Lynn Julian Crisci, a 40-year-old actress with Ehlers-Danlos syndrome, is eager for gene editing treatments; she is pictured here with her service dog, a Maltese named Lil Stinker.
Lynn Julian Crisci, 40, is an actress, a singer-songwriter, and an ambassador for the U.S. Pain Foundation. She is also a Boston Marathon bombing survivor. Crisci has a genetic disorder called Ehlers-Danlos syndrome (EDS), which has magnified the impact of the traumatic brain injury she sustained as a result of the attack that occurred almost five years ago. Having EDS means that her brain tissue is weaker and more prone to injury.
"I would love to learn more about gene editing and the possibilities of using it to lessen the symptoms of EDS, or cure it completely."
"EDS is a genetic tissue disorder that forces the body to make defective collagen," Crisci told LeapsMag. Since collagen is the main component of connective tissue (bones, blood vessels, the gastrointestinal tract, skin, cartilage, etc.), and is the most abundant protein in mammals, EDS can affect virtually every part of the body. "This results in widespread joint pain, usually due to hypermobility, sometimes along with digestive issues such as inflammatory bowel disease, and prolapsed organs."
If life was difficult with Ehlers-Danlos syndrome alone, the addition of the brain injury has made Crisci's life feel unbearable at times. Amidst her week's back-to-back doctor's visits, Crisci said that she would "love to learn more about gene editing and the possibilities of using it to lessen the symptoms of Ehlers-Danlos syndrome, or cure it completely."
With all of the excitement these days around CRISPR, a precise and efficient way to edit DNA that has taken the world by storm, such treatments seem tantalizingly within reach. But is it fair to present the hope of such cures to those with life-limiting genetic disorders?
"From the experience that we've had from gene therapy — we're 20, almost 30 years past some of the initial gene therapy stuff — and there's still not a huge number of applications for it," said Scott Weissman, founder of Chicago Genetic Consultants, a company that provides genetic counseling services to patients. "Unfortunately, we have to wait and see if this is something that's truly viable, or if it's really just hype."
"I expect five years from now we'll look back and say, 'Wow, we were just scratching the surface.'"
Defining Our Terms
The terms "gene therapy" and "gene editing" are often used interchangeably, but not everyone agrees with this usage.
According to Editas Medicine, a leader in CRISPR technology, gene therapy involves the transfer of a new gene into a patient's cells to augment a defective gene, instead of using drugs or surgery to treat a condition. After a teenager's death in 1999 effectively shut down gene therapy research in the U.S., subsequent studies helped the field make a comeback, and the first such treatment for an inherited disease was approved by the FDA just a few weeks ago, for a rare form of vision loss. Called Luxturna, it is for treatment of patients with RPE65-mediated inherited retinal disease (IRD).
Since those with RPE65-mediated IRD typically become blind in childhood and have no pharmacologic treatment options, the FDA's approval of Luxturna is "a significant moment for patients," said Jeffrey Marrazzo, the chief executive officer of the company behind the product, Spark Therapeutics. Two other gene therapy treatments were also approved in the last five months, both for specific cancers.
Gene editing, on the other hand, refers to a group of technologies that enables scientists to precisely and directly change an organism's genes by adding, removing, or altering particular segments of DNA. Gene editing tools include Zinc Finger Nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), and CRISPR/Cas9. The first treatment using ZFNs happened in November in California, when a 44-year-old man with a metabolic ailment called Hunter syndrome was injected with gene editing tools. Results are not yet known.
Dr. David Valle, director of the Institute of Genetic Medicine at Johns Hopkins, said that gene therapy's "significant therapeutic misadventures" have actually been beneficial. They've helped us learn to "be rigorous in our thinking about what we can do and what we can't do with CRISPR" and other gene editing tools.
"It appears like we are really beginning to have, for the first time, some meaningful and good results from gene therapy — it's moving into the clinic now in a meaningful way," Valle said. "I expect five years from now we'll look back and say, 'Wow, we were just at this point in 2017 — we were just scratching the surface.'"
