Anita Freeman, left, hugs her sister Elizabeth Martin at a bakery in Huntington Beach, California, in 2009 — a year before Elizabeth's cancer diagnosis. (Courtesy Anita Freeman)
For five weeks, Anita Freeman watched her sister writhe in pain. The colon cancer diagnosed four years earlier became metastatic.
"I still wouldn't wish that ending on my worst enemy."
At this tormenting juncture, her 66-year-old sister, Elizabeth Martin, wanted to die comfortably in her sleep. But doctors wouldn't help fulfill that final wish.
"It haunts me," Freeman, 74, who lives in Long Beach, California, says in recalling the prolonged agony. Her sister "was breaking out of the house and running in her pajamas down the sidewalk, screaming, 'Help me. Help me.' She just went into a total panic."
Finally, a post-acute care center offered pentobarbital, a sedative that induced a state of unconsciousness, but only after an empathetic palliative care doctor called and insisted on ending the inhumane suffering. "We even had to fight the owners of the facility to get them to agree to the recommendations," Freeman says, describing it as "the only option we had at that time; I still wouldn't wish that ending on my worst enemy."
Her sister died a week later, in 2014. That was two years before California's medical aid-in-dying law took effect, making doctors less reliant on palliative sedation to peacefully end unbearable suffering for terminally ill patients. Now, Freeman volunteers for Compassion & Choices, a national grassroots organization based in Portland, Oregon, that advocates for expanding end-of-life options.
Palliative sedation involves medicating a terminally ill patient into lowered awareness or unconsciousness in order to relieve otherwise intractable suffering at the end of life. It is not intended to cause death, which occurs due to the patient's underlying disease.
In contrast, euthanasia involves directly and deliberately ending a patient's life. Euthanasia is legal only in Canada and some European countries and requires a health care professional to administer the medication. In the United States, laws in seven states and Washington, D.C. give terminally ill patients the option to obtain prescription medication they can take to die peacefully in their sleep, but they must be able to self-adminster it.
Recently, palliative sedation has been gaining more acceptance among medical professionals as an occasional means to relieve suffering, even if it may advance the time of death, as some clinicians believe. However, studies have found no evidence of this claim. Many doctors and bioethicists emphasize that intent is what distinguishes palliative sedation from euthanasia. Others disagree. It's common for controversy to swirl around when and how to apply this practice.
Elizabeth Martin with her sister Anita Freeman in happier times, before metastatic cancer caused her tremendous suffering at the end of her life.
(Courtesy Anita Freeman)
"Intent is everything in ethics. The rigor and protocols we have around palliative sedation therapy also speaks to it being an intervention directed to ease refractory distress," says Martha Twaddle, medical director of palliative medicine and supportive care at Northwestern University's Lake Forest Hospital in Lake Forest, Illinois.
Palliative sedation should be considered only when pain, shortness of breath, and other unbearable symptoms don't respond to conventional treatments. Left to his or her own devices, a patient in this predicament could become restless, Twaddle says, noting that "agitated delirium is a horrible symptom for a family to witness."
At other times, "we don't want to be too quick to sedate," particularly in cases of purely "existential distress"—when a patient experiences anticipatory grief around "saying goodbye" to loved ones, she explains. "We want to be sure we're applying the right therapy for the problem."
Encouraging patients to reconcile with their kin may help them find inner peace. Nonmedical interventions worth exploring include quieting the environment and adjusting lighting to simulate day and night, Twaddle says.
Music-thanatology also can have a calming effect. It is live, prescriptive music, mainly employing the harp or voice, tailored to the patient's physiological needs by tuning into vital signs such as heart rate, respiration, and temperature, according to the Music-Thanatology Association International.
"When we integrated this therapeutic modality in 2003, our need for using palliative sedation therapy dropped 75 percent and has remained low ever since," Twaddle observes. "We have this as part of our care for treating refractory symptoms."
"If palliative sedation is being employed properly with the right patient, it should not hasten death."
Ethical concerns surrounding euthanasia often revolve around the term "terminal sedation," which "can entail a physician deciding that the patient is a lost cause—incurable medically and in substantial pain that cannot adequately be relieved," says John Kilner, professor and director of the bioethics programs at Trinity International University in Deerfield, Illinois.
By halting sedation at reasonable intervals, the care team can determine whether significant untreatable pain persists. Periodic discontinuation serves as "evidence that the physician is still working to restore the patient rather than merely to usher the patient painlessly into death," Kilner explains. "Indeed, sometimes after a period of unconsciousness, with the body relieved of unceasing pain, the body can recover enough to make the pain treatable."
The medications for palliative sedation "are tried and true sedatives that we've had for a long time, for many years, so they're predictable," says Joe Rotella, chief medical officer at the American Academy of Hospice and Palliative Medicine.
