What’s the Right Way to Regulate Gene-Edited Crops?
In the next few decades, humanity faces its biggest food crisis since the invention of the plow. The planet's population, currently 7.6 billion, is expected to reach 10 billion by 2050; to avoid mass famine, according to the World Resource Institute, we'll need to produce 70 percent more calories than we do today.
Imagine that a cheap, easy-to-use, and rapidly deployable technology could make crops more fertile and strengthen their resistance to threats.
Meanwhile, climate change will bring intensifying assaults by heat, drought, storms, pests, and weeds, depressing farm yields around the globe. Epidemics of plant disease—already laying waste to wheat, citrus, bananas, coffee, and cacao in many regions—will spread ever further through the vectors of modern trade and transportation.
So here's a thought experiment: Imagine that a cheap, easy-to-use, and rapidly deployable technology could make crops more fertile and strengthen their resistance to these looming threats. Imagine that it could also render them more nutritious and tastier, with longer shelf lives and less vulnerability to damage in shipping—adding enhancements to human health and enjoyment, as well as reduced food waste, to the possible benefits.
Finally, imagine that crops bred with the aid of this tool might carry dangers. Some could contain unsuspected allergens or toxins. Others might disrupt ecosystems, affecting the behavior or very survival of other species, or infecting wild relatives with their altered DNA.
Now ask yourself: If such a technology existed, should policymakers encourage its adoption, or ban it due to the risks? And if you chose the former alternative, how should crops developed by this method be regulated?
In fact, this technology does exist, though its use remains mostly experimental. It's called gene editing, and in the past five years it has emerged as a potentially revolutionary force in many areas—among them, treating cancer and genetic disorders; growing transplantable human organs in pigs; controlling malaria-spreading mosquitoes; and, yes, transforming agriculture. Several versions are currently available, the newest and nimblest of which goes by the acronym CRISPR.
Gene editing is far simpler and more efficient than older methods used to produce genetically modified organisms (GMOs). Unlike those methods, moreover, it can be used in ways that leave no foreign genes in the target organism—an advantage that proponents argue should comfort anyone leery of consuming so-called "Frankenfoods." But debate persists over what precautions must be taken before these crops come to market.
Recently, two of the world's most powerful regulatory bodies offered very different answers to that question. The United States Department of Agriculture (USDA) declared in March 2018 that it "does not currently regulate, or have any plans to regulate" plants that are developed through most existing methods of gene editing. The Court of Justice of the European Union (ECJ), by contrast, ruled in July that such crops should be governed by the same stringent regulations as conventional GMOs.
Some experts suggest that the broadly permissive American approach and the broadly restrictive EU policy are equally flawed.
Each announcement drew protests, for opposite reasons. Anti-GMO activists assailed the USDA's statement, arguing that all gene-edited crops should be tested and approved before marketing. "You don't know what those mutations or rearrangements might do in a plant," warned Michael Hansen, a senior scientist with the advocacy group Consumers Union. Biotech boosters griped that the ECJ's decision would stifle innovation and investment. "By any sensible standard, this judgment is illogical and absurd," wrote the British newspaper The Observer.
Yet some experts suggest that the broadly permissive American approach and the broadly restrictive EU policy are equally flawed. "What's behind these regulatory decisions is not science," says Jennifer Kuzma, co-director of the Genetic Engineering and Society Center at North Carolina State University, a former advisor to the World Economic Forum, who has researched and written extensively on governance issues in biotechnology. "It's politics, economics, and culture."
The U.S. Welcomes Gene-Edited Food
Humans have been modifying the genomes of plants and animals for 10,000 years, using selective breeding—a hit-or-miss method that can take decades or more to deliver rewards. In the mid-20th century, we learned to speed up the process by exposing organisms to radiation or mutagenic chemicals. But it wasn't until the 1980s that scientists began modifying plants by altering specific stretches of their DNA.
Today, about 90 percent of the corn, cotton and soybeans planted in the U.S. are GMOs; such crops cover nearly 4 million square miles (10 million square kilometers) of land in 29 countries. Most of these plants are transgenic, meaning they contain genes from an unrelated species—often as biologically alien as a virus or a fish. Their modifications are designed primarily to boost profit margins for mechanized agribusiness: allowing crops to withstand herbicides so that weeds can be controlled by mass spraying, for example, or to produce their own pesticides to lessen the need for chemical inputs.