Over 2300 gene therapy clinical trials are planned, ongoing, or have been completed so far. As for gene editing, no treatments are commercially available anywhere in the world. The expectation, however, is that many treatments that are "currently in or soon to enter clinical trials will come up for approval in coming years," according to a November 2016 report by the American Society of Gene & Cell Therapy.
CRISPR Therapeutics of Cambridge, Massachusetts will begin a European gene editing trial this year, with the hopes of creating a treatment for beta thalassemia, an inherited blood disorder. The company will also request approval from the FDA to begin a clinical trial using CRISPR for sickle-cell disease. And Stanford University School of Medicine researchers are planning a similar CRISPR clinical trial for sickle-cell disease. They hope to begin their trial in 2019.
Jim Burns, the president and chief executive officer of Casebia Therapeutics, told Leapsmag that the company will start animal research this year using CRISPR to treat autoimmune diseases, hemophilia A, and retinal diseases. They expect to begin clinical research in humans in 2019 or 2020. [Disclosure: Casebia Therapeutics is a novel joint venture between CRISPR Therapeutics and Leapsmag's founder, Leaps by Bayer, though Leapsmag is editorially independent of Bayer.]
Efforts are well underway to take genome-targeted treatments from the scientist's bench to the patient's bedside.
The Technology Isn't There Yet
Unlike germline gene editing — when egg and sperm cell DNA is edited in an embryo — somatic cell gene editing in adults is not very controversial, because the edits are not heritable. Since somatic cells contribute to the various tissues of the body but not to eggs or sperm cells, changes made to somatic cells are limited to the treated individual.
The number one reason that gene therapy and gene editing treatments are not yet widely available to the adult population is that the technology is not advanced enough. But it's getting there.Efforts are well underway to take genome-targeted treatments from the scientist's bench to the patient's bedside — especially in the case of monogenic diseases.
Roughly 10,000 genetic illnesses are monogenic, meaning that they result from a disease-causing variant in a single gene. Some monogenic diseases that have gene editing treatments currently in development for use in clinical trials include cystic fibrosis, Huntington's disease, Tay-Sachs disease, and sickle cell anemia.
Marrazzo of Spark Therapeutics told LeapsMag that his company is working on gene therapies for monogenic diseases that affect the eye, like the retinal disease that Luxturna targets, as well as neurodegenerative and liver diseases.
But most illnesses are polygenic, meaning that they result from multiple gene mutations that have a combined influence on disease progression. Polygenic diseases, like high blood pressure and diabetes, would therefore be more challenging to treat with genome-targeted interventions. As a result, most research is currently focused on monogenic diseases.
"We don't really know how to target the gene editing to a specific organ in the body once it's fully developed and matured."
A major hurdle of gene editing is the risk of off-target effects. Editing the genome "can have unpredictable effects on gene expression and unintended effects on neighboring genes," wrote Morgan Maeder and Charles Gersbach in a March 2016 article in Molecular Therapy. One such unintended effect is the development of leukemia when a new gene unintentionally activates a cancer gene.
And since there are roughly 37 trillion cells in the adult human body, getting the gene editing machinery to enough cells or target tissues to create a lasting and significant change is a daunting task.
"We don't really know how to target the gene editing to a specific organ in the body once it's fully developed and matured," said Weissman, the genetic counseling expert. If you take an adult patient with known BRCA1 or BRCA2 mutations, for example, how do you then "get the [gene editing] system in the breast so that it accurately cuts out the mutation in every single breast cell that could potentially turn into breast cancer, or in every single ovarian cell that could turn into ovarian cancer? We don't know how to target it like that, and I think that's the biggest reason you're not seeing it more somatically at this point in time."
Approval and Access
Debra Mathews, assistant director for science programs for the Johns Hopkins Berman Institute of Bioethics, told LeapsMag that pre-existing regulatory frameworks surrounding gene therapy have been sufficient for addressing ethical and regulatory concerns surrounding gene editing. A bigger concern, she said, centers around access to future genome-targeted treatments.
"We know more about the genetics of Caucasian populations than other populations," Mathews explained, due to how genomic data is gathered. This "could lead to problems not just of financial but of biological access to new therapies." In other words, she said, "if you're of European ancestry, there may be a greater chance that there's a relevant genetically-targeted therapy for you than if you're of non-European ancestry."
