New Hope for Organ Transplantation: Life Without Anti-Rejection Drugs
Kidney transplant patient Robert Waddell, center, with his wife and children after being off immunosuppresants; photo aken last summer in Perdido Key, FL. Left to right: Christian, Bailey, Rob, Karen (wife), Robby and Casey.
Rob Waddell dreaded getting a kidney transplant. He suffers from a genetic condition called polycystic kidney disease that causes the uncontrolled growth of cysts that gradually choke off kidney function. The inherited defect has haunted his family for generations, killing his great grandmother, grandmother, and numerous cousins, aunts and uncles.
But he saw how difficult it was for his mother and sister, who also suffer from this condition, to live with the side effects of the drugs they needed to take to prevent organ rejection, which can cause diabetes, high blood pressure and cancer, and even kidney failure because of their toxicity. Many of his relatives followed the same course, says Waddell: "They were all on dialysis, then a transplant and ended up usually dying from cancers caused by the medications."
When the Louisville native and father of four hit 40, his kidneys barely functioned and the only alternative was either a transplant or the slow death of dialysis. But in 2009, when Waddell heard about an experimental procedure that could eliminate the need for taking antirejection drugs, he jumped at the chance to be their first patient. Devised by scientists at the University of Louisville and Northwestern University, the innovative approach entails mixing stem cells from the live kidney donor with that of the recipient to create a hybrid immune system, known as a chimera, that would trick the immune system and prevent it from attacking the implanted kidney.
The procedure itself was done at Northwestern Memorial Hospital in Chicago, using a live kidney donated by a neighbor of Waddell's, who camped out in Chicago during his recovery. Prior to surgery, Waddell underwent a conditioning treatment that consisted of low dose radiation and chemotherapy to weaken his own immune system and make room for the infusion of stem cells.
"The low intensity chemo and radiation conditioning regimen create just enough space for the donor stem cells to gain a foothold in the bone marrow and the donor's immune system takes over," says Dr. Joseph Levanthal, the transplant surgeon who performed the operation and director of kidney and pancreas transplantation at Northwestern University Feinberg School of Medicine. "That way the recipient develops an immune system that doesn't see the donor organ as foreign."
"As a surgeon, I saw what my patients had to go through—taking 25 pills a day, dying at an early age from heart disease, or having a 35% chance of dying every year on dialysis."
A week later, Waddell had the kidney transplant. The following day, he was infused with a complex cellular cocktail that included blood-forming stem cells derived from his donor's bone marrow mixed what are called tolerance inducing facilitator cells (FCs); these cells help the foreign stem cells get established in the recipient's bone marrow.
Over the course of the following year, he was slowly weaned off of antirejection medications—a precaution in case the procedure didn't work—and remarkably, hasn't needed them since. "I felt better than I had in decades because my kidneys [had been] degrading," recalls Waddell, now 54 and a CPA for a global beverage company. And what's even better is that this new approach offers hope for one of his sons who has also inherited the disorder.
Kidney transplants are the most frequent organ transplants in the world and more than 23,000 of these procedures were done in the United States in 2019, according to the United Network for Organ Sharing. Of this, about 7,000 operations are done annually using live organ donors; the remainder use organs from people who are deceased. Right now, this revolutionary new approach—as well as a similar strategy formulated by Stanford University scientists--is in the final phase of clinical trials. Ultimately, this research may pave the way towards realizing the holy grail of organ transplantation: preventing organ rejection by creating a tolerant state in which the recipient's immune system is compatible with the donor, which would eliminate the need for a lifetime of medications.
"As a surgeon, I saw what my patients had to go through—taking 25 pills a day, dying at an early age from heart disease, or having a 35% chance of dying every year on dialysis," says Dr. Suzanne Ildstad, a transplant surgeon and director of the Institute for Cellular Therapeutics at the University of Louisville, whose discovery of facilitator cells were the basis for this therapeutic platform. Ildstad, who has spent more than two decades searching for a better way, says, "This is something I have worked for my entire life."
The Louisville group uses a combination of chemo and radiation to replace the recipient's immune and blood forming cells with that of the donor. In contrast, the Stanford protocol involves harvesting the donor's blood stem cells and T-cells, which are the foot soldiers of the immune system that fight off infections and would normally orchestrate the rejection of the transplanted organ. Their transplant recipients undergo a milder form of "conditioning" that only radiates discrete parts of the body and selectively targets the recipient's T-cells, creating room for both sets of T-cells, a strategy these researchers believe has a better safety profile and less of a chance of rejection.
