The opioid crisis depicted with a map of the USA filled with oxycodone and hydrocodone pills.
The largest ever seizure of fentanyl in the United States – 254 pounds of the white powder, enough to kill 1 in 3 Americans by overdose – was found under a shipment of cucumbers recently.
A policing approach alone is insufficient to take on the opioid crisis.
Those types of stories barely make the headlines any more, in part because illicit drugs are no longer just handsold by drug dealers; these sales have gone online. The neighborhood dealer faces the same evolving environment as other retailers and may soon go the way of Sears.
But opioids themselves are not going away. I could make an opioid purchase online in about 30 seconds and have it sent to my door, says Joe Smyser. The epidemiologist and president of The Public Good Projects isn't bragging, he's simply stating a fact about the opioid crisis that has struck the United States. The U.S Drug Enforcement Agency, social media companies, and some foreign governments have undertaken massive efforts to shut down sites selling illegal drugs, and they have gotten very good at it, shuttering most within a day of their opening.
But it's a Whac-A-Mole situation in which new ones pop up as quickly as older ones are closed; they are promoted through hashtags, social media networks, and ubiquitous email spam to lure visitors to a website or call a WhatsApp number to make a purchase. The online disruption by law enforcement has become simply another cost of doing business for drug sellers. Fentanyl, and similar analogues created to evade detection and the law, are at the center of it. Small amounts can be mixed with other "safer" opioids to get a high, and the growth of online sales have all contributed to the surge of opioid-related deaths: about 17,500 in 2006; 47,600 in 2017; and a projected 82,000 a year by 2025.
All of this has occurred even while authorities have been cracking down on the prescribing of opioids, and prescription-related deaths have declined. Clearly a policing approach alone is insufficient to take on the opioid crisis.
Building the Tools
The Public Good Projects (PGP), a nonprofit organization founded by concerned experts, was set up to better understand public health issues in this new online environment and better shape responses. The first step is to understand what people are hearing and the language they are using by monitoring social media and other forms of public communications. "We're collecting data from every publicly available media source that we can get our hands on. It's broadcast television data, it's radio, it's print newspapers and magazines. And then it's online data; it's online video, social media, blogs, websites," Smyser explains.
The purpose was to better understand the opioid crisis and find out if there were differences between affected rural and urban populations.
"Then our job is to create queries, create searches of all of that data so that we find what is the information that Americans are exposed to about a topic, and then what … Americans [are] sharing amongst themselves about that same topic."
He says it's the same thing business has been doing for years to monitor their "brand health" and be prepared for possible negative issues that might arise about their products and services. He believes PGP is the first group to use those tools for public health.
Looking At Opioids
PGP's work on opioids started with a contract from the Substance Abuse and Mental Health Administration (SAMHSA) through the National Science Foundation. The purpose was simply to better understand the opioid crisis in the United States and in particular find out if there were differences between affected rural and urban populations. A team of data scientists, public health professionals, and cultural anthropologists needed several months to sort out and organize the algorithms from the sheer volume of data.
Drug use is particularly rich in slang, where a specific drug or way of using it can be referred to in multiple ways in different towns and social groups. Traditional media often uses clinical terms, Twitter shorthand, and all of that has to be structured and integrated "so that it isn't just spitting out data that is gobbledygook and of no use to anyone," says Smyser.
The data they gather is both cumulative and in real time, tabulated and visually represented in constantly morphing hashtag and word clouds where the color and size of the word indicates the source and volume of its use.
Popular hashtags on Twitter relating to the opioid crisis.
(Credit: The Public Good Projects)
The visual presentation of data helps to understand what different groups are saying and how they are saying it. For example, compare the hashtag and word clouds. Younger people are more likely to use the hashtags of Twitter, while older people are more likely to use older forms of media, and that is reflected in their concerns and language in those clouds.
Popular words relating to the opioid crisis gathered from older forms of media.
(Credit: The Public Good Projects)
A Ping map shows the origin of messages, while a Spidey map shows the network of how messages are being forwarded and shared among people. These sets of data can be overlaid with zip code, census, and socioeconomic data to provide an even deeper sense of who is saying what. And when integrated together, they provide clues to topics and language that might best engage people in each niche.
A Ping map showing the origin of messages around the opioid crisis.
(Credit: The Public Good Projects)
Opioids Speak
One thing that quickly became apparent to PGP in monitoring the media is that "over half of the information that the American public is exposed to about opioids is a very distant policy debate," says Smyser.
It is political pronouncements in DC, the legal system going after pharmaceutical companies that promoted prescription opioids for pain relief (and more), or mandatory prison terms for offenders. Relatively little is about treatment, the impact on families and communities, and what people can do themselves. That is particularly important in light of another key finding: residents of "Trump-land," the rural areas that supported the president and are being ravaged by opioids, talk about the problem and solutions very differently from urban areas.
"In rural communities there is usually a huge emphasis on self-reliance, and we take care of each other; that's why we enjoy living here. We are a neighborhood, we come together and we fix our own problems," according to Smyser.
In contrast, urban communities tend to be more transient, less likely to live in multigenerational households and neighborhoods, and look to formal institutions rather than themselves for solutions. "The message that we're sending people is one where there is really no role whatsoever for self-efficacy...we're giving them nothing to do" to help solve the problem themselves, says Smyser. "In fact, I could argue it is reducing self-efficacy."
Residents of "Trump-land," the rural areas that supported the president and are being ravaged by opioids, talk about the problem and solutions very differently from urban areas.
The opioid crisis is complex and improving the situation will be too. Smyser believes a top-down policing approach alone will not work; it is better to provide front-line public health officers at the state and local level with more and current intelligence so they can respond in their communities.
"I think that would be enormously impactful. But right now, we just don't have that service." SAMHSA declined multiple requests to discuss this project paid for with federal money. A spokesman concluded with: "That project occurred under the previous administration, and we did not have a direct relationship with PGP. As a result, I am unable to comment on the project."
The Milken Institute Center for Public Health, a think tank that is working to find solutions to the opioid epidemic, had an upbeat response. Director Sabrina Spitaletta said, "PGP's work to provide real-time data that monitors topics of high concern in public health has been very helpful to many of the front-line organizations working to combat this crisis."
Swiss researchers have found a type of brain cell that appears to be a hybrid of the two other main types — and it could lead to new treatments for brain disorders.
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.
In a recent research trial, patients with Parkinson's disease reported that their symptoms had improved after stem cells were implanted into their brains. Martin Taylor, far right, was diagnosed at age 32.
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.
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, 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.”