Sarah Gray views data about the use of her deceased son Thomas' retinal tissue in research for retinoblastoma, a cancer of the eye, at the University of Pennsylvania, while her son Callum looks on.
The twin boys growing within her womb filled Sarah Gray with both awe and dread. The sonogram showed that one, Callum, seemed to be the healthy child she and husband Ross had long sought; the other, Thomas, had anencephaly, a fatal developmental disorder of the skull and brain that likely would limit his life to hours. The options were to carry the boys to term or terminate both.
The decision to donate Thomas' tissue to research comforted Sarah. It brought a sense of purpose and meaning to her son's anticipated few breaths.
Sarah learned that researchers prize tissue as essential to better understanding and eventually treating the rare disorder that afflicted her son. And that other tissue from the developing infant might prove useful for transplant or basic research.
Animal models have been useful in figuring out some of the basics of genetics and how the body responds to disease. But a mouse is not a man. The new tools of precision medicine that measure gene expression, proteins and metabolites – the various chemical products and signals that fluctuate in health and illness – are most relevant when studying human tissue directly rather than in animals.
The decision to donate Thomas' tissue to research comforted Sarah. It brought a sense of purpose and meaning to her son's anticipated few breaths.
Thomas Gray
(Photo credit: Mark Walpole)
Later Sarah would track down where some of the donated tissues had been sent and how they were being used. It was a rare initiative that just may spark a new kind of relationship between donor families and researchers who use human tissue.
Organ donation for transplant gets all the attention. That process is simple, direct, life saving, the stories are easy to understand and play out regularly in the media. Reimbursement fully covers costs.
Tissue donation for research is murkier. Seldom is there a direct one-to-one correlation between individual donation and discovery; often hundreds, sometimes thousands of samples are needed to tease out the basic mechanisms of a disease, even more to develop a treatment or cure. The research process can be agonizingly slow. And somebody has to pay for collecting, processing, and getting donations into the hands of appropriate researchers. That story rarely is told, so most people are not even aware it is possible, let alone vital to research.
Gray set out on a quest to follow where Thomas' tissue had gone and how it was being used to advance research and care.
The dichotomy between transplant and research became real for Sarah several months after the birth of her twins, and Thomas' brief life, at a meeting for families of transplant donors. Many of the participants had found closure to their grieving through contact with grateful recipients of a heart, liver, or kidney who had gained a new lease on life. But there was no similar process for those who donated for research. Sarah felt a bit, well, jealous. She wanted that type of connection too.
Gray set out on a quest to follow where Thomas' tissue had gone and how it was being used to advance research and care. Those encounters were as novel for the researchers as they were for Sarah. The experience turned her into an advocate for public education and financial and operational changes to put tissue donation for research on par with donations for transplant.
Thomas' retina had been collected and processed by the National Disease Research Interchange (NDRI), a nonprofit that performs such services for researchers on a cost recovery basis with support from the National Institutes of Health. The tissue was passed on to Arupa Ganguly, who is studying retinoblastoma, a cancer of the eye, at the University of Pennsylvania.
Ganguly was surprised and apprehensive months later when NDRI emailed her saying the mother of donated tissue wanted to learn more about how the retina was being used. That was unusual because research donations generally are anonymous.
The geneticist waited a day or two, then wrote an explanation of her work and forwarded it back through NDRI. Soon the researcher and mother were talking by phone and Sarah would visit the lab. Even then, Ganguly felt very uncomfortable. "Something very bad happened to your son Thomas but it was a benefit for me, so I'm feeling very bad," she told Sarah.
"And Sarah said, Arupa, you were the only ones who wanted his retinas. If you didn't request them, they would be buried in the ground. It gives me a sense of fulfillment to know that they were of some use," Ganguly recalls. And her apprehension melted away. The two became friends and have visited several times.
Sarah Gray visits Dr. Arupa Ganguly at the University of Pennsylvania's Genetic Diagnostic Laboratory.