Ensuring that genome-targeted treatments are accessible to all will require increased cooperation and data-sharing among key stakeholders around the world, as well as increased public engagement that is inclusive of a wide range of voices.
"It's important to be realistic in our predictions to the public."
The Coming Wave of Gene Editing Treatments
Ehlers-Danlos syndrome alone has 13 monogenic subtypes, each with its own genetic basis and set of clinical criteria. Though several of the gene mutations causing EDS subtypes have been identified, the genetic basis for the most common subtype that Lynn Julian Crisci has — hypermobile EDS — remains unknown. What this means, according to Valle, the doctor from Johns Hopkins, is that a gene therapy or gene editing approach "really cannot be contemplated because we don't know what we're trying to fix" yet. This is the case for many genetic illnesses.
Efforts are ongoing in gene discovery by organizations such as the Baylor-Hopkins Center for Mendelian Genomics, of which Valle is the principal investigator. "Our objective," he said, "is to identify the genes and variants responsible" in monogenic disorders.
While Valle is optimistic about the coming wave of commercially available gene therapy and gene editing treatments, he also thinks that "it's important to be realistic in our predictions to the public." As eager as physicians are to offer cures to their patients, "we have to make sure that we're rigorous in our thinking and our ideas are well-buttressed with results."
Estimates vary for how long Crisci and others with genetic illnesses will have to wait for genome-targeted treatment options. Depending on the illness, viable gene editing treatments could hit the market within the next ten years. Though patients have already waited a long while, the revolutionary technology allowing us to fix nature's mistakes could make up for lost time and lost hope.
In a phase 1 research trial announced late last month, patients reported that their symptoms had improved after stem cells were implanted into their brains.
For years, there's been little improvement in the standard treatment. Patients are typically given the drug levodopa, a chemical that's absorbed by the brain’s nerve cells, or neurons, and converted into dopamine. This drug addresses the symptoms but has no impact on the course of the disease as patients continue to lose dopamine producing neurons. Eventually, the treatment stops working effectively.
BlueRock Therapeutics, a cell therapy company based in Massachusetts, is taking a different approach by focusing on the use of stem cells, which can divide into and generate new specialized cells. The company makes the dopamine-producing cells that patients have lost and inserts these cells into patients' brains. “We have a disease with a high unmet need,” says Ahmed Enayetallah, the senior vice president and head of development at BlueRock. “We know [which] cells…are lost to the disease, and we can make them. So it really came together to use stem cells in Parkinson's.”
In a phase 1 research trial announced late last month, patients reported that their symptoms had improved after a year of treatment. Brain scans also showed an increased number of neurons generating dopamine in patients’ brains.
Increases in dopamine signals
The recent phase 1 trial focused on deploying BlueRock’s cell therapy, called bemdaneprocel, to treat 12 patients suffering from Parkinson’s. The team developed the new nerve cells and implanted them into specific locations on each side of the patient's brain through two small holes in the skull made by a neurosurgeon. “We implant cells into the places in the brain where we think they have the potential to reform the neural networks that are lost to Parkinson's disease,” Enayetallah says. The goal is to restore motor function to patients over the long-term.
Five patients were given a relatively low dose of cells while seven got higher doses. Specialized brain scans showed evidence that the transplanted cells had survived, increasing the overall number of dopamine producing cells. The team compared the baseline number of these cells before surgery to the levels one year later. “The scans tell us there is evidence of increased dopamine signals in the part of the brain affected by Parkinson's,” Enayetallah says. “Normally you’d expect the signal to go down in untreated Parkinson’s patients.”
"I think it has a real chance to reverse motor symptoms, essentially replacing a missing part," says Tilo Kunath, a professor of regenerative neurobiology at the University of Edinburgh.
The team also asked patients to use a specific type of home diary to log the times when symptoms are well controlled and when they prevent normal activity. After a year of treatment, patients taking the higher dose reported symptoms were under control for an average of 2.16 hours per day above their baselines. At the smaller dose, these improvements were significantly lower, 0.72 hours per day. The higher-dose patients reported a corresponding decrease in the amount of time when symptoms were uncontrolled, by an average of 1.91 hours, compared to 0.75 hours for the lower dose. The trial was safe, and patients tolerated the year of immunosuppression needed to make sure their bodies could handle the foreign cells.