In the early days, the majority of GM crops were created by extracting the gene for a desired trait from a donor organism, multiplying it, and attaching it to other snippets of DNA—usually from a microbe called an agrobacterium—that could help it infiltrate the cells of the target plant. Biotechnologists injected these particles into the target, hoping at least one would land in a place where it would perform its intended function; if not, they kept trying. The process was quicker than conventional breeding, but still complex, scattershot, and costly.
Because agrobacteria can cause plant tumors, Kuzma explains, policymakers in the U.S. decided to regulate GMO crops under an existing law, the Plant Pest Act of 1957, which addressed dangers like imported trees infested with invasive bugs. Every GMO containing the DNA of agrobacterium or another plant pest had to be tested to see whether it behaved like a pest, and undergo a lengthy approval process. By 2010, however, new methods had been developed for creating GMOs without agrobacteria; such plants could typically be marketed without pre-approval.
Soon after that, the first gene-edited crops began appearing. If old-school genetic engineering was a shotgun, techniques like TALEN and CRISPR were a scalpel—or the search-and-replace function on a computer program. With CRISPR/Cas9, for example, an enzyme that bacteria use to recognize and chop up hostile viruses is reprogrammed to find and snip out a desired bit of a plant or other organism's DNA. The enzyme can also be used to insert a substitute gene. If a DNA sequence is simply removed, or the new gene comes from a similar species, the changes in the target plant's genotype and phenotype (its general characteristics) may be no different from those that could be produced through selective breeding. If a foreign gene is added, the plant becomes a transgenic GMO.
Companies are already teeing up gene-edited products for the U.S. market, like a cooking oil and waxy corn.
This development, along with the emergence of non-agrobacterium GMOs, eventually prompted the USDA to propose a tiered regulatory system for all genetically engineered crops, beginning with an initial screening for potentially hazardous metaboloids or ecological impacts. (The screening was intended, in part, to guard against the "off-target effects"—stray mutations—that occasionally appear in gene-edited organisms.) If no red flags appeared, the crop would be approved; otherwise, it would be subject to further review, and possible regulation.
The plan was unveiled in January 2017, during the last week of the Obama presidency. Then, under the Trump administration, it was shelved. Although the USDA continues to promise a new set of regulations, the only hint of what they might contain has been Secretary of Agriculture Sonny Perdue's statement last March that gene-edited plants would remain unregulated if they "could otherwise have been developed through traditional breeding techniques, as long as they are not plant pests or developed using plant pests."
Because transgenic plants could not be "developed through traditional breeding techniques," this statement could be taken to mean that gene editing in which foreign DNA is introduced might actually be regulated. But because the USDA regulates conventional transgenic GMOs only if they trigger the plant-pest stipulation, experts assume gene-edited crops will face similarly limited oversight.
Meanwhile, companies are already teeing up gene-edited products for the U.S. market. An herbicide-resistant oilseed rape, developed using a proprietary technique, has been available since 2016. A cooking oil made from TALEN-tweaked soybeans, designed to have a healthier fatty-acid profile, is slated for release within the next few months. A CRISPR-edited "waxy" corn, designed with a starch profile ideal for processed foods, should be ready by 2021.
In all likelihood, none of these products will have to be tested for safety.
In the E.U., Stricter Rules Apply
Now let's look at the European Union. Since the late 1990s, explains Gregory Jaffe, director of the Project on Biotechnology at the Center for Science in the Public Interest, the EU has had a "process-based trigger" for genetically engineered products: "If you use recombinant DNA, you are going to be regulated." All foods and animal feeds must be approved and labeled if they consist of or contain more than 0.9 percent GM ingredients. (In the U.S., "disclosure" of GM ingredients is mandatory, if someone asks, but labeling is not required.) The only GM crop that can be commercially grown in EU member nations is a type of insect-resistant corn, though some countries allow imports.
European scientists helped develop gene editing, and they—along with the continent's biotech entrepreneurs—have been busy developing applications for crops. But European farmers seem more divided over the technology than their American counterparts. The main French agricultural trades union, for example, supports research into non-transgenic gene editing and its exemption from GMO regulation. But it was the country's small-farmers' union, the Confédération Paysanne, along with several allied groups, that in 2015 submitted a complaint to the ECJ, asking that all plants produced via mutagenesis—including gene-editing—be regulated as GMOs.
