Regenerative medicine has come a long way, baby
The field of regenerative medicine had a shaky start. In 2002, when news spread about the first cloned animal, Dolly the sheep, a raucous debate ensued. Scary headlines and organized opposition groups put pressure on government leaders, who responded by tightening restrictions on this type of research.
Fast forward to today, and regenerative medicine, which focuses on making unhealthy tissues and organs healthy again, is rewriting the code to healing many disorders, though it’s still young enough to be considered nascent. What started as one of the most controversial areas in medicine is now promising to transform it.
Progress in the lab has addressed previous concerns. Back in the early 2000s, some of the most fervent controversy centered around somatic cell nuclear transfer (SCNT), the process used by scientists to produce Dolly. There was fear that this technique could be used in humans, with possibly adverse effects, considering the many medical problems of the animals who had been cloned.
But today, scientists have discovered better approaches with fewer risks. Pioneers in the field are embracing new possibilities for cellular reprogramming, 3D organ printing, AI collaboration, and even growing organs in space. It could bring a new era of personalized medicine for longer, healthier lives - while potentially sparking new controversies.
Engineering tissues from amniotic fluids
Work in regenerative medicine seeks to reverse damage to organs and tissues by culling, modifying and replacing cells in the human body. Scientists in this field reach deep into the mechanisms of diseases and the breakdowns of cells, the little workhorses that perform all life-giving processes. If cells can’t do their jobs, they take whole organs and systems down with them. Regenerative medicine seeks to harness the power of healthy cells derived from stem cells to do the work that can literally restore patients to a state of health—by giving them healthy, functioning tissues and organs.
Modern-day regenerative medicine takes its origin from the 1998 isolation of human embryonic stem cells, first achieved by John Gearhart at Johns Hopkins University. Gearhart isolated the pluripotent cells that can differentiate into virtually every kind of cell in the human body. There was a raging controversy about the use of these cells in research because at that time they came exclusively from early-stage embryos or fetal tissue.
Back then, the highly controversial SCNT cells were the only way to produce genetically matched stem cells to treat patients. Since then, the picture has changed radically because other sources of highly versatile stem cells have been developed. Today, scientists can derive stem cells from amniotic fluid or reprogram patients’ skin cells back to an immature state, so they can differentiate into whatever types of cells the patient needs.
In the context of medical history, the field of regenerative medicine is progressing at a dizzying speed. But for those living with aggressive or chronic illnesses, it can seem that the wheels of medical progress grind slowly.
The ethical debate has been dialed back and, in the last few decades, the field has produced important innovations, spurring the development of whole new FDA processes and categories, says Anthony Atala, a bioengineer and director of the Wake Forest Institute for Regenerative Medicine. Atala and a large team of researchers have pioneered many of the first applications of 3D printed tissues and organs using cells developed from patients or those obtained from amniotic fluid or placentas.
His lab, considered to be the largest devoted to translational regenerative medicine, is currently working with 40 different engineered human tissues. Sixteen of them have been transplanted into patients. That includes skin, bladders, urethras, muscles, kidneys and vaginal organs, to name just a few.
These achievements are made possible by converging disciplines and technologies, such as cell therapies, bioengineering, gene editing, nanotechnology and 3D printing, to create living tissues and organs for human transplants. Atala is currently overseeing clinical trials to test the safety of tissues and organs engineered in the Wake Forest lab, a significant step toward FDA approval.
In the context of medical history, the field of regenerative medicine is progressing at a dizzying speed. But for those living with aggressive or chronic illnesses, it can seem that the wheels of medical progress grind slowly.
“It’s never fast enough,” Atala says. “We want to get new treatments into the clinic faster, but the reality is that you have to dot all your i’s and cross all your t’s—and rightly so, for the sake of patient safety. People want predictions, but you can never predict how much work it will take to go from conceptualization to utilization.”
As a surgeon, he also treats patients and is able to follow transplant recipients. “At the end of the day, the goal is to get these technologies into patients, and working with the patients is a very rewarding experience,” he says. Will the 3D printed organs ever outrun the shortage of donated organs? “That’s the hope,” Atala says, “but this technology won’t eliminate the need for them in our lifetime.”
New methods are out of this world
Jeanne Loring, another pioneer in the field and director of the Center for Regenerative Medicine at Scripps Research Institute in San Diego, says that investment in regenerative medicine is not only paying off, but is leading to truly personalized medicine, one of the holy grails of modern science.
