Loneliness, Depression, and Euthanasia

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Loneliness is part of the trifecta of modern angst (along with boredom and fragmentation).

A recent study published in JAMA Psychiatry looked at physician-assisted suicide (PAS) cases in Belgium that were approved because the patient had an unbearable psychiatric illness. The study found that in more than half of the cases, the patient declined treatment that could have helped. Often the patient sought approval for euthanasia after visiting with a doctor for the first time, some patients even visiting a mobile clinic that is funded by a euthanasia group. Forty-six of the 66 cases were women. Importantly, loneliness was cited as a common theme.

You can read the research article here, available by subscription, and the New York Times article here.

Last year, Rachel Aviv wrote a poignant and insightful article in The New Yorker on euthanasia for non-terminal people in the Netherlands. In it she recounts the story of Tom whose mother suffered from depression and eventually elected to undergo euthanasia. Tom did not know about it until after the fact and was angry that he was not called so he could talk to his mother. His mother died with three photographs in her pocket: one of her holding Tom as a baby, one of her feeding her granddaughter ice cream, and one of her and her daughter in a field. She had just broken up with her boyfriend and was estranged from her daughter. Tom and his wife could visit her sometimes, but career and children took much of their time. Furthermore, her lifelong struggle with depression and inability to form close relationships contributed to her isolation. She was lonely and she elected to die alone.

Loneliness is pervasive. This is not the idea of someone being by themselves. Many people can be alone and not be lonely. Also, many people can go to parties, have friends, and still feel utterly alone. As social commentators have pointed out, loneliness is part of the trifecta of modern angst: loneliness, boredom (hyperboredom) and fragmentation. Greg Monbiot in an insightful column in The Guardian dubs our time as the “Age of Loneliness.” One of the Dutch psychologists mentioned in Rachel Aviv’s article says that euthanasia for psychiatric disorders is a response to the nihilism pervasive in the Dutch culture. He says that people ask “What is life worth when there is no God?” or “What is life worth when I am not successful?”

In Japan, the incidence of dying alone, and sometimes not being discovered for weeks, has become so common that the Japanese have a word for it: kodokushi. There is an entire industry dedicated to cleaning after the discovery of someone who has died a lonely death with no friends or relatives. In Japan, many of these lonely deaths are men who had dedicated their lives to their jobs only to be laid off or forced into early retirement. They had no relationships outside of work. Their jobs were the essence of their identity. Without it, they were lost.

A 2014 report showed that loneliness has greater negative health effects than obesity, and a Washington Post article from this past January reported more studies on the health effects of loneliness. In sum, scientists have found that loneliness leads to physiological changes and is more damaging to one’s health than cigarettes, diabetes, and obesity. Studies have shown a correlation between loneliness and early death, onset of Alzheimer’s and dementia, and increased risk for cancer and heart attacks. This is likely due to increased activity in genes that cause inflammation coupled with decreased activity in genes that produce antibodies.

Canada recently legalized physician-assisted suicide, and in the U.S., California recently joined Oregon, Vermont, Washington, and Montana as states where PAS is legal. Most of these places have stringent guidelines for who qualifies for euthanasia. The U.S. laws specify that the patient have a terminal illness and some of them require that the patient have less than six months to live. While “slippery slope” arguments can sometimes be spurious, in this case, we do have two examples of what happens when suicide is medicalized and re-framed as a dignified death. Belgium and The Netherlands continue to open up euthanasia to more and more people. They are not required to be terminal and the age limit continues to decrease with some advocating for no age limit for qualifying for euthanasia.

But, if loneliness is a pervasive problem in our culture, medically-endorsed suicide does little to help and may contribute to the sense of isolation. There was a time when suicide was a cry for help. Now, for the depressed and lonely, it affirms their fears that they are unwanted. Mother Teresa is quoted as saying that “the biggest disease today is not leprosy or cancer or tuberculosis, but rather the feeling of being unwanted, uncared for and deserted by everybody.” Rather than trying to care for people who are struggling, doctors are helping lonely people to end it all. Suicide is not a “solution” for someone struggling with a mental health issue. It is abandoning someone in their time of need.

