More Progress, Faster, Is Our Best Defense Against This Pandemic and Future Ones
With a deadly pandemic sweeping the planet, many are questioning the comfort and security we have taken for granted in the modern world.
A century ago, when an influenza pandemic struck, we barely knew what viruses were.
More than a century after the germ theory, we are still at the mercy of a microbe we can neither treat, nor control, nor immunize against. Even more discouraging is that technology has in some ways exacerbated the problem: cars and air travel allow a new disease to quickly encompass the globe.
Some say we have grown complacent, that we falsely assume the triumphs of the past ensure a happy and prosperous future, that we are oblivious to the possibility of unpredictable "black swan" events that could cause our destruction. Some have begun to lose confidence in progress itself, and despair of the future.
But the new coronavirus should not defeat our spirit—if anything, it should spur us to redouble our efforts, both in the science and technology of medicine, and more broadly in the advance of industry. Because the best way to protect ourselves against future disasters is more progress, faster.
Science and technology have overall made us much better able to deal with disease. In the developed world, we have already tamed most categories of infectious disease. Most bacterial infections, such as tuberculosis or bacterial pneumonia, are cured with antibiotics. Waterborne diseases such as cholera are eliminated through sanitation; insect-borne ones such as malaria through pest control. Those that are not contagious until symptoms appear, such as SARS, can be handled through case isolation and contact tracing. For the rest, such as smallpox, polio, and measles, we develop vaccines, given enough time. COVID-19 could start a pandemic only because it fits a narrow category: a new, viral disease that is highly contagious via pre-symptomatic droplet/aerosol transmission, and that has a high mortality rate compared to seasonal influenza.
A century ago, when an influenza pandemic struck, we barely knew what viruses were; no one had ever seen one.Today we know what COVID-19 is down to its exact genome; in fact, we have sequenced thousands of COVID-19 genomes, and can track its history and its spread through their mutations. We can create vaccines faster today, too: where we once developed them in live animals, we now use cell cultures; where we once had to weaken or inactivate the virus itself, we can now produce vaccines based on the virus's proteins. And even though we don't yet have a treatment, the last century-plus of pharmaceutical research has given us a vast catalog of candidate drugs, already proven safe. Even now, over 50 candidate vaccines and almost 100 candidate treatments are in the research pipeline.
It's not just our knowledge that has advanced, but our methods. When smallpox raged in the 1700s, even the idea of calculating a case-fatality rate was an innovation. When the polio vaccine was trialled in the 1950s, the use of placebo-controlled trials was still controversial. The crucial measure of contagiousness, "R0", was not developed in epidemiology until the 1980s. And today, all of these methods are made orders of magnitude faster and more powerful by statistical and data visualization software.
If you're seeking to avoid COVID-19, the hand sanitizer gel you carry in a pocket or purse did not exist until the 1960s. If you start to show symptoms, the pulse oximeter that tests your blood oxygenation was not developed until the 1970s. If your case worsens, the mechanical ventilator that keeps you alive was invented in the 1950s—in fact, no form of artificial respiration was widely available until the "iron lung" used to treat polio patients in the 1930s. Even the modern emergency medical system did not exist until recently: if during the 1918 flu pandemic you became seriously ill, there was no 911 hotline to call, and any ambulance that showed up would likely have been a modified van or hearse, with no equipment or trained staff.
As many of us "shelter in place", we are far more able to communicate and collaborate, to maintain some semblance of normal life, than we ever would have been. To compare again to 1918: long-distance telephone service barely existed at that time, and only about a third of homes in the US even had electricity; now we can videoconference over Zoom and Skype. And the enormous selection and availability provided by online retail and food delivery have kept us stocked and fed, even when we don't want to venture out to the store.
Let the virus push us to redouble our efforts to make scientific, technological, and industrial progress on all fronts.
"Black swan" calamities can strike without warning at any time. Indeed, humanity has always been subject to them—drought and frost, fire and flood, war and plague. But we are better equipped now to deal with them than ever before. And the more progress we make, the better prepared we'll be for the next one. The accumulation of knowledge, technology, industrial infrastructure, and surplus wealth is the best buffer against any shock—whether a viral pandemic, a nuclear war, or an asteroid impact. In fact, the more worried we are about future crises, the more energetically we should accelerate science, technology and industry.