This is because a patient’s own skin cells can be reprogrammed to become replacements for various malfunctioning cells causing incurable diseases, such as diabetes, heart disease, macular degeneration and Parkinson’s. If the cells are obtained from a source other than the patient, they can be rejected by the immune system. This means that patients need lifelong immunosuppression, which isn’t ideal. “With Covid,” says Loring, “I became acutely aware of the dangers of immunosuppression.” Using the patient’s own cells eliminates that problem.
Microgravity conditions make it easier for the cells to form three-dimensional structures, which could more easily lead to the growing of whole organs. In fact, Loring's own cells have been sent to the ISS for study.
Loring has a special interest in neurons, or brain cells that can be developed by manipulating cells found in the skin. She is looking to eventually treat Parkinson’s disease using them. The manipulated cells produce dopamine, the critical hormone or neurotransmitter lacking in the brains of patients. A company she founded plans to start a Phase I clinical trial using cell therapies for Parkinson’s soon, she says.
This is the culmination of many years of basic research on her part, some of it on her own cells. In 2007, Loring had her own cells reprogrammed, so there’s a cell line that carries her DNA. “They’re just like embryonic stem cells, but personal,” she said.
Loring has another special interest—sending immature cells into space to be studied at the International Space Station. There, microgravity conditions make it easier for the cells to form three-dimensional structures, which could more easily lead to the growing of whole organs. In fact, her own cells have been sent to the ISS for study. “My colleagues and I have completed four missions at the space station,” she says. “The last cells came down last August. They were my own cells reprogrammed into pluripotent cells in 2009. No one else can say that,” she adds.
Future controversies and tipping points
Although the original SCNT debate has calmed down, more controversies may arise, Loring thinks.
One of them could concern growing synthetic embryos. The embryos are ultimately derived from embryonic stem cells, and it’s not clear to what stage these embryos can or will be grown in an artificial uterus—another recent invention. The science, so far done only in animals, is still new and has not been widely publicized but, eventually, “People will notice the production of synthetic embryos and growing them in an artificial uterus,” Loring says. It’s likely to incite many of the same reactions as the use of embryonic stem cells.
Bernard Siegel, the founder and director of the Regenerative Medicine Foundation and executive director of the newly formed Healthspan Action Coalition (HSAC), believes that stem cell science is rapidly approaching tipping point and changing all of medical science. (For disclosure, I do consulting work for HSAC). Siegel says that regenerative medicine has become a new pillar of medicine that has recently been fast-tracked by new technology.
Artificial intelligence is speeding up discoveries and the convergence of key disciplines, as demonstrated in Atala’s lab, which is creating complex new medical products that replace the body’s natural parts. Just as importantly, those parts are genetically matched and pose no risk of rejection.
These new technologies must be regulated, which can be a challenge, Siegel notes. “Cell therapies represent a challenge to the existing regulatory structure, including payment, reimbursement and infrastructure issues that 20 years ago, didn’t exist.” Now the FDA and other agencies are faced with this revolution, and they’re just beginning to adapt.
Siegel cited the 2021 FDA Modernization Act as a major step. The Act allows drug developers to use alternatives to animal testing in investigating the safety and efficacy of new compounds, loosening the agency’s requirement for extensive animal testing before a new drug can move into clinical trials. The Act is a recognition of the profound effect that cultured human cells are having on research. Being able to test drugs using actual human cells promises to be far safer and more accurate in predicting how they will act in the human body, and could accelerate drug development.
Siegel, a longtime veteran and founding father of several health advocacy organizations, believes this work helped bring cell therapies to people sooner rather than later. His new focus, through the HSAC, is to leverage regenerative medicine into extending not just the lifespan but the worldwide human healthspan, the period of life lived with health and vigor. “When you look at the HSAC as a tree,” asks Siegel, “what are the roots of that tree? Stem cell science and the huge ecosystem it has created.” The study of human aging is another root to the tree that has potential to lengthen healthspans.
The revolutionary science underlying the extension of the healthspan needs to be available to the whole world, Siegel says. “We need to take all these roots and come up with a way to improve the life of all mankind,” he says. “Everyone should be able to take advantage of this promising new world.”
This spring, just like any other year, thousands of young North American engineers will graduate from their respective colleges ready to start erecting buildings, assembling machinery, and programming software, among other things. But before they take on these complex and important tasks, many of them will recite a special vow stating their ethical obligations to society, not unlike the physicians who take their Hippocratic Oath, affirming their ethos toward the patients they would treat. At the end of the ceremony, the engineers receive an iron ring, as a reminder of their promise to the millions of people their work will serve.