"We try to achieve immune tolerance by a true chimerism," says Dr. Samuel Strober, a professor of medicine for immunology and rheumatology at Stanford University and a leader of this research team. "The recipients immune system cells are maintained but mixed in the blood with that of the donor."
Studies suggest both approaches work. In a 2018 clinical trial conducted by Talaris Therapeutics, a Louisville-based biotech founded by Ildstad, 26 of 37 (70%) of the live donor kidney transplant recipients no longer need immunosuppressants. Last fall, Talaris began the final phase of clinical tests that will eventually encompass more than 120 such patients.
The Stanford group's cell-based immunotherapy, which is called MDR-101 and is sponsored by the South San Francisco biotech, Medeor Therapeutics, has had similar results in patients who received organs from live donors who were either well matched, such as one from siblings, meaning they were immunologically identical, or partially matched; Talaris uses unrelated donors where there is only a partial match.
In their 2020 clinical trial of 51 patients, 29 were fully matched and 22 were a partial match; 22 of the fully matched recipients didn't need antirejection drugs and ten of the partial matches were able to stop taking some of these medications without rejection. "With our fully matched, roughly 80% have been completely off drugs up to 14 years later," says Strober, "and reducing the number of drugs from three to one [in the partial matches] means you have far fewer side effects. The goal is to get them off of all drugs."
But these protocols are limited to a small number of patients—living donor kidney recipients. As a consequence, both teams are experimenting with ways to broaden their approach so they can use cadaver organs from deceased donors, with human tests planned in the coming year. Here's how that would work: after the other organs are removed from a deceased donor, stem cells are harvested from the donor's vertebrae in the spinal column and then frozen for storage.
"We do the transplant and give the patient a chance to recover and maintain them on drugs," says Ildstad. "Then we do the tolerance conditioning at a later stage."
If this strategy is successful, it would be a genuine game changer, and open the door to using these protocols for transplanting other cadaver organs, including the heart, lungs and liver. While the overall procedure is complex and costly, in the long run it's less expensive than repeated transplant surgeries, the cost of medications and hospitalizations for complications caused by the drugs, or thrice weekly dialysis treatments, says Ildstad.
And she adds, you can't put a price tag on the vast improvement in quality of life.
Should We Use Technologies to Enhance Morality?
Should we welcome biomedical technologies that could enhance our ability to tell right from wrong and improve behaviors that are considered immoral such as dishonesty, prejudice and antisocial aggression?
Our moral ‘hardware’ evolved over 100,000 years ago while humans were still scratching the savannah. The perils we encountered back then were radically different from those that confront us now. To survive and flourish in the face of complex future challenges our archaic operating systems might need an upgrade – in non-traditional ways.
Morality refers to standards of right and wrong when it comes to our beliefs, behaviors, and intentions. Broadly, moral enhancement is the use of biomedical technology to improve moral functioning. This could include augmenting empathy, altruism, or moral reasoning, or curbing antisocial traits like outgroup bias and aggression.
The claims related to moral enhancement are grand and polarizing: it’s been both tendered as a solution to humanity’s existential crises and bluntly dismissed as an armchair hypothesis. So, does the concept have any purchase? The answer leans heavily on our definition and expectations.
One issue is that the debate is often carved up in dichotomies – is moral enhancement feasible or unfeasible? Permissible or impermissible? Fact or fiction? On it goes. While these gesture at imperatives, trading in absolutes blurs the realities at hand. A sensible approach must resist extremes and recognize that moral disrupters are already here.
We know that existing interventions, whether they occur unknowingly or on purpose, have the power to modify moral dispositions in ways both good and bad. For instance, neurotoxins can promote antisocial behavior. The ‘lead-crime hypothesis’ links childhood lead-exposure to impulsivity, antisocial aggression, and various other problems. Mercury has been associated with cognitive deficits, which might impair moral reasoning and judgement. It’s well documented that alcohol makes people more prone to violence.
So, what about positive drivers? Here’s where it gets more tangled.
