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.”
Scientists use AI to predict how hospital stays will go
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
Here are the promising studies covered in this week's Friday Five:
- The problem with bedtime munching
- Scientists use AI to predict how stays in hospitals will go
- How to armor the shields of our livers against cancer
- One big step to save the world: turn one kind of plastic into another
- The perfect recipe for tiny brains
And an honorable mention this week: Bigger is better when it comes to super neurons in super agers
The Toxic Effects of Noise and What We’re Not Doing About It
Erica Walker had a studio in her Brookline, Mass. apartment where she worked as a bookbinder and furniture maker. That was until a family with two rowdy children moved in above her.
The kids ran amuck, disrupting her sleep and work. Ear plugs weren’t enough to blot out the commotion. Aside from anger and a sense of lost control, the noise increased her heart rate and made her stomach feel like it was dropping, she says.
That’s when Walker realized that noise is a public health problem, not merely an annoyance. She set up her own “mini study” on how the clamor was affecting her. She monitored sound levels in her apartment and sent saliva samples to a lab to measure her stress levels.
Walker ultimately sold her craft equipment and returned to school to study public health. Today she is assistant professor of epidemiology and director of the Community Noise Lab at the Brown University School of Public Health. “We treat noise like a first world problem—like a sacrifice we should have to make for modern conveniences. But it’s a serious environmental stressor,” she asserts.
Our daily soundscape is a cacophony of earsplitting jets, motorcycles, crying babies, construction sites or gunshots if you’re in the military. Noise exposure is the primary cause of preventable hearing loss. Researchers have identified links between excessive noise and a heightened risk of heart disease, metabolic disorders, anxiety, depression, sleep disorders, and impaired cognition. Even wildlife suffers. Blasting oil drills and loud shipping vessels impede the breeding, feeding and migration of whales and dolphins.
At one time, the federal government had our back… and our ears. Congress passed the Noise Control Act in 1972. The Environmental Protection Agency set up the Office of Noise Abatement and Control (ONAC) to launch research, explore solutions and establish noise emission standards. But ONAC was defunded in 1981 amidst a swirl of antiregulatory sentiment.
Impossibly Loud and Unhealthy
Daniel Fink. a physician, WHO consultant, and board chair of The Quiet Coalition, a program of the nonprofit Quiet Communities, likens the effect of noise to the invisible but cumulative harm of second-hand smoke. About 1 in 4 adults in the U.S. who report excellent to good hearing already have some hearing loss. The injury can happen after one loud concert or from years with a blaring TV. Some people are more genetically susceptible to noise-related hearing loss than others.
“People say noise isn’t a big deal but it bothers your body whether you realize it or not,” says Ted Rueter, director of Noise Free America: A Coalition to Promote Quiet. Noise can chip away at your ears or cardiovascular system even while you’re sleeping. Rueter became a “quiet advocate” while a professor at UCLA two decades ago. He was plagued by headaches, fatigue and sleep deprivation caused by the hubbub of Los Angeles, he says.
The louder a sound is, and the longer you are exposed to it, the more likely it will cause nerve damage and harmful fluid buildup in your inner ear. Normal speech is 50-60 decibels (dBs). The EPA recommends that 24-hour exposure to noise should be no higher than 70 weighted decibels over 24 hours (weighted to approximate how the human ear perceives the sound) to prevent hearing loss but a 55 dB limit is recommended to protect against other harms from noise, too.
The decibel scale is logarithmic. That means 80 dB is 10 times louder than 70 dB. Trucks and motorcycles run 90 dBs. A gas-powered leaf blower, jackhammer or snow blower will cost you 100 dBs. A rock concert is in the 110 dB range. Aircraft takeoffs or sirens? 120 dBs.
Walker, the Brown professor, says that sound measurements often use misleading metrics, though, because they don’t include low frequency sound that disturb the body. The high frequency of a screeching bus will register in decibels but the sound that makes your chest reverberate is not accounted for, she explains. ‘How loud?’ is a superficial take when it comes to noise, Walker says.
After realizing the impact of noise on her own health, Erica Walker was inspired to change careers and become director of the Community Noise Lab at the Brown University School of Public Health.
Erica Walker
Fink adds that the extent to which noise impairs hearing is underestimated. People assume hearing loss is due to age but it’s not inevitable, he says. He cites studies of older people living in quiet, isolated areas who maintain excellent hearing. Just like you can prevent wrinkles by using sunscreen, you can preserve hearing by using ear plugs when attending fireworks or hockey games.
You can enable push notifications on a Smart Watch to alert you at a bar exceeding healthy sound levels. Free apps like SoundPrint, iHEARu, or NoiseTube can do decibel checks, too, but you don’t need one, says Fink. “If you can’t carry a conversation at normal volume, it’s too loud and your auditory health is at risk,” he says.
