working for the Cleveland Clinic while undergoing the naturalization process so he could practice medicine in the U.S. His intent was twofold: Advocate for a wider adoption of dialysis, and work on new projects. He wildly succeeded at both.
By the mid-1950s, dialysis machines had become reliable and life-saving medical devices, and Kolff had become a U.S. citizen. About that time he invented a membrane oxygenator that could be used in heart bypass surgeries. This was a critical component of the heart-lung machine, which would make heart transplants possible and bypass surgeries routine. He also invented among the very first practical artificial hearts, which in 1957 kept a dog alive for 90 minutes.
Kolff moved to the University of Utah in 1967 to become director of its Institute for Biomedical Engineering. It was a promising time for such a move, as the first successful transplant of a donor heart to a human occurred that year. But he was interested in going a step further and creating an artificial heart for human use.
It took more than a decade of tinkering and research, but in 1982, a team of physicians and engineers led by Kolff succeeded in implanting the first artificial heart in dentist Barney Clark, whose failing health disqualified him from a heart transplant. Although Clark died in March 1983 after 112 days tethered to the device, that it kept him alive generated international headlines. While graduate student Robert Jarvik received the named credit for the heart, he was directly supervised by Kolff, whose various endeavors into artificial organ research at the University of Utah were segmented into numerous teams.
Forty years later, several artificial hearts have been approved for use by the Food and Drug Administration, although all are a “bridge” that allow patients to wait for a transplant.
Kolff continued researching and tinkering with biomedical devices – including artificial eyes and ears – until he retired in 1997 at the age of 86. When he died in 2009, the medical community acknowledged that he was not only a pioneer in biotechnology, but the “father” of artificial organs.
The Pandemic Is Ushering in a More Modern—and Ethical—Way of Studying New Drugs and Diseases
Before the onset of the coronavirus pandemic, Dutch doctoral researcher Joep Beumer had used miniature lab-grown organs to study the human intestine as part of his PhD thesis. When lockdown hit, however, he was forced to delay his plans for graduation. Overwhelmed by a sense of boredom after the closure of his lab at the Hubrecht Institute, in the Netherlands, he began reading literature related to COVID-19.
"By February [2020], there were already reports on coronavirus symptoms in the intestinal tract," Beumer says, adding that this piqued his interest. He wondered if he could use his miniature models – called organoids -- to study how the coronavirus infects the intestines.
But he wasn't the only one to follow this train of thought. In the year since the pandemic began, many researchers have been using organoids to study how the coronavirus infects human cells, and find potential treatments. Beumer's pivot represents a remarkable and fast-emerging paradigm shift in how drugs and diseases will be studied in the coming decades. With future pandemics likely to be more frequent and deadlier, such a shift is necessary to reduce the average clinical development time of 5.9 years for antiviral agents.
Part of that shift means developing models that replicate human biology in the lab. Animal models, which are the current standard in biomedical research, fail to do so—96% of drugs that pass animal testing, for example, fail to make it to market. Injecting potentially toxic drugs into living creatures, before eventually slaughtering them, also raises ethical concerns for some. Organoids, on the other hand, respond to infectious diseases, or potential treatments, in a way that is relevant to humans, in addition to being slaughter-free.
Human intestinal organoids infected with SARS-CoV-2 (white).
Credit: Joep Beumer/Clevers group/Hubrecht Institute
Urgency Sparked Momentum
Though brain organoids were previously used to study the Zika virus during the 2015-16 epidemic, it wasn't until COVID-19 that the field really started to change. "The organoid field has advanced a lot in the last year. The speed at which it happened is crazy," says Shuibing Chen, an associate professor at Weill Cornell Medicine in New York. She adds that many federal and private funding agencies have now seen the benefits of organoids, and are starting to appreciate their potential in the biomedical field.
Last summer, the Organo-Strat (OS) network—a German network that uses human organoid models to study COVID-19's effects—received 3.2 million euros in funding from the German government. "When the pandemic started, we became aware that we didn't have the right models to immediately investigate the effects of the virus," says Andreas Hocke, professor of infectious diseases at the Charité Universitätsmedizin in Berlin, Germany, and coordinator of the OS network. Hocke explained that while the World Health Organization's animal models showed an "overlap of symptoms'' with humans, there was "no clear reflection" of the same disease.