See also:
Dutch Treatment: A Eureka Moment for Holland’s Medical Ethics
Daily Killings: Euthanasia Grows in Deepest Darkest Belgium
Dr. Phillip Nitschke and the Reinvention of Assisted Suicide

What Is Natural?

For several weeks now I have been trying to write about the Nuffield Bioethics Report called (un)Natural. The Nuffield Bioethics Council is a non-partisan bioethics think tank that analyzes particular issues of importance in science, medicine, and technology. They are based in the UK and have some influence over policy issues because of their presence in the mainstream media.

Their report with the longer title of “Ideas about naturalness in public and political debates about science, technology, and medicine,” analyzes the various ways that the terms “natural,” “unnatural,” and “nature” are used in the media, in journal articles, and in other venues. They are particularly concerned with how those terms shape people’s perceptions of new technologies. They solicited the help from experts in language and had poetry readings.

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Can We Make an Embryo in a Dish?

Induced pluripotent stem cells and embryonic stem cells are functionally equivalent, but should we be concerned about making embryos in a dish?

Induced pluripotent stem cells (iPSCs) have been hailed as the discovery of the decade, providing an ethical alternative to embryonic stem cells (ESCs). Both types of stem cells are pluripotent, which means they can potentially make all of the cells in they body. This is contrasted to totipotent cells, which can give rise to an entire organism. The very early embryo consists of totipotent cells.

Induced pluripotent stem cells have technical advantages over ESCs because the patient’s cells can be used rather than donor cells, and they are easier to control compared to ESCs. However, one of the concerns with iPSCs was whether they are truly equivalent to ESCs because of the various transcription factors that need to be turned on or off to get the cells to regress back to their pluripotent state. This debate was laid to rest with a new research report in Science, demonstrating that while iPSCs are genetically distinct from ESCs, they are functionally equivalent.

Before deeming every iPSC procedure ethical and effective, consider the question several researchers from Australia, The Netherlands, and the U.K. ask in a Nature Methods commentary “What if stem cells turn into embryos in a dish?” Their reason for asking stems from research that shows how pluripotent stem cells (both iPSCs and ESs) can form organoids, small three-dimensional clumps of cells that are comprised of a particular organ’s cell type. The techniques to make pluripotent stem cells undergo the self-assembly and morphogenesis required to form an organoid also causes these cells to have many of the properties of embryos at the gastrulation stage of development.

Without delving too deeply into the complexities of embryonic development, the gastrulation stage is a key point when it comes to regulations for human embryo research. (See here for a simple summary of recent research about stem cells that have been dubbed “gastruloids”). The U.K. has a fourteen-day limit on human embryonic research. Human embryos are not allowed to remain intact in vitro beyond the fourteen-day point or after the formation of the primitive streak, whichever comes first. Australia has similar regulations. The pluripotent cells that appeared to reach the gastrulation stage seemed to form a primitive streak and showed signs of forming the beginnings of the Central Nervous System.

There are two things to consider. First, while these are hallmarks of a particular point in embryonic development, it is not the case that this clump of cells is an embryo. The stem cells are self-organizing, but they are without the same kind of holistic directionality that an embryo has. So while these stem cells proliferate in a more “organized” way than, say, a tumor, they lack key embryonic features. However, the authors pose an important question that needs to be addressed because the technology could eventually make embryos in a dish.

Consider two situations in which it is possible to make an embryo without two genetic contributors, a mother and a father. The first is cloning, or somatic cell nuclear transfer, and the second is making gametes using iPSCs.

