This Resistance Fighter Invented Dialysis in Nazi-Occupied Holland
When Willem Johan Kolff invented dialysis, the "father" of artificial organs was just getting started.
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 Women of RNA: Two Award-Winners Share Why They Spent Their Careers Studying DNA's Lesser-Known Cousin
When Lynne Maquat, who leads the Center for RNA Biology at the University of Rochester, became interested in the ribonucleic acid molecule in the 1970s, she was definitely in the minority. The same was true for Joan Steitz, now professor of molecular biophysics and biochemistry at Yale University, who began to study RNA a decade earlier in the 1960s.
"My first RNA experiment was a failure, because we didn't understand how things worked," Steitz recalls. In her first undergraduate experiment, she unwittingly used a lab preparation that destroyed the RNA. "Unknowingly, our preparation contained enzymes that degraded our RNA."
At the time, scientists pursuing genetic research tended to focus on DNA, or deoxyribonucleic acid — and for good reason. It was clear that the enigmatic double-helix ribbon held the answers to organisms' heredity, genetic traits, development, growth and aging. If scientists could decipher the secrets of DNA and understand how its genetic instructions translate into the body's functions in health and disease, they could develop treatments for all kinds of diseases. On the contrary, the prevailing dogma of the time viewed RNA as merely a helper that passively carried out DNA's genetic instructions for protein-making — so it received much less attention.
But Maquat and Steitz weren't interested in heredity. They studied biochemistry and biophysics, so they wanted to understand how RNA functioned on the molecular level — how it carried instructions, catalyzed reactions, and helped build protein bonds, among other things.
"I'm a mechanistic biochemist, so I like to know how things happen," Maquat says. "Once you understand the mechanism, you can think of how to solve problems." And so the quest to understand how RNA does its job became the focus of both women's careers.
"People can now appreciate why some of us studied RNA for such a long time."
Half a century later, in 2021, their RNA work has earned two prestigious recognitions only months from each other. In February, they received the Wolf Prize in Medicine, followed by the Warren Alpert Foundation Prize in May, awarded to scientists whose achievements led to prevention, cure or treatments of human diseases.
It was the development of the COVID-19 vaccines that made RNA a household name. Made by Moderna and Pfizer, the vaccines use the RNA molecule to deliver genetic instructions for making SARS-CoV-2's characteristic spike protein in our cells. The presence of this foreign-looking protein triggers the immune system to attack and remember the pathogen. As the vaccines reached the finish line, RNA took center stage, and it was Maquat's and Steitz's research that helped reveal how these molecular cogwheels drive many biological functions within cells.
If you think of a cell as a kingdom, the DNA plays the role of a queen. Like a monarch in a palace, DNA nestles inside the cell's nucleus issuing instructions needed for the cell to function. But no queen can successfully govern without her court, her messengers, and her soldiers, as well as other players that make her kingdom work. That's what RNAs do — they act as the DNA's vassals. They carry instructions for protein assembly, catalyze reactions and supervise many other processes to make sure the cellular kingdom performs as it should.
There are a myriad of these RNA vassals in our cells, and each type has its own specific task. There are messenger RNAs that deliver genetic instructions for protein synthesis from DNA to ribosomes, the cells' protein-making factories. There are ribosomal RNAs that help stitch together amino acids to make proteins. There are transfer RNAs that can bring amino acids to this protein synthesis machine, keeping it going. Then there are circular RNAs that act as sponges, absorbing proteins to help regulate the activity of genes. And that's only the tip of the iceberg when it comes to RNA diversity, researchers say.
"We know what the most abundant and important RNAs are doing," says Steitz. "But there are thousands of different ones, and we still don't have a full knowledge of them."
Critical to RNA's proper functioning is a process called splicing, in which a precursor mRNA is transformed into mature, fully-functional mRNA — a phenomenon that Steitz's work helped elucidate. The splicing process, which takes place in cellular assembly lines, involves removing extra RNA sequences and stringing the remaining RNA pieces together. Steitz found that tiny RNA particles called snRNPs are crucial to this process. They act as handy helpers, finding and removing errant genetic material from the mRNA molecules.
A dysfunctional RNA assembly line leads to diseases, including many cancers. For instance, Steitz found that people with Lupus — an autoimmune disorder — have antibodies that mistakenly attack the little snRNP helpers. She also discovered that when snRNPs don't do their job properly, they can cause what scientists call mis-splicing, producing defective mRNAs.