The ceremony isn’t just another graduation formality. As a profession, engineering has ethical weight. Moreover, engineering mistakes can be even more deadly than medical ones. A doctor’s error may cost a patient their life. But an engineering blunder may bring down a plane or crumble a building, resulting in many more fatalities. When larger projects—such as fracking, deep-sea mining or building nuclear reactors—malfunction and backfire, they can cause global disasters, afflicting millions. A vow that reminds an engineer that their work directly affects humankind and their planet is no less important than a medical oath that summons one to do no harm.
The tradition of taking an engineering oath began over a century ago in Canada. In 1922, Herbert E.T. Haultain, professor of mining engineering at the University of Toronto, presented the idea at the annual meeting of the Engineering Institute of Canada. The seven past presidents of that body were in attendance, heard Haultain’s speech and accepted his suggestion to form a committee to create an honor oath. Later, they formed the nonprofit Corporation of the Seven Wardens, which would oversee the ritual. Next year, in 1923, with the encouragement of the Seven Wardens, Haultain wrote to poet and writer Rudyard Kipling, asking him to develop a professional oath for engineers. “We are a tribe—a very important tribe within the community,” Haultain said in the letter, “but we are lacking in tribal spirit, or perhaps I should say, in manifestation of tribal spirit. Also, we are inarticulate. Can you help us?”
While Kipling is most famous now for “The Jungle Book” and perhaps his poem “Gunga Din,” he had also written a short story about engineers, “The Bridge Builders.” His poem “The Sons of Martha” can be read as a celebration of engineers:
It is their care in all the ages to take the buffet and cushion the shock.
It is their care that the gear engages; it is their care that the switches lock.
It is their care that the wheels run truly; it is their care to embark and entrain,
Tally, transport, and deliver duly the Sons of Mary by land and main.
Kipling accepted the ask and wrote the Ritual of the Calling of an Engineer, which he sent to Haultain a month later. In his response to Haultain, he stated that he preferred the word “Obligation” to “Oath.” He wrote the Obligation using Old English lettering and the old-fashioned capitalization. Kipling’s Obligation binds engineers upon their “Honor and Cold Iron” to not “suffer or pass, or be privy to the passing of, Bad Workmanship or Faulty Material,” and pardon is asked “in the presence of my betters and my equals in my Calling” for the engineer’s “assured failures and derelictions.” The hope is that when one is tempted to shoddy work by weakness or weariness, the memory of the Obligation “and the company before whom it was entered into, may return to me to aid, comfort, and restrain.”
Using the Obligation, The Seven Wardens created an induction ceremony, which seeks to unify the profession and recognize engineering’s ethics, including responsibility to the public and the need to make the best decisions possible. The induction ceremony included recitation of Kipling’s “Obligation” and incorporated an anvil, a hammer, an iron chain, and an iron ring. The inductee engineers sat inside an area marked off by the iron chain, with their more senior colleagues outside that area. At the start of the ritual, the leader beat out S-S-T in Morse code with the hammer and anvil—the letters standing for Steel, Stone, and Time. A more experienced and previously obligated engineer placed the ring on the small finger of the inductee engineer’s working hand. As per Kipling, the ring’s rough, faceted texture symbolized “the young engineer’s mind” and the difficulties engineers face in mastering their discipline.
A persistent myth purports that the original iron rings were made from the beams or bolts of the Quebec Bridge that failed twice during construction.
The first induction ceremony took place on April 25, 1925, in Montreal to obligate two of the Seven Wardens, along with four graduates from the University of Toronto class of 1893. On May 1 of that year, 14 more engineers were obligated at the University of Toronto. From that time to today most Canadian professional engineers have gone through that same ritual in their various camps, called Kipling camps—local chapters associated with various Canadian universities.
Henry Petroski, Duke University’s professor of civil engineering and history, notes in his book, “Forgive Design: Understanding Failure,” that Kipling’s poem “Sons of Martha” is often read as part of the ritual. However, sometimes inductees read Kipling’s “Hymn of Breaking Strain,” instead, which graphically depicts disastrous outcomes of engineering mistakes. The first stanza of that poem says:
The careful text-books measure
(Let all who build beware!)
The load, the shock, the pressure
Material can bear.
So, when the buckled girder
Lets down the grinding span,
'The blame of loss, or murder,
Is laid upon the man.
Not on the Stuff—the Man!