Medicine has long treated psychiatric disorders with drugs like sedatives and antipsychotics. However, there’s short mention of morality in the Diagnostic and Statistical Manual of Mental Disorders (DSM) despite the moral merits of pharmacotherapy – these effects are implicit and indirect. Such cases are regarded as treatments rather than enhancements.
It would be dangerously myopic to assume that moral augmentation is somehow beyond reach.
Conventionally, an enhancement must go beyond what is ‘normal,’ species-typical, or medically necessary – this is known as the ‘treatment-enhancement distinction.’ But boundaries of health and disease are fluid, so whether we call a procedure ‘moral enhancement’ or ‘medical treatment’ is liable to change with shifts in social values, expert opinions, and clinical practices.
Human enhancements are already used for a range of purported benefits: caffeine, smart drugs, and other supplements to boost cognitive performance; cosmetic procedures for aesthetic reasons; and steroids and stimulants for physical advantage. More boldly, cyborgs like Moon Ribas and Neil Harbisson are pushing transpecies boundaries with new kinds of sensory perception. It would be dangerously myopic to assume that moral augmentation is somehow beyond reach.
How might it work?
One possibility for shaping moral temperaments is with neurostimulation devices. These use electrodes to deliver a low-intensity current that alters the electromagnetic activity of specific neural regions. For instance, transcranial Direct Current Stimulation (tDCS) can target parts of the brain involved in self-awareness, moral judgement, and emotional decision-making. It’s been shown to increase empathy and valued-based learning, and decrease aggression and risk-taking behavior. Many countries already use tDCS to treat pain and depression, but evidence for enhancement effects on healthy subjects is mixed.
Another suggestion is targeting neuromodulators like serotonin and dopamine. Serotonin is linked to prosocial attributes like trust, fairness, and cooperation, but low activity is thought to motivate desires for revenge and harming others. It’s not as simple as indiscriminately boosting brain chemicals though. While serotonin is amenable to SSRIs, precise levels are difficult to measure and track, and there’s no scientific consensus on the “optimum” amount or on whether such a value even exists. Fluctuations due to lifestyle factors such as diet, stress, and exercise add further complexity. Currently, more research is needed on the significance of neuromodulators and their network dynamics across the moral landscape.
There are a range of other prospects. The ‘love drugs’ oxytocin and MDMA mediate pair bonding, cooperation, and social attachment, although some studies suggest that people with high levels of oxytocin are more aggressive toward outsiders. Lithium is a mood stabilizer that has been shown to reduce aggression in prison populations; beta-blockers like propranolol and the supplement omega-3 have similar effects. Increasingly, brain-computer interfaces augur a world of brave possibilities. Such appeals are not without limitations, but they indicate some ways that external tools can positively nudge our moral sentiments.
Who needs morally enhancing?
A common worry is that enhancement technologies could be weaponized for social control by authoritarian regimes, or used like the oppressive eugenics of the early 20th century. Fortunately, the realities are far more mundane and such dystopian visions are fantastical. So, what are some actual possibilities?
Some researchers suggest that neurotechnologies could help to reactivate brain regions of those suffering from moral pathologies, including healthy people with psychopathic traits (like a lack of empathy). Another proposal is using such technology on young people with conduct problems to prevent serious disorders in adulthood.
Most of us aren’t always as ethical as we would like – given the option of ‘priming’ yourself to act in consistent accord with your higher values, would you take it?
A question is whether these kinds of interventions should be compulsory for dangerous criminals. On the other hand, a voluntary treatment for inmates wouldn’t be so different from existing incentive schemes. For instance, some U.S. jurisdictions already offer drug treatment programs in exchange for early release or instead of prison time. Then there’s the difficult question of how we should treat non-criminal but potentially harmful ‘successful’ psychopaths.
Others argue that if virtues have a genetic component, there is no technological reason why present practices of embryo screening for genetic diseases couldn’t also be used for selecting socially beneficial traits.
Perhaps the most immediate scenario is a kind of voluntary moral therapy, which would use biomedicine to facilitate ideal brain-states to augment traditional psychotherapy. Most of us aren’t always as ethical as we would like – given the option of ‘priming’ yourself to act in consistent accord with your higher values, would you take it? Approaches like neurofeedback and psychedelic-assisted therapy could prove helpful.
What are the challenges?
