One Day, There Might Be a Drug for a Broken Heart
For Tony Y., 37, healing from heartbreak is slow and incomplete. Each of several exes is associated with a cluster of sore memories. Although he loves the Blue Ridge Mountains, he can't visit because they remind him of a romantic holiday years ago.
If a new drug made rejections less painful, one expert argues, it could relieve or even prevent major depression.
Like some 30 to 40 percent of depressed patients, Tony hasn't had success with current anti-depressants. One day, psychiatrists may be able to offer him a new kind of opioid, an anti-depressant for people suffering from the cruel pain of rejection.
A Surprising Discovery
As we move through life, rejections -- bullying in school, romantic breakups, and divorces -- are powerful triggers to depressive episodes, observes David Hsu, a neuroscientist at Stony Brook University School of Medicine in Long Island, New York. If a new drug made them less painful, he argues, it could relieve or even prevent major depression.
Our bodies naturally produce opioids to soothe physical pain, and opioid drugs like morphine and oxycodone work by plugging into the same receptors in our brains. The same natural opioids may also respond to emotional hurts, and painkillers can dramatically affect mood. Today's epidemic of opioid abuse raises the question: How many lives might have been saved if we had a safe, non-addictive option for medicating emotional pain?
Already one anti-depressant, tianeptine, locks into the mu opioid receptor, the target of morphine and oxycodone. Scientists knew that tianeptine, prescribed in some countries in Europe, Asia, and Latin America, acted differently than the most common anti-depressants in use today, which affect the levels of other brain chemicals, serotonin and norepinephrine. But the discovery in 2014 that tianeptine tapped the mu receptor was a "huge surprise," says co-author Jonathan Javitch, chief of the Division of Molecular Therapeutics at Columbia University.
The news arrived when scientists' basic understanding of depression is in flux; viewed biologically, it may cover several disorders. One of them could hinge on opioids. It's possible that some people release fewer opioids naturally or that the receptors for it are less effective.
Javitch has launched a startup, Kures, to make tianeptine more effective and convenient and to find other opioid-modulators. That may seem quixotic in the midst of an opioid epidemic, but tianeptine doesn't create dependency in low, prescription doses and has been used safely around the world for decades. To identify likely patients, cofounder Andrew Kruegel is looking for ways to "segment the depressed population by measures that have to do with opioid release," he says.
Is Emotional Pain Actually "Pain"?
No one imagines that the pain from rejection or loss is the same as pain from a broken leg. Physical pain is two perceptions—a sensory perception and an "affective" one, which makes pain unpleasant.
Exploration of an overlap between physical and what research psychologists call "social pain" has heated up since the mid-2000s.
The sensory perception, processed by regions of the brain called the primary and secondary somatosensory cortices and the posterior insula, tells us whether the pain is in your arm or your leg, how strong it is and whether it is a sting, ache, or has some other quality. The affective perception, in another part of the brain called the dorsal anterior cingulate cortex and the anterior insula, tells us that we want the pain to stop, fast! When people with lesions in the latter areas experience a stimulus that ordinarily would be painful, they don't mind it.
Science now suggests that emotional pain arises in the affective brain circuits. Exploration of an overlap between physical and what research psychologists call "social pain" has heated up since the mid-2000s. Animal evidence goes back to the 1970s: babies separated from their mothers showed less distress when given morphine, and more if dosed with naloxone, the opioid antagonist.
Parents, of course, face the question of whether Baby feels alone or wet whenever she howls. And the answer is: both hurt. Being abandoned is the ultimate threat in our early life, and it makes sense that a brain system to monitor social threats would piggyback upon an existing system for pain. Piggybacking is a feature of evolution. An ancestor who felt "hurt" when threatened by rejection might learn adaptive behavior: to cooperate or run.
In 2010, a large multi-university team led by Nathan DeWall at the University of Kentucky, reported that acetaminophen (Tylenol) reduced social pain. Undergraduates took 500 mg of acetaminophen upon awakening and at bedtime every day for three weeks and reported nightly about their day using a previously-tested "Hurt Feelings Scale," rating how strongly they agreed with questions like, "Today, being teased hurt my feelings."