Somatic cell nuclear transfer has been successfully done in both animals and humans, although only animal cloned embryos have been implanted and birthed. Cloned animals tend to be unhealthy and often die young. This continues to be an area of research, as evidenced by a recent article in Cell Stem Cell in which researchers from South Korea reported more efficient methods for cloning human embryos.*

Gametogenesis is another active area of research. If induced pluripotent stem cells could be induced to differentiate into gametes (egg and sperm), then this would theoretically allow the creation of an embryo. This embryo may only have one parent if the egg and sperm were made from the same donor. Or, it could be made from two parents who are the same gender. This is not yet possible because the oocyte is particularly tricky to form, but there is ongoing research attempting to produce both types of gametes from induced pluripotent stem cells.

Whether one uses somatic cell nuclear transfer or gametogenesis via iPSCs, the creation of a human embryo is ethically problematic for many reasons. The authors of the Nature Methods commentary raise important questions that hinge on when an embryo becomes an embryo in the laboratory setting. There are valid reasons to give the embryo a special status whether it is ever implanted in a uterus or not. As technology allows us to unravel the complex operations that go into meiosis and embryogenesis, we must carefully consider where moral lines are drawn.

Because making an embryo in a dish would be taking the technology too far, drawing ethical lines may require a nuanced approach to just what types of experiments are okay and where in the technical process the line must be drawn so that pluripotent stem cells remain at the pluripotent stage.

* Technically, “clones” like Dolly the sheep are really chimeras, meaning there is a small amount of DNA from the oocyte donor that is different from the nuclear DNA. The clone would produce an embryo from one genetic source if both the original cell and the oocyte came from the same animal.

11/07/15 – This post has been changed from the original to clarify some of the scientific terms.

The New Compassion: California Is the Fifth State to Legalize Physician-Assisted Suicide

John is an 18-year-old young man who has struggled with depression for most of his life. He has tried to commit suicide in the past. Now that he is an adult, he has decided to take his own life and end his struggle. He purchased a gasoline-powered water pump to poison himself with carbon monoxide.

 

Mark is a 40-year-old man who just received a diagnosis of terminal cancer. He has a wife and young children.  He would like the option to take a lethal drug that would allow him to die peacefully before his health declines to the point that he is in unbearable pain and a burden on his family.

 

