New Hope for Organ Transplantation: Life Without Anti-Rejection Drugs
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.
Forcing Vaccination on Every Child Undermines Civil Liberties
[Editor's Note: This opinion essay is in response to our current Big Question, which we posed to experts with different viewpoints: "Where should society draw the line between requiring vaccinations for children and allowing parental freedom of choice?"]
Our children are the future. The survival of humanity is advanced by the biological imperative that mothers and fathers want and need to protect their children and other children from being harmed for any reason.
Science is not perfect, doctors are not infallible, and medical interventions come with risks.
In the 21st century, consensus science considers vaccination to be one of the greatest inventions in the history of medicine and the greatest achievement of public health programs. The national vaccination rate for U.S. kindergarten children is 94 percent and most children today receive 69 doses of 16 federally recommended vaccines. However, public health is not simply measured by high vaccination rates and absence of infectious disease, which is evidenced by the chronic inflammatory disease and disability epidemic threatening to bankrupt the U.S. health care system.
Science is not perfect, doctors are not infallible, and medical interventions come with risks, which is why parents have the power to exercise informed consent to medical risk taking on behalf of their minor children.
As a young mother, I learned that vaccine risks are 100 percent for some children because, while we are all born equal under the law, we are not born all the same. Each one of us enters this world with different genes, a unique microbiome and epigenetic influences that affect how we respond to the environments in which we live. We do not all respond the same way to infectious diseases or to pharmaceutical products like vaccines.
Few parents were aware of vaccine side effects in 1980, when my bright, healthy two-and-a-half year-old son, Chris, suffered a convulsion, collapse, and state of unconsciousness (encephalopathy) within hours of his fourth DPT shot, and then regressed physically, mentally and emotionally and became a totally different child. Chris was eventually diagnosed with multiple learning disabilities and confined to a special education classroom throughout his public school education, but he and I both know his vaccine reaction could have been much worse. Today, Chris is an independent adult but many survivors of brain injury are not.
Barbara Loe Fisher and her son, Chris, in December 1981 after his fourth DPT shot.
(Courtesy Fisher)
The public conversation about several hundred cases of measles reported in the U.S. this year is focused on whether every parent has a social obligation to vaccinate every child to maintain "community immunity," but vaccine failures are rarely discussed. Emerging science reveals that there are differences in naturally and vaccine acquired immunity, and both vaccinated and unvaccinated children and adults transmit infections, sometimes with few or no symptoms.
Nearly 40 percent of cases reported in the 2015 U.S. measles outbreak occurred in recently vaccinated individuals who developed vaccine reactions that appeared indistinguishable from measles. Outbreaks of pertussis (whooping cough) in highly vaccinated child populations have been traced to waning immunity and evolution of the B. pertussis microbe to evade the vaccines. Influenza vaccine effectiveness was less than 50 percent in 11 of the past 15 flu seasons.
Vaccine policymakers recognize that children with severe combined immune deficiency or those undergoing chemotherapy or organ transplants are at increased risk for complications of infectious diseases and vaccines. However, there is no recognition of the risks to healthy infants and children with unidentified susceptibility to vaccine reactions, including children whose health suddenly deteriorates without explanation after vaccination. Medical care is being denied to children and adults in the U.S. if even one government recommended vaccination is declined, regardless of health or vaccine reaction history.
When parents question the risks and failures of a commercial pharmaceutical product being mandated for every child, the answer is not more force but better science and respect for the informed consent ethic.
The social contract we have with each other when we live in communities, whether we belong to the majority or a minority, is to care about and protect every individual living in the community. One-size-fits-all vaccine policies and laws, which fail to respect biodiversity and force everyone to be treated the same, place an unequal risk burden on a minority of unidentified individuals unable to survive vaccination without being harmed.
A law that requires certain minorities to bear a greater risk of injury or sacrifice their lives in service to the majority is not just or moral.
Between 1991 and 2013, the Institute of Medicine (IOM) published reports documenting that vaccines can cause brain inflammation and other serious reactions, injuries and death. A 2012 IOM report acknowledged that there are genetic, biological, and environmental risk factors that make some individuals more susceptible to adverse responses to vaccines but often doctors cannot identify who they are because of gaps in vaccine science. Congress acknowledged this fact a quarter century earlier in the 1986 National Childhood Vaccine Injury Act, which created a federal vaccine injury compensation program alternative to a lawsuit that has awarded more than $4 billion to vaccine-injured children and adults.
We give up the human right to autonomy and informed consent at our peril, no matter where or in what century we live.
Vaccine manufacturers and administrators have liability protection, yet today almost no health condition qualifies for a medical vaccine exemption under government guidelines. Now, there is a global call by consensus science advocates for elimination of all personal belief vaccine exemptions and censorship of books and public conversations that criticize vaccine safety or government vaccine policy. Some are calling for quarantine of all who refuse vaccinations and criminal prosecution, fines and imprisonment of parents with unvaccinated children, as well as punishment of doctors who depart from government policy.
There is no civil liberty more fundamentally a natural, inalienable right than exercising freedom of thought and conscience when deciding when and for what reason we are willing to risk our life or our child's life. That is why voluntary, informed consent to medical risk-taking has been defined as a human right governing the ethical practice of modern medicine.
In his first Presidential inaugural address, Thomas Jefferson warned:
"All, too, will bear in mind this sacred principle, that though the will of the majority is in all cases to prevail, that will to be rightful must be reasonable; that the minority posses their equal rights, which equal law must protect, and to violate would be oppression."