Over the weeks, their reports of hurt feelings steadily declined, while remaining flat in a control group that took placebos. In a second experiment, the research group showed that, compared to controls, people who had taken acetaminophen for three weeks showed less brain activity in the affective brain circuits while they experienced rejection during a virtual ball-tossing game. Later, Hsu's brain scan research supported the idea that rejection triggers the mu opioid receptor system, which normally provides pain-dampening opioids.
More evidence comes from nonhuman primates with lesions in the affective circuits: They cry less when separated from caregivers or social groups.
Heartbreak seems to lie in those regions: women with major depression are more hurt by romantic rejection than normal controls are and show more activity in those areas in brain scans, Hsu found. Also, factors that make us more vulnerable to rejection -- like low self-esteem -- are linked to more activity in the key areas, studies show.
The trait "high rejection sensitivity" increases your risk of depression more than "global neuroticism" does, Hsu observes, and predicts a poor recovery from depression. Pain sensitivity is another clue: People with a gene linked to it seem to be more hurt by social exclusion. Once you're depressed, you become more rejection-sensitive and prone to pain—a classic bad feedback loop.
"Ideally, we'd have biomarkers to distinguish when loss becomes complicated grief and then depression, and we might prevent the transition with a drug."
Helen Mayberg, a neurologist renowned for her study of brain circuits in depression, sees, as Hsu does, the possibility of preventing depressions. "Nobody would suggest we treat routine bad social pain with drugs. But it is true that in susceptible people, losing a partner, for example, can lead to a full-blown depression," says Mayberg, who is the founding director of The Center for Advanced Circuit Therapeutics at Mount Sinai's Icahn School of Medicine in New York City. "Ideally, we'd have biomarkers to distinguish when loss becomes complicated grief and then depression, and we might prevent the transition with a drug. It would be like taking medication when you feel the warning symptoms of a headache to prevent a full-blown migraine."
A Way Out of the Opioid Crisis?
The exploration of social pain should lead us to a deeper understanding of pain, beyond the sharp distinctions between "physical" and "psychological." Finding our way out of the current crisis may require that deeper understanding. About half of the people with opioid prescriptions have mental health disorders. "I expect there are a lot of people using street opioids—heroin or prescriptions purchased from others--to self-medicate psychological pain," Kreugel says.
What we may need, he suggests, is "a new paradigm for using opioids in psychiatry: low, sub-analgesic, sub-euphoric dosing." But so far it hasn't been easy. Investors don't flock to fund psychiatric drugs and in 2018, the word opioid is poison.
As for Tony Y., he's struggled for three years to recover from his most serious relationship. "Driving around highways looking at exit signs toward places we visited together sometimes fills me with unbearable anguish," he admits. "And because we used to do so much bird watching together, sometimes a mere glimpse of a random bird sets me off." He perks up at the idea of a heartbreak drug. "If the side effects didn't seem bad, I would consider it, absolutely."
In May 2022, Californian biotech Ultima Genomics announced that its UG 100 platform was capable of sequencing an entire human genome for just $100, a landmark moment in the history of the field. The announcement was particularly remarkable because few had previously heard of the company, a relative unknown in an industry long dominated by global giant Illumina which controls about 80 percent of the world’s sequencing market.
Ultima’s secret was to completely revamp many technical aspects of the way Illumina have traditionally deciphered DNA. The process usually involves first splitting the double helix DNA structure into single strands, then breaking these strands into short fragments which are laid out on a glass surface called a flow cell. When this flow cell is loaded into the sequencing machine, color-coded tags are attached to each individual base letter. A laser scans the bases individually while a camera simultaneously records the color associated with them, a process which is repeated until every single fragment has been sequenced.