Some patients prefer to keep their eyes open and remain conscious to answer by name, while others tell their doctors in advance that they want to be more heavily sedated while receiving medications to manage pain and other symptoms. "We adjust the dosage until the patient is sleeping at a desired level of sedation," Rotella says.
Sedation is an intrinsic side effect of most medications prescribed to control severe symptoms in terminally ill patients. In general, most people die in a sleepy state, except for instances of sudden, dramatic death resulting from a major heart attack or stroke, says Ryan R. Nash, a palliative medicine physician and director of The Ohio State University Center for Bioethics in Columbus.
"Using those medications to treat pain or shortness of breath is not palliative sedation," Nash says. In addition, providing supplemental nutrition and hydration in situations where death is imminent—with a prognosis limited to hours or days—generally doesn't help prolong life. "If palliative sedation is being employed properly with the right patient," he adds, "it should not hasten death."
Nonetheless, hospice nurses sometimes feel morally distressed over carrying out palliative sedation. Implementing protocols at health systems would help guide them and alleviate some of their concerns, says Gregg VandeKieft, medical director for palliative care at Providence St. Joseph Health's Southwest Washington Region in Olympia, Washington. "It creates guardrails by sort of standardizing and normalizing things," he says.
"Our goal is to restore our patient. It's never to take their life."
The concept of proportionality weighs heavily in the process of palliative sedation. But sometimes substantial doses are necessary. For instance, an opioid-tolerant patient recently needed an unusually large amount of medication to control symptoms. She was in a state of illness-induced confusion and pain, says David E. Smith, a palliative medicine physician at Baptist Health Supportive Care in Little Rock, Arkansas.
Still, "we are parsimonious in what we do. We only use as much therapeutic force as necessary to achieve our goals," Smith says. "Our goal is to restore our patient. It's never to take their life."
Alida de Flamingh and her team are collecting elephant dung. It holds a trove of information about animal health, diet and genetic diversity.
Approximately 27 percent of mammals and 28 percent of all assessed species are close to dying out. The IUCN Red List of threatened species, simply called the Red List, is the world’s most comprehensive record of animals’ risk of extinction status. The more information scientists gather, the better their chances of reducing those risks. In Africa, populations of vertebrates declined 69 percent between 1970 and 2022, according to the World Wildlife Fund (WWF).
“We put on sterile gloves and use a sterile swab to collect wet mucus and materials from the outside of the dung ball,” says Alida de Flamingh, a postdoctoral researcher at the University of Illinois Urbana-Champaign.
“When people talk about species, they often talk about ecosystems, but they often overlook genetic diversity,” says Christina Hvilsom, senior geneticist at the Copenhagen Zoo. “It’s easy to count (individuals) to assess whether the population size is increasing or decreasing, but diversity isn’t something we can see with our bare eyes. Yet, it’s actually the foundation for the species and populations.” DNA analysis can provide this critical information.
Assessing elephants’ health
“Africa’s elephant populations are facing unprecedented threats,” says de Flamingh, the postdoc, who has studied them since 2009. Challenges include ivory poaching, habitat destruction and smaller, more fragmented habitats that result in smaller mating pools with less genetic diversity. Additionally, de Flamingh studies the microbial communities living on and in elephants – their microbiomes – looking for parasites or dangerous microbes.
Approximately 415,000 elephants inhabit Africa today, but de Flamingh says the number would be four times higher without these challenges. The IUCN Red List reports African savannah elephants are endangered and African forest elephants are critically endangered. Elephants support ecosystem biodiversity by clearing paths that help other species travel. Their very footprints create small puddles that can host smaller organisms such as tadpoles. Elephants are often described as ecosystems’ engineers, so if they disappear, the rest of the ecosystem will suffer too.
There’s a process to collecting elephant feces. “We put on sterile gloves (which we change for each sample) and use a sterile swab to collect wet mucus and materials from the outside of the dung ball,” says de Flamingh. They rub a sample about the size of a U.S. quarter onto a paper card embedded with DNA preservation technology. Each card is air dried and stored in a packet of desiccant to prevent mold growth. This way, samples can be stored at room temperature indefinitely without the DNA degrading.
Earlier methods required collecting dung in bags, which needed either refrigeration or the addition of preservatives, or the riskier alternative of tranquilizing the animals before approaching them to draw blood samples. The ability to collect and sequence the DNA made things much easier and safer.
“Our research provides a way to assess elephant health without having to physically interact with elephants,” de Flamingh emphasizes. “We also keep track of the GPS coordinates of each sample so that we can create a map of the sampling locations,” she adds. That helps researchers correlate elephants’ health with geographic areas and their conditions.
Although de Flamingh works with elephants in the wild, the contributions of zoos in the United States and collaborations in South Africa (notably the late Professor Rudi van Aarde and the Conservation Ecology Research Unit at the University of Pretoria) were key in studying this method to ensure it worked, she points out.