Fortunately, cells have a built-in quality-control process that can spot and correct these mistakes, which is what Maquat studied in her work. In 1981, she discovered a molecular quality-control system that spots and destroys such incorrectly assembled mRNA. With the cryptic name "nonsense-mediated mRNA decay" or NMD, this process is vital to the health and wellbeing of a cellular kingdom in humans — because splicing mistakes happen far more often than one would imagine.
"We estimate that about a third of our mRNA are mistakes," Maquat says. "And nonsense-mediated mRNA decay cleans up these mistakes." When this quality-control system malfunctions, defective mRNA forge faulty proteins, which mess up the cellular machinery and cause disease, including various forms of cancer.
Scientists' newfound appreciation of RNA opens door to many novel treatments.
Now that the first RNA-based shots were approved, the same principle can be used for create vaccines for other diseases, the two RNA researchers say. Moreover, the molecule has an even greater potential — it can serve as a therapeutic target for other disorders. For example, Spinraza, a groundbreaking drug approved in 2016 for spinal muscular atrophy, uses small snippets of synthetic genetic material that bind to the RNA, helping fix splicing errors. "People can now appreciate why some of us studied RNA for such a long time," says Maquat.
Steitz is thrilled that the entire field of RNA research is enjoying the limelight. "I'm delighted because the prize is more of a recognition of the field than just our work," she says. "This is a more general acknowledgment of how basic research can have a remarkable impact on human health."
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.
In 2010, a 67-year-old former executive assistant for a Fortune 500 company was diagnosed with mild cognitive impairment. By 2014, her doctors confirmed she had Alzheimer's disease.
As her disease progressed, she continued to live independently but wasn't able to drive anymore. Today, she can manage most of her everyday tasks, but her two daughters are considering a live-in caregiver. Despite her condition, the woman may represent a beacon of hope for the approximately 44 million people worldwide living with Alzheimer's disease. The now 74-year-old is among a small cadre of Alzheimer's patients who have undergone an experimental ultrasound procedure aimed at slowing cognitive decline.
In November 2020, Elisa Konofagou, a professor of biomedical engineering and director of the Ultrasound and Elasticity Imaging Laboratory at Columbia University, and her team used ultrasound to noninvasively open the woman's blood-brain barrier. This barrier is a highly selective membrane of cells that prevents toxins and pathogens from entering the brain while allowing vital nutrients to pass through. This regulatory function means the blood-brain barrier filters out most drugs, making treating Alzheimer's and other brain diseases a challenge.
Ultrasound uses high-frequency sound waves to produce live images from the inside of the human body. But scientists think it could also be used to boost the effectiveness of Alzheimer's drugs, or potentially even improve brain function in dementia patients without the use of drugs.
The procedure, which involves a portable ultrasound system, is the culmination of 17 years of lab work. As part of a small clinical trial, scientists positioned a sensor transmitting ultrasound waves on top of the woman's head while she sat in a chair. The sensor sends ultrasound pulses throughout the target region. Meanwhile, investigators intravenously infused microbubbles into the woman to boost the effects of the ultrasound. Three days after the procedure, scientists scanned her brain so that they could measure the effects of the treatments. Five months later, they took more images of her brain to see if the effects of the treatment lasted.
Promising Signs
After the first brain scan, Konofagou and her team found that amyloid-beta, the protein that clumps together in the brains of Alzheimer's patients and disrupts cell function, had declined by 14%. At the woman's second scan, amyloid levels were still lower than before the experimental treatment, but only by 10% this time. Konofagou thinks repeat ultrasound treatments given early on in the development of Alzheimer's may have the best chance at keeping amyloid plaques at bay.
This reduction in amyloid appeared to halt the woman's cognitive decline, at least temporarily. Following the ultrasound treatment, the woman took a 30-point test used to measure cognitive impairment in Alzheimer's. Her score — 22, indicating mild cognitive impairment — remained the same as before the intervention. Konofagou says this was actually a good sign.
"Typically, every six months an Alzheimer's patient scores two to three points lower, so this is highly encouraging," she says.