Instead, Ultima has found a series of shortcuts to slash the cost and boost efficiency. “Ultima Genomics has developed a fundamentally new sequencing architecture designed to scale beyond conventional approaches,” says Josh Lauer, Ultima’s chief commercial officer.
This ‘new architecture’ is a series of subtle but highly impactful tweaks to the sequencing process ranging from replacing the costly flow cell with a silicon wafer which is both cheaper and allows more DNA to be read at once, to utilizing machine learning to convert optical data into usable information.
To put $100 genome in perspective, back in 2012 the cost of sequencing a single genome was around $10,000, a price tag which dropped to $1,000 a few years later. Before Ultima’s announcement, the cost of sequencing an individual genome was around $600.
Several studies have found that nearly 12 percent of healthy people who have their genome sequenced, then discover they have a variant pointing to a heightened risk of developing a disease that can be monitored, treated or prevented.
While Ultima’s new machine is not widely available yet, Illumina’s response has been rapid. In September 2022, the company unveiled the NovaSeq X series, which it describes as its fastest most cost-efficient sequencing platform yet, capable of sequencing genomes at $200, with further price cuts likely to follow.
But what will the rapidly tumbling cost of sequencing actually mean for medicine? “Well to start with, obviously it’s going to mean more people getting their genome sequenced,” says Michael Snyder, professor of genetics at Stanford University. “It'll be a lot more accessible to people.”
At the moment sequencing is mainly limited to certain cancer patients where it is used to inform treatment options, and individuals with undiagnosed illnesses. In the past, initiatives such as SeqFirst have attempted further widen access to genome sequencing based on growing amounts of research illustrating the potential benefits of the technology in healthcare. Several studies have found that nearly 12 percent of healthy people who have their genome sequenced, then discover they have a variant pointing to a heightened risk of developing a disease that can be monitored, treated or prevented.
“While whole genome sequencing is not yet widely used in the U.S., it has started to come into pediatric critical care settings such as newborn intensive care units,” says Professor Michael Bamshad, who heads the genetic medicine division in the University of Washington’s pediatrics department. “It is also being used more often in outpatient clinical genetics services, particularly when conventional testing fails to identify explanatory variants.”
But the cost of sequencing itself is only one part of the price tag. The subsequent clinical interpretation and genetic counselling services often come to several thousand dollars, a cost which insurers are not always willing to pay.
As a result, while Bamshad and others hope that the arrival of the $100 genome will create new opportunities to use genetic testing in innovative ways, the most immediate benefits are likely to come in the realm of research.
Bigger Data
There are numerous ways in which cheaper sequencing is likely to advance scientific research, for example the ability to collect data on much larger patient groups. This will be a major boon to scientists working on complex heterogeneous diseases such as schizophrenia or depression where there are many genes involved which all exert subtle effects, as well as substantial variance across the patient population. Bigger studies could help scientists identify subgroups of patients where the disease appears to be driven by similar gene variants, who can then be more precisely targeted with specific drugs.
If insurers can figure out the economics, Snyder even foresees a future where at a certain age, all of us can qualify for annual sequencing of our blood cells to search for early signs of cancer or the potential onset of other diseases like type 2 diabetes.
David Curtis, a genetics professor at University College London, says that scientists studying these illnesses have previously been forced to rely on genome-wide association studies which are limited because they only identify common gene variants. “We might see a significant increase in the number of large association studies using sequence data,” he says. “It would be far preferable to use this because it provides information about rare, potentially functional variants.”
Cheaper sequencing will also aid researchers working on diseases which have traditionally been underfunded. Bamshad cites cystic fibrosis, a condition which affects around 40,000 children and adults in the U.S., as one particularly pertinent example.
“Funds for gene discovery for rare diseases are very limited,” he says. “We’re one of three sites that did whole genome sequencing on 5,500 people with cystic fibrosis, but our statistical power is limited. A $100 genome would make it much more feasible to sequence everyone in the U.S. with cystic fibrosis and make it more likely that we discover novel risk factors and pathways influencing clinical outcomes.”