About 40 million U.S. adults, ages 20-69, have noise-induced hearing loss. Fink is among them after experiencing tinnitus (ringing or buzzing in the ears) on leaving a raucous New Year’s Eve party in 2007. The condition is permanent and he wears earplugs now for protection.
Fewer are aware of the link between noise pollution and heart disease. Piercing noise is stressful, raising blood pressure and heart rate. If you live near a freeway or constantly barking dog, the chronic sound stress can trigger systemic inflammation and the vascular changes associated with heart attacks and stroke.
Researchers at Rutgers University’s Robert Wood Johnson Medical School, working with data from the state’s Bureau of Transportation, determined that 1 in 20 heart attacks in New Jersey during 2018 were due to noise from highways, trains and air traffic. That’s 800 heart attack hospitalizations in the state that year.
Another study showed that incidence of hypertension and hardening arteries decreased during the Covid-19 air lockdown among Poles in Krakow routinely exposed to aircraft noise. The authors, comparing their pre-pandemic 2015 results to 2020 data, concluded it was no coincidence.
Mental health takes a hit, too. Chronic noise can provoke anxiety, depression and violence. Cognitively, there is ample evidence that noise disturbance lowers student achievement and worker productivity, and hearing loss among older people can speed up cognitive decline.
Noise also contributes to health disparities. People in neighborhoods with low socioeconomic status and a higher percentage of minority residents bear the brunt of noise. Affluent people have the means to live far from airports, factories, and honking traffic.
Out, Out, Damn Noise
Europe is ahead of the U.S. in tackling noise pollution. The World Health Organization developed policy guidelines used by the European Environment Agency to establish noise regulations and standards, and progress reports are issued.
Americans are relying too much on personal protective equipment (PPE) instead of eliminating or controlling noise. The Centers of Disease Control and Prevention rank PPE as the least useful response. Earplugs and muffs are effective, says Walker, but these devices are “a band-aid on a waterfall.”
Editing out noise during product design is the goal. Engineers have an arsenal of techniques and know-how for that. The problem is that these solutions aren’t being applied.
A better way to lower the volume is by maintaining or substituting equipment intended for common use. Piercing building alarms can be replaced with visual signals that flash alerts. Clanking chain and gear drives can be swapped out with belt drives. Acoustical barriers can wall off highway noise. Hospitals can soften beeping monitors and limit loudspeaker blasts. Double paned windows preserve quiet.
Editing out noise during product design is the goal. Engineers have an arsenal of techniques and know-how for that. The problem is that these solutions aren’t being applied, says Jim Thompson, an engineer and editor of the Noise Control Engineering Journal, published by the Institute of Noise Control Engineering of the USA
Engineers have materials to insulate, absorb, reflect, block, seal or diffuse noise. Building walls can be padded. Metal gears and parts can be replaced with plastic. Clattering equipment wheels can be rubberized. In recent years, building certifications such as LEED have put more emphasis on designs that minimize harmful noise.
Walker faults urban planners, too. A city’s narrow streets and taller buildings create a canyon effect which intensifies noise. City planners could use bypasses, rerouting, and other infrastructure strategies to pump down traffic volume. Sound-absorbing asphalt pavement exists, too.
Some municipalities are taking innovative measures on their own. Noise cameras have been installed in Knoxville, Miami and New York City this year and six California cities will join suit next year. If your muffler or audio system registers 86 dB or higher, you may receive a warning, fine or citation, similar to how a red-light camera works. Rueter predicts these cameras will become commonplace.
Based on understanding how metabolic processes affect noise-induced hearing loss in animal models, scientists are exploring whether pharmacological interventions might work to inhibit cellular damage or improve cellular defenses against noise.
Washington, DC, and the University of Southern California have banned gas-powered leaf blowers in lieu of quieter battery-powered models to reduce both noise and air pollution. California will be the first state to ban the sale of gas-powered lawn equipment starting 2024.
New York state legislators enacted the SLEEP (Stop Loud and Excessive Exhaust Pollution) Act in 2021. This measure increases enforcement and fines against motorists and repair shops that illegally modify mufflers and exhaust systems for effect.
“A lot more basic science and application research is needed [to control noise],” says Thompson, noting that funding for this largely dried up after the 1970s. Based on understanding how metabolic processes affect noise-induced hearing loss in animal models, scientists are exploring whether pharmacological interventions might work to inhibit cellular damage or improve cellular defenses against noise.
Studying biochemical or known genetic markers for noise risk could lead to other methods for preventing hearing loss. This would offer an opportunity to identify people with significant risk so those more susceptible to hearing loss could start taking precautions to avoid noise or protect their ears in childhood.
These efforts could become more pressing in the near future, with the anticipated onslaught of drones, rising needs for air conditioners, and urban sprawl boding poorly for the soundscape. This, as deforestation destroys natural carbon absorption reservoirs and removes sound-buffering trees.
“Local and state governments don’t have a plan to deal with [noise] now or in the future,” says Walker. “We need to think about this with intentionality.”