In this sense, we have grown complacent. We take the modern world for granted, so much so that some question whether further progress is even still needed. The new virus proves how much we do need it, and how far we still have to go. Imagine how different things would be if we had broad-spectrum antiviral drugs, or a way to enhance the immune system to react faster to infection, or a way to detect infection even before symptoms appear. These technologies may seem to belong to a Star Trek future—but so, at one time, did cell phones.
The virus reminds us that nature is indifferent to us, leaving us to fend entirely for ourselves. As we go to war against it, let us not take the need for such a war as reason for despair. Instead, let it push us to redouble our efforts to make scientific, technological, and industrial progress on all fronts. No matter the odds, applied intelligence is our best weapon against disaster.
Swiss researchers have discovered a third type of brain cell that appears to be a hybrid of the two other primary types — and it could lead to new treatments for many brain disorders.
The challenge: Most of the cells in the brain are either neurons or glial cells. While neurons use electrical and chemical signals to send messages to one another across small gaps called synapses, glial cells exist to support and protect neurons.
Astrocytes are a type of glial cell found near synapses. This close proximity to the place where brain signals are sent and received has led researchers to suspect that astrocytes might play an active role in the transmission of information inside the brain — a.k.a. “neurotransmission” — but no one has been able to prove the theory.
A new brain cell: Researchers at the Wyss Center for Bio and Neuroengineering and the University of Lausanne believe they’ve definitively proven that some astrocytes do actively participate in neurotransmission, making them a sort of hybrid of neurons and glial cells.
According to the researchers, this third type of brain cell, which they call a “glutamatergic astrocyte,” could offer a way to treat Alzheimer’s, Parkinson’s, and other disorders of the nervous system.
“Its discovery opens up immense research prospects,” said study co-director Andrea Volterra.
The study: Neurotransmission starts with a neuron releasing a chemical called a neurotransmitter, so the first thing the researchers did in their study was look at whether astrocytes can release the main neurotransmitter used by neurons: glutamate.
By analyzing astrocytes taken from the brains of mice, they discovered that certain astrocytes in the brain’s hippocampus did include the “molecular machinery” needed to excrete glutamate. They found evidence of the same machinery when they looked at datasets of human glial cells.
Finally, to demonstrate that these hybrid cells are actually playing a role in brain signaling, the researchers suppressed their ability to secrete glutamate in the brains of mice. This caused the rodents to experience memory problems.
“Our next studies will explore the potential protective role of this type of cell against memory impairment in Alzheimer’s disease, as well as its role in other regions and pathologies than those explored here,” said Andrea Volterra, University of Lausanne.
But why? The researchers aren’t sure why the brain needs glutamatergic astrocytes when it already has neurons, but Volterra suspects the hybrid brain cells may help with the distribution of signals — a single astrocyte can be in contact with thousands of synapses.
“Often, we have neuronal information that needs to spread to larger ensembles, and neurons are not very good for the coordination of this,” researcher Ludovic Telley told New Scientist.
Looking ahead: More research is needed to see how the new brain cell functions in people, but the discovery that it plays a role in memory in mice suggests it might be a worthwhile target for Alzheimer’s disease treatments.
The researchers also found evidence during their study that the cell might play a role in brain circuits linked to seizures and voluntary movements, meaning it’s also a new lead in the hunt for better epilepsy and Parkinson’s treatments.
“Our next studies will explore the potential protective role of this type of cell against memory impairment in Alzheimer’s disease, as well as its role in other regions and pathologies than those explored here,” said Volterra.
Martin Taylor was only 32 when he was diagnosed with Parkinson's, a disease that causes tremors, stiff muscles and slow physical movement - symptoms that steadily get worse as time goes on.
“It's horrible having Parkinson's,” says Taylor, a data analyst, now 41. “It limits my ability to be the dad and husband that I want to be in many cruel and debilitating ways.”
Today, more than 10 million people worldwide live with Parkinson's. Most are diagnosed when they're considerably older than Taylor, after age 60. Although recent research has called into question certain aspects of the disease’s origins, Parkinson’s eventually kills the nerve cells in the brain that produce dopamine, a signaling chemical that carries messages around the body to control movement. Many patients have lost 60 to 80 percent of these cells by the time they are diagnosed.
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 were well controlled and when they prevented 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 called Sumitomo is using a different strategy; instead of stem cells from embryos, they’re reprogramming adults' blood or skin cells into induced pluripotent stem cells - meaning they can turn into any cell type - and then directing 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.
“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, he says, but, “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.”