Claire Bale, the associate director of research at Parkinson's U.K., sees the promise of BlueRock's approach, while noting the need for more research on a possible placebo effect. The trial participants knew they were getting the active treatment, and placebo effects are known to be a potential factor in Parkinson’s research. Even so, “The results indicate that this therapy produces improvements in symptoms for Parkinson's, which is very encouraging,” Bale says.
Tilo Kunath, a professor of regenerative neurobiology at the University of Edinburgh, also finds the results intriguing. “I think it's excellent,” he says. “I think it has a real chance to reverse motor symptoms, essentially replacing a missing part.” However, it could take time for this therapy to become widely available, Kunath says, and patients in the late stages of the disease may not benefit as much. “Data from cell transplantation with fetal tissue in the 1980s and 90s show that cells did not survive well and release dopamine in these [late-stage] patients.”
Searching for the right approach
There's a long history of using cell therapy as a treatment for Parkinson's. About four decades ago, scientists at the University of Lund in Sweden developed a method in which they transferred parts of fetal brain tissue to patients with Parkinson's so that their nerve cells would produce dopamine. Many benefited, and some were able to stop their medication. However, the use of fetal tissue was highly controversial at that time, and the tissues were difficult to obtain. Later trials in the U.S. showed that people benefited only if a significant amount of the tissue was used, and several patients experienced side effects. Eventually, the work lost momentum.
“Like many in the community, I'm aware of the long history of cell therapy,” says Taylor, the patient living with Parkinson's. “They've long had that cure over the horizon.”
In 2000, Lorenz Studer led a team at the Memorial Sloan Kettering Centre, in New York, to find the chemical signals needed to get stem cells to differentiate into cells that release dopamine. Back then, the team managed to make cells that produced some dopamine, but they led to only limited improvements in animals. About a decade later, in 2011, Studer and his team found the specific signals needed to guide embryonic cells to become the right kind of dopamine producing cells. Their experiments in mice, rats and monkeys showed that their implanted cells had a significant impact, restoring lost movement.
Studer then co-founded BlueRock Therapeutics in 2016. Forming the most effective stem cells has been one of the biggest challenges, says Enayetallah, the BlueRock VP. “It's taken a lot of effort and investment to manufacture and make the cells at the right scale under the right conditions.” The team is now using cells that were first isolated in 1998 at the University of Wisconsin, a major advantage because they’re available in a virtually unlimited supply.
Other efforts underway
In the past several years, University of Lund researchers have begun to collaborate with the University of Cambridge on a project to use embryonic stem cells, similar to BlueRock’s approach. They began clinical trials this year. A company in Japan, Sumitomo, is using a different strategy; instead of stem cells from embryos, they’re inducing pluripotent stem cells made from adults’ blood or skin and then reprogramming them into dopamine producing neurons. Although Sumitomo started clinical trials earlier than BlueRock, they haven’t yet revealed any results.
“It's a rapidly evolving field,” says Emma Lane, a pharmacologist at the University of Cardiff who researches clinical interventions for Parkinson’s. “But BlueRock’s trial is the first full phase 1 trial to report such positive findings with stem cell based therapies.” The company’s upcoming phase 2 research will be critical to show how effectively the therapy can improve disease symptoms, she added.
The cure over the horizon
BlueRock will continue to look at data from patients in the phase 1 trial to monitor the treatment’s effects over a two-year period. Meanwhile, the team is planning the phase 2 trial with more participants, including a placebo group.
For patients with Parkinson’s like Martin Taylor, the therapy offers some hope, though Taylor recognizes that more research is needed.
BlueRock Therapeutics
“Like many in the community, I'm aware of the long history of cell therapy,” he says. “They've long had that cure over the horizon.” His expectations are somewhat guarded but, he says, “it's certainly positive to see…movement in the field again.”