Protecting chimpanzees
Genetic work with chimpanzees began about a decade ago. Hvilsom and her group at the Copenhagen Zoo analyzed DNA from nearly 1,000 fecal samples collected between 2003 and 2018 by a team of international researchers. The goal was to assess the status of the West African subspecies, which is critically endangered after rapid population declines. Of the four subspecies of chimpanzees, the West African subspecies is considered the most at-risk.
In total, the WWF estimates the numbers of chimpanzees inhabiting Africa’s forests and savannah woodlands at between 173,000 and 300,000. Poaching, disease and human-caused changes to their lands are their major risks.
By analyzing genetics obtained from fecal samples, Hvilsom estimated the chimpanzees’ population, ascertained their family relationships and mapped their migration routes.
“One of the threats is mining near the Nimba Mountains in Guinea,” a stronghold for the West African subspecies, Hvilsom says. The Nimba Mountains are a UNESCO World Heritage Site, but they are rich in iron ore, which is used to make the steel that is vital to the Asian construction boom. As she and colleagues wrote in a recent paper, “Many extractive industries are currently developing projects in chimpanzee habitat.”
Analyzing DNA allows researchers to identify individual chimpanzees more accurately than simply observing them, she says. Normally, field researchers would install cameras and manually inspect each picture to determine how many chimpanzees were in an area. But, Hvilsom says, “That’s very tricky. Chimpanzees move a lot and are fast, so it’s difficult to get clear pictures. Often, they find and destroy the cameras. Also, they live in large areas, so you need a lot of cameras.”
By analyzing genetics obtained from fecal samples, Hvilsom estimated the chimpanzees’ population, ascertained their family relationships and mapped their migration routes based upon DNA comparisons with other chimpanzee groups. The mining companies and builders are using this information to locate future roads where they won’t disrupt migration – a more effective solution than trying to build artificial corridors for wildlife.
“The current route cuts off communities of chimpanzees,” Hvilsom elaborates. That effectively prevents young adult chimps from joining other groups when the time comes, eventually reducing the currently-high levels of genetic diversity.
“The mining company helped pay for the genetics work,” Hvilsom says, “as part of its obligation to assess and monitor biodiversity and the effect of the mining in the area.”
Of 50 toucan subspecies, 11 are threatened or near-threatened with extinction because of deforestation and poaching.
Identifying toucan families
Feces aren't the only substance researchers draw DNA samples from. Jeffrey Coleman, a Ph.D. candidate at the University of Texas at Austin relies on blood tests for studying the genetic diversity of toucans---birds species native to Central America and nearby regions. They live in the jungles, where they hop among branches, snip fruit from trees, toss it in the air and catch it with their large beaks. “Toucans are beautiful, charismatic birds that are really important to the ecosystem,” says Coleman.
Of their 50 subspecies, 11 are threatened or near-threatened with extinction because of deforestation and poaching. “When people see these aesthetically pleasing birds, they’re motivated to care about conservation practices,” he points out.
Coleman works with the Dallas World Aquarium and its partner zoos to analyze DNA from blood draws, using it to identify which toucans are related and how closely. His goal is to use science to improve the genetic diversity among toucan offspring.
Specifically, he’s looking at sections of the genome of captive birds in which the nucleotides repeat multiple times, such as AGATAGATAGAT. Called microsatellites, these consecutively-repeating sections can be passed from parents to children, helping scientists identify parent-child and sibling-sibling relationships. “That allows you to make strategic decisions about how to pair (captive) individuals for mating...to avoid inbreeding,” Coleman says.
Jeffrey Coleman is studying the microsatellites inside the toucan genomes.
Courtesy Jeffrey Coleman
The alternative is to use a type of analysis that looks for a single DNA building block – a nucleotide – that differs in a given sequence. Called single nucleotide polymorphisms (SNPs, pronounced “snips”), they are very common and very accurate. Coleman says they are better than microsatellites for some uses. But scientists have already developed a large body of microsatellite data from multiple species, so microsatellites can shed more insights on relations.
Regardless of whether conservation programs use SNPs or microsatellites to guide captive breeding efforts, the goal is to help them build genetically diverse populations that eventually may supplement endangered populations in the wild. “The hope is that the ecosystem will be stable enough and that the populations (once reintroduced into the wild) will be able to survive and thrive,” says Coleman. History knows some good examples of captive breeding success.
The California condor, which had a total population of 27 in 1987, when the last wild birds were captured, is one of them. A captive breeding program boosted their numbers to 561 by the end of 2022. Of those, 347 of those are in the wild, according to the National Park Service.
Conservationists hope that their work on animals’ genetic diversity will help preserve and restore endangered species in captivity and the wild. DNA analysis is crucial to both types of efforts. The ability to apply genome sequencing to wildlife conservation brings a new level of accuracy that helps protect species and gives fresh insights that observation alone can’t provide.
“A lot of species are threatened,” Coleman says. “I hope this research will be a resource people can use to get more information on longer-term genealogies and different populations.”