Konofagou speculates that the results might have been even more impressive had they applied the ultrasound on a larger section of the brain at a higher frequency. The selected site was just 4 cubic centimeters. Current safety protocols set by the U.S. Food and Drug Administration stipulate that investigators conducting such trials only treat one brain region with the lowest pressure possible.
The Columbia trial is aided by microbubble technology. During the procedure, investigators infused tiny, gas-filled spheres into the woman's veins to enhance the ultrasound reflection of the sound waves.
The big promise of ultrasound is that it could eventually make drugs for Alzheimer's obsolete.
"Ultrasound with microbubbles wakes up immune cells that go on to discard amyloid-beta," Konofagou says. "In this way, we can recover the function of brain neurons, which are destroyed by Alzheimer's in a sort of domino effect." What's more, a drug delivered alongside ultrasound can penetrate the brain at a dose up to 10 times higher.
Costas Arvanitis, an assistant professor at Georgia Institute of Technology who studies ultrasonic biophysics and isn't involved in the Columbia trial, is excited about the research. "First, by applying ultrasound you can make larger drugs — picture an antibody — available to the brain," he says. Then, you can use ultrasound to improve the therapeutic index, or the ratio of the effectiveness of a drug versus the ratio of adverse effects. "Some drugs might be effective but because we have to provide them in high doses to see significant responses they tend to come with side effects. By improving locally the concentration of a drug, you open up the possibility to reduce the dose."
The Columbia trial will enroll just six patients and is designed to test the feasibility and safety of the approach, not its efficacy. Still, Arvantis is hopeful about the potential benefits of the technique. "The technology has already been demonstrated to be safe, its components are now tuned to the needs of this specific application, and it's safe to say it's only a matter of time before we are able to develop personalized treatments," he says.
Konofagou and her colleagues recently presented their findings at the 20th Annual International Symposium for Therapeutic Ultrasound and intend to publish them in a scientific journal later this year. They plan to recruit more participants for larger trials, which will determine how effective the therapy is at improving memory and brain function in Alzheimer's patients. They're also in talks with pharmaceutical companies about ways to use their therapeutic approach to improve current drugs or even "create new drugs," says Konofagou.
A New Treatment Approach
On June 7, the FDA approved the first Alzheimer's disease drug in nearly two decades. Aducanumab, a drug developed by Biogen, is an antibody designed to target and reduce amyloid plaques. The drug has already sparked immense enthusiasm — and controversy. Proponents say the drug is a much-needed start in the fight against the disease, but others argue that the drug doesn't substantially improve cognition. They say the approval could open the door to the FDA greenlighting more Alzheimer's drugs that don't have a clear benefit, giving false hope to both patients and their families.
Konofagou's ultrasound approach could potentially boost the effects of drugs like aducanumab. "Our technique can be seamlessly combined with aducanumab in early Alzheimer's, where it has shown the most promise, to further enhance both its amyloid load reduction and further reduce cognitive deficits while using exactly the same drug regimen otherwise," she says. For the Columbia team, the goal is to use ultrasound to maximize the effects of aducanumab, as they've done with other drugs in animal studies.
But Konofagou's approach could transcend drug controversies, and even drugs altogether. The big promise of ultrasound is that it could eventually make drugs for Alzheimer's obsolete.
"There are already indications that the immune system is alerted each time ultrasound is exerted on the brain or when the brain barrier is being penetrated and gets activated, which on its own may have sufficient therapeutic effects," says Konofagou. Her team is now working with psychiatrists in hopes of using brain stimulation to treat patients with depression.
The potential to modulate the brain without drugs is huge and untapped, says Kim Butts Pauly, a professor of radiology, electrical engineering and bioengineering at Stanford University, who's not involved in the Columbia study. But she admits that scientists don't know how to fully control ultrasound in the brain yet. "We're only at the starting point of getting the tools to understand and harness how ultrasound microbubbles stimulate an immune response in the brain."
Meanwhile, the 74-year-old woman who received the ultrasound treatment last year, goes on about her life, having "both good days and bad days," her youngest daughter says. COVID-19's isolation took a toll on her, but both she and her daughters remain grateful for the opportunity to participate in the ultrasound trial.
"My mother wants to help, if not for herself, then for those who will follow her," the daughter says. She hopes her mother will be able to join the next phase of the trial, which will involve a drug in conjunction with the ultrasound treatment. "This may be the combination where the magic will happen," her daughter says.