Amos is an 81-year-old man who is in generally good health, but is unable to do some of the things he used to enjoy doing. He feels that he has led a good life and is ready to move on before he physically declines any more than he already has. He would like to go to a clinic in Europe to die.

~~~

Somewhere in the last twenty years, the idea of compassion changed. There was a time when compassion meant caring for the suicidal person, not enabling him to go through with it. Compassion used to mean stepping into a messy situation and convincing the person that he didn’t have to end it all, that his life still had meaning and value. Now compassion means providing a way for certain groups of suicidal people to end their lives because they want relief from physical, emotional, or financial pain more than they want to continue living.

In the above examples, John’s story is based on an incident out of Massachusetts in which a young man’s girlfriend, who lived 50-miles away, encouraged him to follow through with his plan to commit suicide over text messages and phone calls. Currently, there is a lawsuit to determine whether she is guilty of manslaughter.

Amos is a fictional character inspired by a nurse who decided that she did not want to grow old and physically decline. She was a healthy 75-year-old woman with a partner of 25 years and adult children who stay in contact with her. She didn’t want to age, and she didn’t want to be a burden on people. She went to Switzerland to die.

Mark is a fictional character loosely based on a man who chose to go to Switzerland to die after he found out he had cancer. In the real-life case, the man was not terminal, and his wife and daughters did not want him to go through with it.

These stories can help us understand the new legislation out of California. California is the fifth state to legalize physician-assisted suicide. Advocates tout the bill (ABX2 15, “End of Life Option Act”) as providing an option for terminally ill people who wish to end their lives peacefully and at a time that they desire. Detractors say that the bill opens the door for abuse and exploitation, and if other countries are any indicator, physician-assisted suicide will expand beyond the terminally ill.

The California bill is for people like Mark. Or, real-life people like Brittaney Maynard, the 29-year-old woman who was diagnosed with terminal brain cancer. She died by assisted suicide last year after moving from California to Oregon where physician-assisted suicide is legal. Her case sparked a national debate over legalizing physician-assisted suicide in various states, including California.

In our three examples, the arguments for why it is okay to provide pills to let someone like Mark commit suicide could easily apply to John or to Amos. The argument for physician-assisted suicide is based on the newer version of compassion, one that elevates choice and autonomy over care and dignity. An argument from compassion could apply to John and Amos’s cases as much as it does to Mark’s case. Indeed, all three would qualify for assisted suicide in places like Belgium or the Netherlands where laws have expanded to include physician-assisted suicide for people with depression or for children over the age of twelve.

Advocates of physician-assisted suicide tell stories of their loved ones being placed on machines at the end of their life or undergoing painful chemo, suffering and in pain until the end. Often people will say that they never want to go through what one of their parents or a loved one went through before they died. To them, the option of a peaceful death via suicide keeps them from this bitter fate. However, there are other options that do not involve suicide and maintains the dignity of the individual. There is comfort care.

A quote attributed to Hippocrates reads that physicians should “cure sometimes, treat often, and comfort always.” In medicine there is an in-between state where the goals are no longer curing, but switch to comfort so that the person can still have meaningful interactions with her loved ones and not suffer unbearable pain. For example, a person can decide not to undergo chemo therapy and, instead, have a better quality of life for her last few months. A palliative care physician who taught one of my clinical ethics classes said that there have been great advances in palliative care therapy. People do not have to die in pain.

As to the fear of being hooked up to machines, there are times when a machine would be burdensome and yet due to its minor efficacy, should not be part of a patient’s treatment plan. This isn’t giving up on a patient. It is not negligence, and it is not physician-assisted suicide. It is recognizing that this machine will cause more harm than good by burdening the patient rather than helping him.

There are even cases when it would be ethical to withdraw machine support because the machine is doing nothing to help the patient’s condition and is not staving off the progression of the disease. This can be an ethically gray area where the clinical details make a difference, but in the cases when treatment is not working, then the patient is often weaned off of the machine and the goals are switched to comfort care as the untreatable disease finally takes the person’s life.

Often, the person who wishes to have physician-assisted suicide says that she does not want to be a burden on anybody. While this is a noble sentiment, it is wrong. Every one of us, from the moment we came out of the womb as a vulnerable, helpless baby, has been a burden on our loved ones and on society. That is part of being human. Even in the prime of our lives, we affect the people around us. We can burden them and we can help others carry their burdens. Indeed, love is often about helping someone carry their burden. As noble as the sentiment sounds, it dismisses what it means to be human and live in community.