For progressive diseases that are more common like cancer and type 2 diabetes, as well as neurodegenerative conditions like multiple sclerosis and ALS, geneticists will be able to go even further and afford to sequence individual tumor cells or neurons at different time points. This will enable them to analyze how individual DNA modifications like methylation, change as the disease develops.
In the case of cancer, this could help scientists understand how tumors evolve to evade treatments. Within in a clinical setting, the ability to sequence not just one, but many different cells across a patient’s tumor could point to the combination of treatments which offer the best chance of eradicating the entire cancer.
“What happens at the moment with a solid tumor is you treat with one drug, and maybe 80 percent of that tumor is susceptible to that drug,” says Neil Ward, vice president and general manager in the EMEA region for genomics company PacBio. “But the other 20 percent of the tumor has already got mutations that make it resistant, which is probably why a lot of modern therapies extend life for sadly only a matter of months rather than curing, because they treat a big percentage of the tumor, but not the whole thing. So going forwards, I think that we will see genomics play a huge role in cancer treatments, through using multiple modalities to treat someone's cancer.”
If insurers can figure out the economics, Snyder even foresees a future where at a certain age, all of us can qualify for annual sequencing of our blood cells to search for early signs of cancer or the potential onset of other diseases like type 2 diabetes.
“There are companies already working on looking for cancer signatures in methylated DNA,” he says. “If it was determined that you had early stage cancer, pre-symptomatically, that could then be validated with targeted MRI, followed by surgery or chemotherapy. It makes a big difference catching cancer early. If there were signs of type 2 diabetes, you could start taking steps to mitigate your glucose rise, and possibly prevent it or at least delay the onset.”
This would already revolutionize the way we seek to prevent a whole range of illnesses, but others feel that the $100 genome could also usher in even more powerful and controversial preventative medicine schemes.
Newborn screening
In the eyes of Kári Stefánsson, the Icelandic neurologist who been a visionary for so many advances in the field of human genetics over the last 25 years, the falling cost of sequencing means it will be feasible to sequence the genomes of every baby born.
“We have recently done an analysis of genomes in Iceland and the UK Biobank, and in 4 percent of people you find mutations that lead to serious disease, that can be prevented or dealt with,” says Stefansson, CEO of deCODE genetics, a subsidiary of the pharmaceutical company Amgen. “This could transform our healthcare systems.”
As well as identifying newborns with rare diseases, this kind of genomic information could be used to compute a person’s risk score for developing chronic illnesses later in life. If for example, they have a higher than average risk of colon or breast cancer, they could be pre-emptively scheduled for annual colonoscopies or mammograms as soon as they hit adulthood.
To a limited extent, this is already happening. In the UK, Genomics England has launched the Newborn Genomes Programme, which plans to undertake whole-genome sequencing of up to 200,000 newborn babies, with the aim of enabling the early identification of rare genetic diseases.
"I have not had my own genome sequenced and I would not have wanted my parents to have agreed to this," Curtis says. "I don’t see that sequencing children for the sake of some vague, ill-defined benefits could ever be justifiable.”
However, some scientists feel that it is tricky to justify sequencing the genomes of apparently healthy babies, given the data privacy issues involved. They point out that we still know too little about the links which can be drawn between genetic information at birth, and risk of chronic illness later in life.
“I think there are very difficult ethical issues involved in sequencing children if there are no clear and immediate clinical benefits,” says Curtis. “They cannot consent to this process. I have not had my own genome sequenced and I would not have wanted my parents to have agreed to this. I don’t see that sequencing children for the sake of some vague, ill-defined benefits could ever be justifiable.”
Curtis points out that there are many inherent risks about this data being available. It may fall into the hands of insurance companies, and it could even be used by governments for surveillance purposes.
“Genetic sequence data is very useful indeed for forensic purposes. Its full potential has yet to be realized but identifying rare variants could provide a quick and easy way to find relatives of a perpetrator,” he says. “If large numbers of people had been sequenced in a healthcare system then it could be difficult for a future government to resist the temptation to use this as a resource to investigate serious crimes.”