A general challenge is that of setting. Morality is context dependent; what’s good in one environment may be bad in another and vice versa, so we don’t want to throw out the baby with the bathwater. Of course, common sense tells us that some tendencies are more socially desirable than others: fairness, altruism, and openness are clearly preferred over aggression, dishonesty, and prejudice.
One argument is that remoulding ‘brute impulses’ via biology would not count as moral enhancement. This view claims that for an action to truly count as moral it must involve cognition – reasoning, deliberation, judgement – as a necessary part of moral behavior. Critics argue that we should be concerned more with ends rather than means, so ultimately it’s outcomes that matter most.
Another worry is that modifying one biological aspect will have adverse knock-on effects for other valuable traits. Certainly, we must be careful about the network impacts of any intervention. But all stimuli have distributed effects on the body, so it’s really a matter of weighing up the cost/benefit trade-offs as in any standard medical decision.
Is it ethical?
Our values form a big part of who we are – some bioethicists argue that altering morality would pose a threat to character and personal identity. Another claim is that moral enhancement would compromise autonomy by limiting a person’s range of choices and curbing their ‘freedom to fall.’ Any intervention must consider the potential impacts on selfhood and personal liberty, in addition to the wider social implications.
This includes the importance of social and genetic diversity, which is closely tied to considerations of fairness, equality, and opportunity. The history of psychiatry is rife with examples of systematic oppression, like ‘drapetomania’ – the spurious mental illness that was thought to cause African slaves’ desire to flee captivity. Advocates for using moral enhancement technologies to help kids with conduct problems should be mindful that they disproportionately come from low-income communities. We must ensure that any habilitative practice doesn’t perpetuate harmful prejudices by unfairly targeting marginalized people.
Human capacities are the result of environmental influences, and external conditions still coax our biology in unknown ways. Status quo bias for ‘letting nature take its course’ may actually be worse long term – failing to utilize technology for human development may do more harm than good.
Then, there are concerns that morally-enhanced persons would be vulnerable to predation by those who deliberately avoid moral therapies. This relates to what’s been dubbed the ‘bootstrapping problem’: would-be moral enhancement candidates are the types of individuals that benefit from not being morally enhanced. Imagine if every senator was asked to undergo an honesty-boosting procedure prior to entering public office – would they go willingly? Then again, perhaps a technological truth-serum wouldn’t be such a bad requisite for those in positions of stern social consequence.
Advocates argue that biomedical moral betterment would simply offer another means of pursuing the same goals as fixed social mechanisms like religion, education, and community, and non-invasive therapies like cognitive-behavior therapy and meditation. It’s even possible that technological efforts would be more effective. After all, human capacities are the result of environmental influences, and external conditions still coax our biology in unknown ways. Status quo bias for ‘letting nature take its course’ may actually be worse long term – failing to utilize technology for human development may do more harm than good. If we can safely improve ourselves in direct and deliberate ways then there’s no morally significant difference whether this happens via conventional methods or new technology.
Future prospects
Where speculation about human enhancement has led to hype and technophilia, many bioethicists urge restraint. We can be grounded in current science while anticipating feasible medium-term prospects. It’s unlikely moral enhancement heralds any metamorphic post-human utopia (or dystopia), but that doesn’t mean dismissing its transformative potential. In one sense, we should be wary of transhumanist fervour about the salvatory promise of new technology. By the same token we must resist technofear and alarmist efforts to balk social and scientific progress. Emerging methods will continue to shape morality in subtle and not-so-subtle ways – the critical steps are spotting and scaffolding these with robust ethical discussion, public engagement, and reasonable policy options. Steering a bright and judicious course requires that we pilot the possibilities of morally-disruptive technologies.
Podcast: The Friday Five - your health research roundup
The Friday Five is a new series in which Leaps.org covers five breakthroughs in research over the previous week that you may have missed.
The Friday Five is a new podcast series in which Leaps.org covers five breakthroughs in research over the previous week that you may have missed. There are plenty of controversies and ethical issues in science – and we get into many of them in our online magazine – but there’s also plenty to be excited about, and this news roundup is focused on inspiring scientific work to give you some momentum headed into the weekend.
Covered in this week's Friday Five:
- Puffer fish chemical for treating chronic pain
- Sleep study on the health benefits of waking up multiples times per night
- Best exercise regimens for reducing the risk of mortality aka living longer
- AI breakthrough in mapping protein structures with DeepMind
- Ultrasound stickers to see inside your body