At this point, it should be mentioned that in the past 30 years, large population studies have found no sign that consuming GM foods is harmful to human health. GMO critics can, however, point to evidence that herbicide-resistant crops have encouraged overuse of herbicides, giving rise to poison-proof "superweeds," polluting the environment with suspected carcinogens, and inadvertently killing beneficial plants. Those allegations were key to the French plaintiffs' argument that gene-edited crops might similarly do unexpected harm. (Disclosure: Leapsmag's parent company, Bayer, recently acquired Monsanto, a maker of herbicides and herbicide-resistant seeds. Also, Leaps by Bayer, an innovation initiative of Bayer and Leapsmag's direct founder, has funded a biotech startup called JoynBio that aims to reduce the amount of nitrogen fertilizer required to grow crops.)
The ruling was "scientifically nonsensical. It's because of things like this that I'll never go back to Europe."
In the end, the EU court found in the Confédération's favor on gene editing—though the court maintained the regulatory exemption for mutagenesis induced by chemicals or radiation, citing the 'long safety record' of those methods.
The ruling was "scientifically nonsensical," fumes Rodolphe Barrangou, a French food scientist who pioneered CRISPR while working for DuPont in Wisconsin and is now a professor at NC State. "It's because of things like this that I'll never go back to Europe."
Nonetheless, the decision was consistent with longstanding EU policy on crops made with recombinant DNA. Given the difficulty and expense of getting such products through the continent's regulatory system, many other European researchers may wind up following Barrangou to America.
Getting to the Root of the Cultural Divide
What explains the divergence between the American and European approaches to GMOs—and, by extension, gene-edited crops? In part, Jennifer Kuzma speculates, it's that Europeans have a different attitude toward eating. "They're generally more tied to where their food comes from, where it's produced," she notes. They may also share a mistrust of government assurances on food safety, borne of the region's Mad Cow scandals of the 1980s and '90s. In Catholic countries, consumers may have misgivings about tinkering with the machinery of life.
But the principal factor, Kuzma argues, is that European and American agriculture are structured differently. "GM's benefits have mostly been designed for large-scale industrial farming and commodity crops," she says. That kind of farming is dominant in the U.S., but not in Europe, leading to a different balance of political power. In the EU, there was less pressure on decisionmakers to approve GMOs or exempt gene-edited crops from regulation—and more pressure to adopt a GM-resistant stance.
Such dynamics may be operating in other regions as well. In China, for example, the government has long encouraged research in GMOs; a state-owned company recently acquired Syngenta, a Swiss-based multinational corporation that is a leading developer of GM and gene-edited crops. GM animal feed and cooking oil can be freely imported. Yet commercial cultivation of most GM plants remains forbidden, out of deference to popular suspicions of genetically altered food. "As a new item, society has debates and doubts on GMO techniques, which is normal," President Xi Jinping remarked in 2014. "We must be bold in studying it, [but] be cautious promoting it."
The proper balance between boldness and caution is still being worked out all over the world. Europe's process-based approach may prevent researchers from developing crops that, with a single DNA snip, could rescue millions from starvation. EU regulations will also make it harder for small entrepreneurs to challenge Big Ag with a technology that, as Barrangou puts it, "can be used affordably, quickly, scalably, by anyone, without even a graduate degree in genetics." America's product-based approach, conversely, may let crops with hidden genetic dangers escape detection. And by refusing to investigate such risks, regulators may wind up exacerbating consumers' doubts about GM and gene-edited products, rather than allaying them.
"Science...can't tell you what to regulate. That's a values-based decision."
Perhaps the solution lies in combining both approaches, and adding some flexibility and nuance to the mix. "I don't believe in regulation by the product or the process," says CSPI's Jaffe. "I think you need both." Deleting a DNA base pair to silence a gene, for example, might be less risky than inserting a foreign gene into a plant—unless the deletion enables the production of an allergen, and the transgene comes from spinach.
Kuzma calls for the creation of "cooperative governance networks" to oversee crop genome editing, similar to bodies that already help develop and enforce industry standards in fisheries, electronics, industrial cleaning products, and (not incidentally) organic agriculture. Such a network could include farmers, scientists, advocacy groups, private companies, and governmental agencies. "Safety isn't an all-or-nothing concept," Kuzma says. "Science can tell you what some of the issues are in terms of risk and benefit, but it can't tell you what to regulate. That's a values-based decision."
By drawing together a wide range of stakeholders to make such decisions, she adds, "we're more likely to anticipate future consequences, and to develop a robust approach—one that not only seems more legitimate to people, but is actually just plain old better."