While sequencing becoming more widely available will present difficult ethical and moral challenges, it will offer many benefits for society as a whole. Cheaper sequencing will help boost the diversity of genomic datasets which have traditionally been skewed towards individuals of white, European descent, meaning that much of the actionable medical information which has come out of these studies is not relevant to people of other ethnicities.
Ward predicts that in the coming years, the growing amount of genetic information will ultimately change the outcomes for many with rare, previously incurable illnesses.
“If you're the parent of a child that has a susceptible or a suspected rare genetic disease, their genome will get sequenced, and while sadly that doesn’t always lead to treatments, it’s building up a knowledge base so companies can spring up and target that niche of a disease,” he says. “As a result there’s a whole tidal wave of new therapies that are going to come to market over the next five years, as the genetic tools we have, mature and evolve.”
This article was first published by Leaps.org in October 2022.
The livestock trucks arrived all night. One after the other they backed up to the wood chute leading to a dusty corral and loosed their cargo — 580 head of cattle by the time the last truck pulled away at 3pm the next afternoon. Dan Probert, astride his horse, guided the cows to paddocks of pristine grassland stretching alongside the snow-peaked Wallowa Mountains. They’d spend the summer here grazing bunchgrass and clovers and biscuitroot. The scuffle of their hooves and nibbles of their teeth would mimic the elk, antelope and bison that are thought to have historically roamed this portion of northeastern Oregon’s Zumwalt Prairie, helping grasses grow and restoring health to the soil.
The cows weren’t Probert’s, although the fifth-generation rancher and one other member of the Carman Ranch Direct grass-fed beef collective also raise their own herds here for part of every year. But in spring, when the prairie is in bloom, Probert receives cattle from several other ranchers. As the grasses wither in October, the cows move on to graze fertile pastures throughout the Columbia Basin, which stretches across several Pacific Northwest states; some overwinter on a vegetable farm in central Washington, feeding on corn leaves and pea vines left behind after harvest.
Sharing land and other resources among farmers isn’t new. But research shows it may be increasingly relevant in a time of climatic upheaval, potentially influencing “farmers to adopt environmentally friendly practices and agricultural innovation,” according to a 2021 paper in the Journal of Economic Surveys. Farmers might share knowledge about reducing pesticide use, says Heather Frambach, a supply chain consultant who works with farmers in California and elsewhere. As a group they may better qualify for grants to monitor soil and water quality.
Most research around such practices applies to cooperatives, whose owner-members equally share governance and profits. But a collective like Carman Ranch’s — spearheaded by fourth-generation rancher Cory Carman, who purchases beef from eight other ranchers to sell under one “regeneratively” certified brand — shows when producers band together, they can achieve eco-benefits that would be elusive if they worked alone.
Vitamins and minerals in soil pass into plants through their roots, then into cattle as they graze, then back around as the cows walk around pooping.
Carman knows from experience. Taking over her family's land in 2003, she started selling grass-fed beef “because I really wanted to figure out how to not participate in the feedlot world, to have a healthier product. I didn't know how we were going to survive,” she says. Part of her land sits on a degraded portion of Zumwalt Prairie replete with invasive grasses; working to restore it, she thought, “What good does it do to kill myself trying to make this ranch more functional? If you want to make a difference, change has to be more than single entrepreneurs on single pieces of land. It has to happen at a community level.” The seeds of her collective were sown.
Raising 100 percent grass-fed beef requires land that’s got something for cows to graze in every season — which most collective members can’t access individually. So, they move cattle around their various parcels. It’s practical, but it also restores nutrient flows “to the way they used to move, from lowlands and canyons during the winter to higher-up places as the weather gets hot,” Carman says. Meaning, vitamins and minerals in soil pass into plants through their roots, then into cattle as they graze, then back around as the cows walk around pooping.
Cory Carman sells grass-fed beef, which requires land that’s got something for cows to graze in every season.