However, there is one burden that a person does not have a right to require of someone. It is the burden of taking another life. The physicians who prescribe these medicines are asked to carry the burden of administering death, a burden that physicians were never meant to carry. Originally, the Hippocratic Oath said that a physician should not give poison to anyone even if asked to do so. Physician-assisted suicide changes the role of the physician from doing no harm to doing what the patient asks whether it brings him harm or not.

Governor Jerry Brown ultimately decided to sign the bill because he would want the option of physician-assisted suicide in the face of “prolonged and excruciating pain.” Not only does this fly in the face of medicine, but it ignores hospice and palliative care.

Rather than adopting legislation that would provide adequate comfort care to those populations that do not have access to it, something that is badly needed in our skewed healthcare system, the California bill and Governor Brown’s reasoning helps promote the notion that suicide is at best, as compassionate an option as palliative care, and at worst, the only option in the face of suffering at the end of life. In the midst of a terminal diagnosis in which a person’s life is already cut short, a truly compassionate perspective would seek to manage the pain and provide opportunities for more meaningful moments with loved ones, not eliminate suffering by eliminating the person.

Synthetic Biology and Making Morphine in the Lab

Prescription pain medicine addiction has become prevalent and widespread with several areas in the U.S. calling it a public health crisis. Opiates include prescription pain medicines, such as Vicodin, OxyContin, or fentanyl. The surge in opiate drug addiction can be traced to changes in the increase in prescriptions for opiate drugs beginning in the 1990s. Now headlines tout the possibility of a “home-brewed heroin.”

If we unpack the headline, it turns out this “home-brewed” heroin is not exactly here yet. Scientists have replicated all of the metabolic processes that opium poppies use to turn glucose into morphine. They have replicated parts of this process in yeast strains in an effort to make less addictive pain medicines as well as other analgesics. This synthesis of cellular processes is called synthetic biology. By way of a quick review, synthetic biology involves creating the digital DNA code to make proteins, the internal machinery of a cell, in the lab. Yeast and e.coli are simple organisms and are often used to insert the DNA in a cell fitted with the necessary equipment to replicate and express the DNA. Craig Venter, in his book on synthetic biology, Life at the Speed of Light, calls DNA the software and yeast provides the hardware. Scientists want to tweak the software to make tailor-made drugs.

Synthetic biology overlaps with genetic engineering, but where it differs is that synthetic biology allows scientists to replicate an entire cellular pathway within an organism, such as yeast, as opposed to inserting or deleting mutations in a DNA strand and then inserting it in a cell.

The metabolic pathway reported in Nature (See the Nature News article) is the first part of the glucose-to-morphine pathway. The second part of the pathway, as well as a reaction that links the two parts, was recently reported by other research groups. All of these parts have been demonstrated separately in various yeast strains. If scientists were to combine these parts in one yeast strain, then theoretically, they would be able to convert glucose to morphine. This has not been done yet, but will likely occur soon.

The process for making morphine from glucose is complex (it’s approximately eighteen steps), and because scientists do not know the whole genome for the opium poppy, they have had difficulty identifying the enzymes that catalyze each step in the reaction pathway. To overcome this hurdle, scientists turned to enzymes in other organisms to that catalyze similar reactions. The most recent research that identifies the first half of the morphine pathway used an enzyme from sugar beets that scientists mutated to ensure that it produced the product they needed without unwanted byproducts.

The question remains, are we at a point where people can brew their own synthetic morphine? The short answer is no, not yet.

First, all of the steps have not been combined into a yeast strain. While this may be the next step in making synthetic morphine in the lab, it will need to be tested, and it may not work at first. Once scientists succeed at creating a yeast strain that can accomplish all of the steps, the process will need to be refined and optimized.

Secondly, in order for someone to brew their own morphine, he would have to acquire the yeast strain containing the synthetic DNA. This would mean acquiring the yeast from someone who not only knows the DNA code, but also has a PCR machine or some way to make synthetic DNA and then incorporate it into yeast.

Lastly, even if someone did acquire the yeast strain, according to Christine Smolke of Stanford University whose lab has made a semi-synthetic opioid using yeast, in an interview with Wired, said that the fermentation process would require specialized equipment and conditions that would be difficult to do outside a laboratory. It would also not produce enough morphine to make it cost effective.

While we are not at the point of worrying about home-brewed liquid morphine, the authors of the study were concerned about future consequences of their research. One of the motivations for designing the synthetic pathway is to tweak it to make less addictive pain medicine or to make medicines for other uses. This same ability to tweak the morphine-producing pathway could also be used for nefarious purposes.