How the Human Brain Project Built a Mind of its Own
In 2009, neuroscientist Henry Markram gave an ambitious TED talk. “Our mission is to build a detailed, realistic computer model of the human brain,” he said, naming three reasons for this unmatched feat of engineering. One was because understanding the human brain was essential to get along in society. Another was because experimenting on animal brains could only get scientists so far in understanding the human ones. Third, medicines for mental disorders weren’t good enough. “There are two billion people on the planet that are affected by mental disorders, and the drugs that are used today are largely empirical,” Markram said. “I think that we can come up with very concrete solutions on how to treat disorders.”
Markram's arguments were very persuasive. In 2013, the European Commission launched the Human Brain Project, or HBP, as part of its Future and Emerging Technologies program. Viewed as Europe’s chance to try to win the “brain race” between the U.S., China, Japan, and other countries, the project received about a billion euros in funding with the goal to simulate the entire human brain on a supercomputer, or in silico, by 2023.
Now, after 10 years of dedicated neuroscience research, the HBP is coming to an end. As its many critics warned, it did not manage to build an entire human brain in silico. Instead, it achieved a multifaceted array of different goals, some of them unexpected.
Scholars have found that the project did help advance neuroscience more than some detractors initially expected, specifically in the area of brain simulations and virtual models. Using an interdisciplinary approach of combining technology, such as AI and digital simulations, with neuroscience, the HBP worked to gain a deeper understanding of the human brain’s complicated structure and functions, which in some cases led to novel treatments for brain disorders. Lastly, through online platforms, the HBP spearheaded a previously unmatched level of global neuroscience collaborations.
Simulating a human brain stirs up controversy
Right from the start, the project was plagued with controversy and condemnation. One of its prominent critics was Yves Fregnac, a professor in cognitive science at the Polytechnic Institute of Paris and research director at the French National Centre for Scientific Research. Fregnac argued in numerous articles that the HBP was overfunded based on proposals with unrealistic goals. “This new way of over-selling scientific targets, deeply aligned with what modern society expects from mega-sciences in the broad sense (big investment, big return), has been observed on several occasions in different scientific sub-fields,” he wrote in one of his articles, “before invading the field of brain sciences and neuromarketing.”
"A human brain model can simulate an experiment a million times for many different conditions, but the actual human experiment can be performed only once or a few times," said Viktor Jirsa, a professor at Aix-Marseille University.
Responding to such critiques, the HBP worked to restructure the effort in its early days with new leadership, organization, and goals that were more flexible and attainable. “The HBP got a more versatile, pluralistic approach,” said Viktor Jirsa, a professor at Aix-Marseille University and one of the HBP lead scientists. He believes that these changes fixed at least some of HBP’s issues. “The project has been on a very productive and scientifically fruitful course since then.”
After restructuring, the HBP became a European hub on brain research, with hundreds of scientists joining its growing network. The HBP created projects focused on various brain topics, from consciousness to neurodegenerative diseases. HBP scientists worked on complex subjects, such as mapping out the brain, combining neuroscience and robotics, and experimenting with neuromorphic computing, a computational technique inspired by the human brain structure and function—to name just a few.
Simulations advance knowledge and treatment options
In 2013, it seemed that bringing neuroscience into a digital age would be farfetched, but research within the HBP has made this achievable. The virtual maps and simulations various HBP teams create through brain imaging data make it easier for neuroscientists to understand brain developments and functions. The teams publish these models on the HBP’s EBRAINS online platform—one of the first to offer access to such data to neuroscientists worldwide via an open-source online site. “This digital infrastructure is backed by high-performance computers, with large datasets and various computational tools,” said Lucy Xiaolu Wang, an assistant professor in the Resource Economics Department at the University of Massachusetts Amherst, who studies the economics of the HBP. That means it can be used in place of many different types of human experimentation.
Jirsa’s team is one of many within the project that works on virtual brain models and brain simulations. Compiling patient data, Jirsa and his team can create digital simulations of different brain activities—and repeat these experiments many times, which isn’t often possible in surgeries on real brains. “A human brain model can simulate an experiment a million times for many different conditions,” Jirsa explained, “but the actual human experiment can be performed only once or a few times.” Using simulations also saves scientists and doctors time and money when looking at ways to diagnose and treat patients with brain disorders.
Compiling patient data, scientists can create digital simulations of different brain activities—and repeat these experiments many times.
The Human Brain Project
Simulations can help scientists get a full picture that otherwise is unattainable. “Another benefit is data completion,” added Jirsa, “in which incomplete data can be complemented by the model. In clinical settings, we can often measure only certain brain areas, but when linked to the brain model, we can enlarge the range of accessible brain regions and make better diagnostic predictions.”