(Photo credit: Daniel Burke)
Reading Sarah Gray's story led Gregory Grossman to reach out to the young mother and to create Hope and Healing, a program that brings donors and researchers together. Grossman is director of research programs at Eversight, a large network of eye banks that stretches from the Midwest to the East Coast. It supplies tissue for transplant and ocular research.
"Research seems a cold and distant thing," Grossman says, "we need to educate the general public on the importance and need for tissue donations for research, which can help us better understand disease and find treatments."
"Our own internal culture needs to be shifted too," he adds. "Researchers and surgeons can forget that these are precious gifts, they're not a commodity, they're not manufactured. Without people's generosity this doesn't exist."
The initial Hope and Healing meetings between researchers and donor families have gone well and Grossman hopes to increase them to three a year with support from the Lions Club. He sees it as a crucial element in trying to reverse the decline in ocular donations even while research needs continue to grow.
What people hear about is "Tuskegee, Henrietta Lacks, they hear about the scandals, they don't hear about the good news. I would like to change that."
Since writing about her experience in the 2016 book "A Life Everlasting," Gray has come to believe that potential donor families, and even people who administer donation programs, often are unaware of the possibility of donating for research.
And roadblocks are common for those who seek to do so. Just like her, many families have had to be persistent in their quest to donate, and even educate their medical providers. But Sarah believes the internet is facilitating creation of a grassroots movement of empowered donors who are pushing procurement systems to be more responsive to their desires to donate for research. A lot of it comes through anecdote, stories, and people asking, if they have done it in Virginia, or Ohio, why can't we do it here?
Callum Gray and Dr. Arupa Ganguly hug during his family's visit to the lab.
(Photo credit: Daniel Burke)
Gray has spoken at medical and research facilities and at conferences. Some researchers are curious to have contact with the families of donors, but she believes the research system fosters the belief that "you don't want to open that can of worms." And lurking in the background may be a fear of liability issues somehow arising.
"I believe that 99 percent of what happens in research is very positive, and those stories would come out if the connections could be made," says Sarah Gray. But what they hear about is "Tuskegee, Henrietta Lacks, they hear about the scandals, they don't hear about the good news. I would like to change that."
Today's podcast episode features Doug Drysdale, CEO of Cybin, a company that is leading innovations in psilocybin, mushrooms that may help people with anxiety and depression.
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These mushrooms have been used for religious, spiritual and medicinal purposes for thousands of years, but only in the past several decades have scientists brought psychedelics into the lab to enhance them and maximize their therapeutic value.
Today’s podcast guest, Doug Drysdale, is doing important work to lead this effort. Drysdale is the CEO of a company called Cybin that has figured out how to make psilocybin more potent, so it can be administered in smaller doses without side effects.
The natural form of psilocybin has been studied increasingly in the realm of mental health. Taking doses of these mushrooms appears to help people with anxiety and depression by spurring the development of connections in the brain, an example of neuroplasticity. The process basically shifts the adult brain from being fairly rigid like dried clay into a malleable substance like warm wax - the state of change that's constantly underway in the developing brains of children.
Neuroplasticity in adults seems to unlock some of our default ways of of thinking, the habitual thought patterns that’ve been associated with various mental health problems. Some promising research suggests that psilocybin causes a reset of sorts. It makes way for new, healthier thought patterns.
So what is Drysdale’s secret weapon to bring even more therapeutic value to psilocybin? It’s a process called deuteration. It focuses on the hydrogen atoms in psilocybin. These atoms are very light and don’t stick very well to carbon, which is another atom in psilocybin. As a result, our bodies can easily breaks down the bonds between the hydrogen and carbon atoms. For many people, that means psilocybin gets cleared from the body too quickly, before it can have a therapeutic benefit.
In deuteration, scientists do something simple but ingenious: they replace the hydrogen atoms with a molecule called deuterium. It’s twice as heavy as hydrogen and forms tighter bonds with the carbon. Because these pairs are so rock-steady, they slow down the rate at which psilocybin is metabolized, so it has more sustained effects on our brains.