The authors of the study sought ethical guidance from biotechnology-policy specialists Kenneth Oye, of MIT and Tania Bubela, of the University of Alberta. They published an article in Nature with Chappell Lawson, also from MIT, that came out in tandem with the research article. Oye, Bubela, and Chappell delineate the ethical and legal considerations for such research and provide four broad areas that should be considered:

  • Engineering – The yeast strains could be engineered to make them less appealing to criminals and more difficult to cultivate outside of a laboratory setting, similar to biocontainment practices with e. coli.
  • Screening – Since the DNA sequence would need to be ordered from a lab, there could be a screening process in place that flags orders of opiate-producing yeast strains
  • Security – They could employ biosecurity measures, such as watermarking yeast made from certain labs and background checks on people working with the strains.
  • Regulation – Opium is a globally controlled substance. The laws that apply to opium could be extended to cover opiate-producing yeast strains.

Overall, the headlines are a little misleading in that we are not yet on the cusp of people brewing their own morphine. However, the authors should be commended for considering the consequences of publishing their research and seeking ethical guidance. It is a good example of pre-emptively considering the hazards and consequences of technological advancement rather than responding to a crisis.

For more information, see my article in Salvo 31, “Dying to Feel Good: Modern Self-Realization & the Painkiller Addiction Epidemic

Indiana’s HIV crisis

Indiana is dealing with an incredible HIV outbreak, centralized in Scott County. The HIV outbreak has been directly tied to needle use for opiate drug users. The Governor has called it a public health crisis, and while normally an opponent to needle exchanges, he is allowing for a 30-day needle exchange to curb the outbreak of HIV.

To give you a sense of the numbers, typically Scott County will see about five new cases of HIV in a year. They saw 26 new cases between mid-December and the beginning of March, and the count is up to 72 cases as of March 26.

The cause of the cases has been traced to intravenous drug use of a liquid form of Opana, a prescription painkiller. Doctors in the area report that the drug addiction problem, like many other places in the US, has been going on for at least the last ten years, with increasing incidences of other blood-borne diseases from needle sharing and deaths due to overdose.

Scott County is struggling against poverty as well as addiction. However, opiate drug addiction is a problem that is spanning all demographics across the US. My article in Salvo Issue 31 looks at nationwide statistics of opiate drug addiction from both prescription pain medicine and heroin use and the underlying causes.

Typically, people start with prescription pain medicines. It can even be from their own prescription that they obtained legitimately for a hurt back or a tooth extraction or any number of reasons that physicians dole out prescriptions for hydrocodone. One guy, mentioned in my article, got hooked on fentanyl after receiving it as an anesthetic for a colonoscopy. He was already abusing alcohol and other substances in an effort to cope with depression over a break-up. Fentanyl, indeed, served as a pain reliever in more ways than one.

Not everyone becomes addicted to opiate drugs when they take pain medicines, but with chronic use, many people do become addicted. And, unfortunately, it is a very difficult addiction to break. Once you’ve tickled those paths in your brain, the tracks that usually take naturally produced endorphins (named for endogenous morphine), you wear a neurological path that is VERY difficult to undo. Unlike endorphins, which our bodies administer through a sophisticated regulatory process that ensures you are receiving the right amounts, opiate drugs stand in as stronger, more potent endorphin replacements.

On a short-term, temporary basis, opiate drugs, like hydrocodone, are supposed to decrease pain, and many of them, when in pill form, are time-released. When our bodies experience pain, endorphins help to quell the effects; however, the endorphins are not enough for injury or sickness, so people take pain medicine. Sometimes people will experience some physical withdrawal symptoms when they stop taking pain medicine if they have been taking them for a while, but physical withdrawal does not necessarily mean the person is addicted. Even physical tolerance is not the full picture of addiction. Addiction has to do with seeking out a high, and in an effort to do so, the person becomes consumed with overcoming physical tolerance to the point that he or she may grind pills and take them intravenously or turn to heroin which is cheaper and sometimes easier to obtain. Scott County is seeing the effects of people sharing needles for opiate drug use.

My article gets into both the neuroscience as well as the cultural and psychological factors that lead to addiction. Suffice it to say that one of the problems is accessibility to a substance that is too potent and too addictive to be administered for trivial reasons (such as tooth aches or minor aches and pains).

Prior to 1990, opioids were not typically prescribed as painkillers except for cancer patients. But in 1990, that all changed. Doctors wanted a solution to patients’ chronic pain,  patients were desperate for relief, and big pharma was ready to profit from the situation. Fast forward to now. The CDC reports that in 2014, physicians wrote 259 million painkiller prescriptions in a single year, the equivalent of one bottle of pills per American. They have seen a four-fold increase in overdose deaths since 2000.

At the end of the Washington Post article reporting on Scott County’s crisis, Dr. William Cooke points out that this issue is not unique to Scott County, Indiana. They are the canary in the coal mine.