"If we can demonstrate what we’re seeing today in a more robust study, that would be great,” Enayetallah says. “At the end of the day, we want to address that unmet need in a field that's been waiting for a long time.”
Sparklers produce a beautiful display of light and heat by burning metal dust, which contains iron. The recent work of Canadian and Dutch researchers suggests we can use iron as a cheap, carbon-free fuel.
Iron as a fuel
Iron is abundantly available and cheap. More importantly, the byproduct of burning iron is rust (iron oxide), a solid material that is easy to collect and recycle. Neither burning iron nor converting its oxide back produces any carbon in the process.
Iron oxide is potentially renewable by reacting with electricity or hydrogen to become iron again.
Iron has a high energy density: it requires almost the same volume as gasoline to produce the same amount of energy. However, iron has poor specific energy: it’s a lot heavier than gas to produce the same amount of energy. (Think of picking up a jug of gasoline, and then imagine trying to pick up a similar sized chunk of iron.) Therefore, its weight is prohibitive for many applications. Burning iron to run a car isn’t very practical if the iron fuel weighs as much as the car itself.
In its powdered form, however, iron offers more promise as a high-density energy carrier or storage system. Iron-burning furnaces could provide direct heat for industry, home heating, or to generate electricity.
Plus, iron oxide is potentially renewable by reacting with electricity or hydrogen to become iron again (as long as you’ve got a source of clean electricity or green hydrogen). When there’s excess electricity available from renewables like solar and wind, for example, rust could be converted back into iron powder, and then burned on demand to release that energy again.
However, these methods of recycling rust are very energy intensive and inefficient, currently, so improvements to the efficiency of burning iron itself may be crucial to making such a circular system viable.
The science of discrete burning
Powdered particles have a high surface area to volume ratio, which means it is easier to ignite them. This is true for metals as well.
Under the right circumstances, powdered iron can burn in a manner known as discrete burning. In its most ideal form, the flame completely consumes one particle before the heat radiating from it combusts other particles in its vicinity. By studying this process, researchers can better understand and model how iron combusts, allowing them to design better iron-burning furnaces.
Discrete burning is difficult to achieve on Earth. Perfect discrete burning requires a specific particle density and oxygen concentration. When the particles are too close and compacted, the fire jumps to neighboring particles before fully consuming a particle, resulting in a more chaotic and less controlled burn.
Presently, the rate at which powdered iron particles burn or how they release heat in different conditions is poorly understood. This hinders the development of technologies to efficiently utilize iron as a large-scale fuel.
Burning metal in microgravity
In April, the European Space Agency (ESA) launched a suborbital “sounding” rocket, carrying three experimental setups. As the rocket traced its parabolic trajectory through the atmosphere, the experiments got a few minutes in free fall, simulating microgravity.
One of the experiments on this mission studied how iron powder burns in the absence of gravity.
In microgravity, particles float in a more uniformly distributed cloud. This allows researchers to model the flow of iron particles and how a flame propagates through a cloud of iron particles in different oxygen concentrations.
Existing fossil fuel power plants could potentially be retrofitted to run on iron fuel.
Insights into how flames propagate through iron powder under different conditions could help design much more efficient iron-burning furnaces.
Clean and carbon-free energy on Earth
Various businesses are looking at ways to incorporate iron fuels into their processes. In particular, it could serve as a cleaner way to supply industrial heat by burning iron to heat water.
For example, Dutch brewery Swinkels Family Brewers, in collaboration with the Eindhoven University of Technology, switched to iron fuel as the heat source to power its brewing process, accounting for 15 million glasses of beer annually. Dutch startup RIFT is running proof-of-concept iron fuel power plants in Helmond and Arnhem.
As researchers continue to improve the efficiency of burning iron, its applicability will extend to other use cases as well. But is the infrastructure in place for this transition?
Often, the transition to new energy sources is slowed by the need to create new infrastructure to utilize them. Fortunately, this isn’t the case with switching from fossil fuels to iron. Since the ideal temperature to burn iron is similar to that for hydrocarbons, existing fossil fuel power plants could potentially be retrofitted to run on iron fuel.
This article originally appeared on Freethink, home of the brightest minds and biggest ideas of all time.