Courtesy Cory Carman
Each collective member has individual ecological goals: Carman brought in pigs to root out invasive grasses and help natives flourish. Probert also heads a more conventional grain-finished beef collective with 100 members, and their combined 6.5 million ranchland acres were eligible for a grant supporting climate-friendly practices, which compels them to improve soil and water health and biodiversity and make their product “as environmentally friendly as possible,” Probert says. The Washington veg farmer reduced tilling and pesticide use thanks to the ecoservices of visiting cows. Similarly, a conventional hay farmer near Carman has reduced his reliance on fertilizer by letting cattle graze the cover crops he plants on 80 acres.
Additionally, the collective must meet the regenerative standards promised on their label — another way in which they work together to achieve ecological goals. Says David LeZaks, formerly a senior fellow at finance-focused ecology nonprofit Croatan Institute, it’s hard for individual farmers to access monetary assistance. “But it's easier to get financing flowing when you increase the scale with cooperatives or collectives,” he says. “This supports producers in ways that can lead to better outcomes on the landscape.”
New, smaller scale farmers might gain the most from collective and cooperative models.
For example, it can help them minimize waste by using more of an animal, something our frugal ancestors excelled at. Small-scale beef producers normally throw out hides; Thousand Hills’ 50 regenerative beef producers together have enough to sell to Timberland to make carbon-neutral leather. In another example, working collectively resulted in the support of more diverse farms: Meadowlark Community Mill in Wisconsin went from working with one wheat grower, to sourcing from several organic wheat growers marketing flour under one premium brand.
Another example shows how these collaborations can foster greater equity, among other benefits: The Federation of Southern Cooperatives has a mission to support Black farmers as they build community health. It owns several hundred forest acres in Alabama, where it teaches members to steward their own forest land and use it to grow food — one member coop raises goats to graze forest debris and produce milk. Adding the combined acres of member forest land to the Federation’s, the group qualified for a federal conservation grant that will keep this resource available for food production, and community environmental and mental health benefits. “That's the value-add of the collective land-owner structure,” says Dãnia Davy, director of land retention and advocacy.
New, smaller scale farmers might gain the most from collective and cooperative models, says Jordan Treakle, national program coordinator of the National Family Farm Coalition (NFFC). Many of them enter farming specifically to raise healthy food in healthy ways — with organic production, or livestock for soil fertility. With land, equipment and labor prohibitively expensive, farming collectively allows shared costs and risk that buy farmers the time necessary to “build soil fertility and become competitive” in the marketplace, Treakle says. Just keeping them in business is an eco-win; when small farms fail, they tend to get sold for development or absorbed into less-diversified operations, so the effects of their success can “reverberate through the entire local economy.”
Frambach, the supply chain consultant, has been experimenting with what she calls “collaborative crop planning,” where she helps farmers strategize what they’ll plant as a group. “A lot of them grow based on what they hear their neighbor is going to do, and that causes really poor outcomes,” she says. “Nobody replanted cauliflower after the [atmospheric rivers in California] this year and now there's a huge shortage of cauliflower.” A group plan can avoid the under-planting that causes farmers to lose out on revenue.
It helps avoid overplanted crops, too, which small farmers might have to plow under or compost. Larger farmers, conversely, can sell surplus produce into the upcycling market — to Matriark Foods, for example, which turns it into value-add products like pasta sauce for companies like Sysco that supply institutional kitchens at colleges and hospitals. Frambach and Anna Hammond, Matriark’s CEO, want to collectivize smaller farmers so that they can sell to the likes of Matriark and “not lose an incredible amount of income,” Hammond says.
Ultimately, farming is fraught with challenges and even collectivizing doesn’t guarantee that farms will stay in business. But with agriculture accounting for almost 30 percent of greenhouse gas emissions globally, there's an “urgent” need to shift farming practices to more environmentally sustainable models, as well as a “demand in the marketplace for it,” says NFFC’s Treakle. “The growth of cooperative and collective farming can be a huge, huge boon for the ecological integrity of the system.”