With time, Jirsa’s team was able to move into patient-specific simulations. “We advanced from generic brain models to the ability to use a specific patient’s brain data, from measurements like MRI and others, to create individualized predictive models and simulations,” Jirsa explained. He and his team are working on this personalization technique to treat patients with epilepsy. According to the World Health Organization, about 50 million people worldwide suffer from epilepsy, a disorder that causes recurring seizures. While some epilepsy causes are known others remain an enigma, and many are hard to treat. For some patients whose epilepsy doesn’t respond to medications, removing part of the brain where seizures occur may be the only option. Understanding where in the patients’ brains seizures arise can give scientists a better idea of how to treat them and whether to use surgery versus medications.
“We apply such personalized models…to precisely identify where in a patient’s brain seizures emerge,” Jirsa explained. “This guides individual surgery decisions for patients for which surgery is the only treatment option.” He credits the HBP for the opportunity to develop this novel approach. “The personalization of our epilepsy models was only made possible by the Human Brain Project, in which all the necessary tools have been developed. Without the HBP, the technology would not be in clinical trials today.”
Personalized simulations can significantly advance treatments, predict the outcome of specific medical procedures and optimize them before actually treating patients. Jirsa is watching this happen firsthand in his ongoing research. “Our technology for creating personalized brain models is now used in a large clinical trial for epilepsy, funded by the French state, where we collaborate with clinicians in hospitals,” he explained. “We have also founded a spinoff company called VB Tech (Virtual Brain Technologies) to commercialize our personalized brain model technology and make it available to all patients.”
The Human Brain Project created a level of interconnectedness within the neuroscience research community that never existed before—a network not unlike the brain’s own.
Other experts believe it’s too soon to tell whether brain simulations could change epilepsy treatments. “The life cycle of developing treatments applicable to patients often runs over a decade,” Wang stated. “It is still too early to draw a clear link between HBP’s various project areas with patient care.” However, she admits that some studies built on the HBP-collected knowledge are already showing promise. “Researchers have used neuroscientific atlases and computational tools to develop activity-specific stimulation programs that enabled paraplegic patients to move again in a small-size clinical trial,” Wang said. Another intriguing study looked at simulations of Alzheimer’s in the brain to understand how it evolves over time.
Some challenges remain hard to overcome even with computer simulations. “The major challenge has always been the parameter explosion, which means that many different model parameters can lead to the same result,” Jirsa explained. An example of this parameter explosion could be two different types of neurodegenerative conditions, such as Parkinson’s and Huntington’s diseases. Both afflict the same area of the brain, the basal ganglia, which can affect movement, but are caused by two different underlying mechanisms. “We face the same situation in the living brain, in which a large range of diverse mechanisms can produce the same behavior,” Jirsa said. The simulations still have to overcome the same challenge.
Understanding where in the patients’ brains seizures arise can give scientists a better idea of how to treat them and whether to use surgery versus medications.
The Human Brain Project
A network not unlike the brain’s own
Though the HBP will be closing this year, its legacy continues in various studies, spin-off companies, and its online platform, EBRAINS. “The HBP is one of the earliest brain initiatives in the world, and the 10-year long-term goal has united many researchers to collaborate on brain sciences with advanced computational tools,” Wang said. “Beyond the many research articles and projects collaborated on during the HBP, the online neuroscience research infrastructure EBRAINS will be left as a legacy even after the project ends.”
Those who worked within the HBP see the end of this project as the next step in neuroscience research. “Neuroscience has come closer to very meaningful applications through the systematic link with new digital technologies and collaborative work,” Jirsa stated. “In that way, the project really had a pioneering role.” It also created a level of interconnectedness within the neuroscience research community that never existed before—a network not unlike the brain’s own. “Interconnectedness is an important advance and prerequisite for progress,” Jirsa said. “The neuroscience community has in the past been rather fragmented and this has dramatically changed in recent years thanks to the Human Brain Project.”
According to its website, by 2023 HBP’s network counted over 500 scientists from over 123 institutions and 16 different countries, creating one of the largest multi-national research groups in the world. Even though the project hasn’t produced the in-silico brain as Markram envisioned it, the HBP created a communal mind with immense potential. “It has challenged us to think beyond the boundaries of our own laboratories,” Jirsa said, “and enabled us to go much further together than we could have ever conceived going by ourselves.”
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.”