As if to strengthen the importance of these concepts, a persistent myth purports that the original iron rings were made from the beams or bolts of the Quebec Bridge that failed twice during construction. The bridge spans the St. Lawrence River upriver from Quebec City, and at the time of its construction was the world’s longest at 1,800 feet. Due to engineering errors and poor oversight, the bridge’s own weight exceeded its carrying capacity. Moreover, engineers downplayed danger when bridge beams began to warp under stress, saying that they were probably warped before they were installed. On August 29, 1907, the bridge collapsed, killing 75 of 86 workers. A second collapse occurred in 1916 when lifting equipment failed, and thirteen more workers died.
The ring myth, however, couldn’t be true. The original iron rings couldn’t have come from the failed bridge since it was made of steel, not wrought iron. Today the rings are made from stainless steel because iron deteriorates and stains engineers’ finger black.
On August 14, 2018, Morandi Bridge over Polcevera River in Genoa, Italy, collapsed from structural failure, killing 43 people.
Adobe Stock
The Seven Wardens decided to restrict the ritual to engineers trained in Canada. They copyrighted the obligation oath in Canada and the United States in 1935. Although the ritual is not a requirement for professional licensing, just like the Hippocratic Oath is not part of medical licensing, it remains a long-standing tradition.
The American Obligation of the Engineer has its own creation story, albeit a very different one. The American Order of the Engineer (OOE) was initiated in 1970, during the era of the anti-war protests, Apollo missions and the first Earth Day. On May 4, 1970, the National Guard shot into a crowd of protesters at Kent State University, killing four people. The two authors of the American obligation—Cleveland State University’s (CSU) engineering professor John Janssen and his wife Susan—reflected these historical events in the oath they wrote. Their version of the oath binds engineers to “practice integrity and fair dealing.” It also notes that their “skill carries with it the obligation to serve humanity by making the best use of the Earth’s precious wealth.” As Petroski explains in his book, “campus antiwar protestors around the country tended to view engineers as complicit in weapons proliferation [which] prompted some [CSU] engineering student leaders to look for a means of asserting some more positive values.”
Kip A. Wedel, associate professor of history and politics at Bethel College, wrote in his book, “The Obligation: A History of the Order of the Engineer,” that the ceremony was not a direct response to the Kent State shootings—it was already scheduled when the shootings happened. Yet, engineering students found the ceremony a positive action they could take in contrast to the overall turmoil. The first American ritual took place on June 4, 1970, at CSU. In total, 170 students, faculty members, and practicing engineers took the obligation. This established CSU as the first Link of the Order, as the OOE designates its local chapters. For their first ceremony, the CSU students fabricated smooth, unfaceted rings from stainless steel pipe. Later they were replaced by factory-made rings. According to Paula Ostaff, OOE’s Executive Director, about 20,000 eligible students and alumni obligate themselves yearly.
Societies hope that every engineer is imbued with a strong ethical sense and that their pledges are never far from mind. For some, the rings they wear serve a daily reminder that every paper they sign off on is touched by a physical reminder of their commitment.
These ethical and responsible engineering practices are especially salient today, when one in three American bridges needs repair or replacement, some have already collapsed, and engineers are working on projects related to the bipartisan infrastructure bill President Biden signed into law in 2021. Canada has committed $33 billion to its Investing in Canada Infrastructure Program. At the heart of these grand projects are many thousands of professional engineers, collectively working millions of hours. The professional vows they took aim to assure that the homes, bridges and airplanes they build will work as expected.
In the 1966 movie "Fantastic Voyage," actress Raquel Welch and her submarine were shrunk to the size of a cell in order to eliminate a blood clot in a scientist's brain. Now, 55 years later, the scenario is becoming closer to reality.
California-based startup Bionaut Labs has developed a nanobot about the size of a grain of rice that's designed to transport medication to the exact location in the body where it's needed. If you think about it, the conventional way to deliver medicine makes little sense: A painkiller affects the entire body instead of just the arm that's hurting, and chemotherapy is flushed through all the veins instead of precisely targeting the tumor.
"Chemotherapy is delivered systemically," Bionaut-founder and CEO Michael Shpigelmacher says. "Often only a small percentage arrives at the location where it is actually needed."
But what if it was possible to send a tiny robot through the body to attack a tumor or deliver a drug at exactly the right location?