"The network functions as a way of connecting organoid experts with infectious disease experts across Germany," Hocke continues. "Having organoid models on demand means we can understand how a virus infects human cells from the first moment it's isolated." Overall, OS aims to create infrastructure that could be applied to future pandemics. There are 28 sub-projects involved in the network, covering a wide assortment of individual organoids.
Cost, however, remains an obstacle to scaling up, says Chen. She says there is also a limit to what we can learn from organoids, given that they only represent a single organ. "We can add drugs to organoids to see how the cells respond, but these tests don't tell us anything about drug metabolism, for example," she explains.
A Related "Leaps" in Progress
One way to solve this issue is to use an organ-on-a-chip system. These are miniature chips containing a variety of human cells, as well as small channels along which functions like blood or air flow can be recreated. This allows scientists to perform more complex experiments, like studying drug metabolism, while producing results that are relevant to humans.
An organ-on-a-chip system.
Credit: Fraunhofer IGB
Such systems are also able to elicit an immune response. The FDA has even entered into an agreement with Wyss Institute spinoff Emulate to use their lung-on-a-chip system to test COVID-19 vaccines. Representing multiple organs in one system is also possible. Berlin-based TissUse are aiming to make a so-called 'human on a chip' system commercially available. But TissUse senior scientist Ilka Maschmeyer warns that there is a limit to how far the technology can go. "The system will not think or feel, so it wouldn't be possible to test for illnesses affecting these abilities," she says.
Some challenges also remain in the usability of organs-on-a-chip. "Specialized training is required to use them as they are so complex," says Peter Loskill, assistant professor and head of the organ-on-a-chip group at the University of Tübingen, Germany. Hocke agrees with this. "Cell culture scientists would easily understand how to use organoids in a lab, but when using a chip, you need additional biotechnology knowledge," he says.
One major advantage of both technologies is the possibility of personalized medicine: Cells can be taken from a patient and put onto a chip, for example, to test their individual response to a treatment. Loskill also says there are other uses outside of the biomedical field, such as cosmetic and chemical testing.
"Although these technologies offer a lot of possibilities, they need time to develop," Loskill continues. He stresses, however, that it's not just the technology that needs to change. "There's a lot of conservative thinking in biomedical research that says this is how we've always done things. To really study human biology means approaching research questions in a completely new way."
Even so, he thinks that the pandemic marked a shift in people's thinking—no one cared how the results were found, as long as it was done quickly. But Loskill adds that it's important to balance promise, potential, and expectations when it comes to these new models. "Maybe in 15 years' time we will have a limited number of animal models in comparison to now, but the timescale depends on many factors," he says.
Beumer, now a post-doc, was eventually allowed to return to the lab to develop his coronavirus model, and found working on it to be an eye-opening experience. He saw first-hand how his research could have an impact on something that was affecting the entire human race, as well as the pressure that comes with studying potential treatments. Though he doesn't see a future for himself in infectious diseases, he hopes to stick with organoids. "I've now gotten really excited about the prospect of using organoids for drug discovery," he says.
The coronavirus pandemic has slowed society down in many respects, but it has flung biomedical research into the future—from mRNA vaccines to healthcare models based on human biology. It may be difficult to fully eradicate animal models, but over the coming years, organoids and organs-on-a-chip may become the standard for the sake of efficacy -- and ethics.
Jack McGovan is a freelance science writer based in Berlin. His main interests center around sustainability, food, and the multitude of ways in which the human world intersects with animal life. Find him on Twitter @jack_mcgovan."
New Podcast: Why Dr. Ashish Jha Expects a Good Summer
Making Sense of Science features interviews with leading medical and scientific experts about the latest developments and the big ethical and societal questions they raise. This monthly podcast is hosted by journalist Kira Peikoff, founding editor of the award-winning science outlet Leaps.org.
Hear the 30-second trailer:
Listen to the whole episode: "Why Dr. Ashish Jha Expects a Good Summer"
Dr. Ashish Jha, dean of public health at Brown University, discusses the latest developments around the Covid-19 vaccines, including supply and demand, herd immunity, kids, vaccine passports, and why he expects the summer to look very good.
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.