The seminal 1905 U.S. Supreme Court decision, Jacobson v. Massachusetts, affirmed the constitutional authority of states to enact mandatory smallpox vaccination laws. However, the justices made it clear that implementation of a vaccination law should not become "cruel and inhuman to the last degree." They warned, "All laws, this court has said, should receive a sensible construction. General terms should be so limited in their application as not to lead to injustice, oppression, or an absurd consequence. It will always, therefore, be presumed that the legislature intended exceptions to its language, which would avoid results of this character."
Mothers and fathers, who know and love their children better than anyone else, depend upon sound science and compassionate public health policies to help them protect their own and other children from harm. If individuals susceptible to vaccine injury cannot be reliably identified, the accuracy of vaccine benefit and risk calculations must be reexamined. Yet, consensus science and medicine around vaccination discourages research into the biological mechanisms of vaccine injury and death and identification of individual risk factors to better inform public health policy.
A critic of consensus science, physician and author Michael Crichton said, "Let's be clear: the work of science has nothing whatever to do with consensus. Consensus is the business of politics. Period."
Condoning elimination of civil liberties, including freedom of speech and the right to dissent guaranteed under the First Amendment of the U.S. Constitution, to enforce vaccination creates a slippery slope. Coercion, punishment and censorship will destroy, not instill, public trust in the integrity of medical practice and public health laws.
There are more than a dozen new vaccines being fast tracked to market by industry and governments. Who in society should be given the power to force all children to use every one of them without parental consent regardless of how small or great the risk?
We give up the human right to autonomy and informed consent at our peril, no matter where or in what century we live. Just and compassionate public health laws that protect parental and human rights will include flexible medical, religious and conscientious belief vaccine exemptions to affirm the informed consent ethic and prevent discrimination against vulnerable minorities.
[Editor's Note: Read the opposite viewpoint here.]
Not Vaccinating Your Kids Endangers Public Health
[Editor's Note: This opinion essay is in response to our current Big Question, which we posed to experts with different viewpoints: "Where should society draw the line between requiring vaccinations for children and allowing parental freedom of choice?"]
Society has a right and at times an obligation to require children to be vaccinated. Vaccines are one of the most effective medical and public health interventions. They save lives and prevent suffering. The vast majority of parents in the United States fully vaccinate their children according to the recommended immunization schedule. These parents are making decisions so that the interests of their children and the interest of society are the same. There are no ethical tensions.
"Measles is only a plane ride away from American children."
A strong scientific basis supports the recommended immunization schedule. The benefits of recommended vaccines are much bigger than the risks. However, a very small proportion of parents are ideologically opposed to vaccines. A slightly larger minority of parents do not believe that all of the recommended vaccines are in their child's best interests.
Forgoing vaccinations creates risk to the child of contracting diseases. It also creates risk to communities and vulnerable groups of people who cannot be vaccinated because of their age or health status.
For example, many vaccines are not able to be given to newborns, such as the measles vaccine which is recommended at 12-15 months of age, leaving young children vulnerable. Many diseases are particularly dangerous for young children. There are also some children who can't be vaccinated, such as pediatric cancer patients who are undergoing chemotherapy or radiation treatment. These children are at increased risk of serous complication or death.
Then there are people who are vaccinated but remain susceptible to disease because no vaccine is 100% effective. In the case of measles, two doses of vaccines protect 97% of people, leaving 3% still susceptible even after being fully vaccinated. All of these groups of people – too young, not eligible, and vaccinated but still susceptible – are dependent on almost everyone else to get vaccinated in order for them to be protected.
Sadly, even though measles has been largely controlled because most people get the very safe and very effective vaccine, we are now seeing dangerous new outbreaks because some parents are refusing vaccines for their children, especially in Europe. Children have died. Measles is only a plane ride away from American children.
There have been repeated measles outbreaks in the United States – such as the Disneyland outbreak and six outbreaks already this year - because of communities where too many parents refuse the vaccine and measles is brought over, often from Europe.
The public health benefits cannot be emphasized enough: Vaccines are not just about protecting your child. Vaccines protect other children and the entire community. Vaccine-preventable diseases (with the exception of tetanus) are spread from person to person. The decision of a parent to not vaccinate their child can endanger other children and vulnerable people.
As a vaccine safety researcher for 20 years, I believe that the community benefit of vaccination can provide justification to limit parental autonomy.
Given these tensions between parental autonomy and the protective value of vaccines, the fundamental question remains: Should society require all children to submit to vaccinations? As a vaccine safety researcher for 20 years, I believe that the community benefit of vaccination can provide justification to limit parental autonomy.
In the United States, we see this balancing act though state requirements for vaccinations to enter school and the varying availability of non-medical exemptions to these laws. Mandatory vaccination in the United States are all state laws. All states require children entering school to receive vaccines and permit medical exemptions. There are a lot of differences between states regarding which vaccines are required, target populations (daycare, school entry, middle school, college), and existence and types of non-medical (religious or philosophical) exemptions that are permitted.
Amid recent measles outbreaks, for instance, California eliminated all non-medical exemptions, making it one of three states that only permit medical exemptions. The existence and enforcement of these school laws reflect broad public support for vaccines to protect the community from disease outbreaks.
I worry about how many kids must suffer, and even die, from diseases like measles until enough is enough. Such tragedies have no place in the modern era. All parents want to do right by their children. All parents deserve autonomy when it comes to decision-making. But when their choices confer serious risks to others, the buck should stop. Our nation would be better off—both medically and ethically—if we did not turn our backs on our most vulnerable individuals.
[Editor's Note: Read the opposite viewpoint here.]