Several startups and academic institutes worldwide are working to develop such a solution but Bionaut Labs seems the furthest along in advancing its invention. "You can think of the Bionaut as a tiny screw that moves through the veins as if steered by an invisible screwdriver until it arrives at the tumor," Shpigelmacher explains. Via Zoom, he shares the screen of an X-ray machine in his Culver City lab to demonstrate how the half-transparent, yellowish device winds its way along the spine in the body. The nanobot contains a tiny but powerful magnet. The "invisible screwdriver" is an external magnetic field that rotates that magnet inside the device and gets it to move and change directions.
The current model has a diameter of less than a millimeter. Shpigelmacher's engineers could build the miniature vehicle even smaller but the current size has the advantage of being big enough to see with bare eyes. It can also deliver more medicine than a tinier version. In the Zoom demonstration, the micorobot is injected into the spine, not unlike an epidural, and pulled along the spine through an outside magnet until the Bionaut reaches the brainstem. Depending which organ it needs to reach, it could be inserted elsewhere, for instance through a catheter.
"The hope is that we can develop a vehicle to transport medication deep into the body," says Max Planck scientist Tian Qiu.
Imagine moving a screw through a steak with a magnet — that's essentially how the device works. But of course, the Bionaut is considerably different from an ordinary screw: "At the right location, we give a magnetic signal, and it unloads its medicine package," Shpigelmacher says.
To start, Bionaut Labs wants to use its device to treat Parkinson's disease and brain stem gliomas, a type of cancer that largely affects children and teenagers. About 300 to 400 young people a year are diagnosed with this type of tumor. Radiation and brain surgery risk damaging sensitive brain tissue, and chemotherapy often doesn't work. Most children with these tumors live less than 18 months. A nanobot delivering targeted chemotherapy could be a gamechanger. "These patients really don't have any other hope," Shpigelmacher says.
Of course, the main challenge of the developing such a device is guaranteeing that it's safe. Because tissue is so sensitive, any mistake could risk disastrous results. In recent years, Bionaut has tested its technology in dozens of healthy sheep and pigs with no major adverse effects. Sheep make a good stand-in for humans because their brains and spines are similar to ours.
The Bionaut device is about the size of a grain of rice.
Bionaut Labs
"As the Bionaut moves through brain tissue, it creates a transient track that heals within a few weeks," Shpigelmacher says. The company is hoping to be the first to test a nanobot in humans. In December 2022, it announced that a recent round of funding drew $43.2 million, for a total of 63.2 million, enabling more research and, if all goes smoothly, human clinical trials by early next year.
Once the technique has been perfected, further applications could include addressing other kinds of brain disorders that are considered incurable now, such as Alzheimer's or Huntington's disease. "Microrobots could serve as a bridgehead, opening the gateway to the brain and facilitating precise access of deep brain structure – either to deliver medication, take cell samples or stimulate specific brain regions," Shpigelmacher says.
Robot-assisted hybrid surgery with artificial intelligence is already used in state-of-the-art surgery centers, and many medical experts believe that nanorobotics will be the instrument of the future. In 2016, three scientists were awarded the Nobel Prize in Chemistry for their development of "the world's smallest machines," nano "elevators" and minuscule motors. Since then, the scientific experiments have progressed to the point where applicable devices are moving closer to actually being implemented.
Bionaut's technology was initially developed by a research team lead by Peer Fischer, head of the independent Micro Nano and Molecular Systems Lab at the Max Planck Institute for Intelligent Systems in Stuttgart, Germany. Fischer is considered a pioneer in the research of nano systems, which he began at Harvard University more than a decade ago. He and his team are advising Bionaut Labs and have licensed their technology to the company.
"The hope is that we can develop a vehicle to transport medication deep into the body," says Max Planck scientist Tian Qiu, who leads the cooperation with Bionaut Labs. He agrees with Shpigelmacher that the Bionaut's size is perfect for transporting medication loads and is researching potential applications for even smaller nanorobots, especially in the eye, where the tissue is extremely sensitive. "Nanorobots can sneak through very fine tissue without causing damage."
In "Fantastic Voyage," Raquel Welch's adventures inside the body of a dissident scientist let her swim through his veins into his brain, but her shrunken miniature submarine is attacked by antibodies; she has to flee through the nerves into the scientist's eye where she escapes into freedom on a tear drop. In reality, the exit in the lab is much more mundane. The Bionaut simply leaves the body through the same port where it entered. But apart from the dramatization, the "Fantastic Voyage" was almost prophetic, or, as Shpigelmacher says, "Science fiction becomes science reality."
This article was first published by Leaps.org on April 12, 2021.