Cybin isn’t Drysdale’s first go around at this - far from it. He has over 30 years of experience in the healthcare sector. During this time he’s raised around $4 billion of both public and private capital, and has been named Ernst and Young Entrepreneur of the Year. Before Cybin, he was the founding CEO of a pharmaceutical company called Alvogen, leading it from inception to around $500 million in revenues, across 35 countries. Drysdale has also been the head of mergers and acquisitions at Actavis Group, leading 15 corporate acquisitions across three continents.
In this episode, Drysdale walks us through the promising research of his current company, Cybin, and the different therapies he’s developing for anxiety and depression based not just on psilocybin but another psychedelic compound found in plants called DMT. He explains how they seem to have such powerful effects on the brain, as well as the potential for psychedelics to eventually support other use cases, including helping us strive toward higher levels of well-being. He goes on to discuss his views on mindfulness and lifestyle factors - such as optimal nutrition - that could help bring out hte best in psychedelics.
Show links:
Doug Drysdale full bio
Doug Drysdale twitter
Cybin website
Cybin development pipeline
Cybin's promising phase 2 research on depression
Johns Hopkins psychedelics research and psilocybin research
Mets owner Steve Cohen invests in psychedelic therapies
Doug Drysdale, CEO of Cybin
Immune cells battle an infection.
Measuring immune resilience
The researchers measured immune resilience in two ways. The first is based on the relative quantities of two types of immune cells, CD4+ T cells and CD8+ T cells. CD4+ T cells coordinate the immune system’s response to pathogens and are often used to measure immune health (with higher levels typically suggesting a stronger immune system). However, in 2021, the researchers found that a low level of CD8+ T cells (which are responsible for killing damaged or infected cells) is also an important indicator of immune health. In fact, patients with high levels of CD4+ T cells and low levels of CD8+ T cells during SARS-CoV-2 and HIV infection were the least likely to develop severe COVID and AIDS.
Individuals with optimal levels of immune resilience were more likely to live longer.
In the same 2021 study, the researchers identified a second measure of immune resilience that involves two gene expression signatures correlated with an infected person’s risk of death. One of the signatures was linked to a higher risk of death; it includes genes related to inflammation — an essential process for jumpstarting the immune system but one that can cause considerable damage if left unbridled. The other signature was linked to a greater chance of survival; it includes genes related to keeping inflammation in check. These genes help the immune system mount a balanced immune response during infection and taper down the response after the threat is gone. The researchers found that participants who expressed the optimal combination of genes lived longer.
Immune resilience and longevity
The researchers assessed levels of immune resilience in nearly 50,000 participants of different ages and with various types of challenges to their immune systems, including acute infections, chronic diseases, and cancers. Their evaluation demonstrated that individuals with optimal levels of immune resilience were more likely to live longer, resist HIV and influenza infections, resist recurrence of skin cancer after kidney transplant, survive COVID infection, and survive sepsis.
However, a person’s immune resilience fluctuates all the time. Study participants who had optimal immune resilience before common symptomatic viral infections like a cold or the flu experienced a shift in their gene expression to poor immune resilience within 48 hours of symptom onset. As these people recovered from their infection, many gradually returned to the more favorable gene expression levels they had before. However, nearly 30% who once had optimal immune resilience did not fully regain that survival-associated profile by the end of the cold and flu season, even though they had recovered from their illness.
Intriguingly, some people who are 90+ years old still have optimal immune resilience, suggesting that these individuals’ immune systems have an exceptional capacity to control inflammation and rapidly restore proper immune balance.
This could suggest that the recovery phase varies among people and diseases. For example, young female sex workers who had many clients and did not use condoms — and thus were repeatedly exposed to sexually transmitted pathogens — had very low immune resilience. However, most of the sex workers who began reducing their exposure to sexually transmitted pathogens by using condoms and decreasing their number of sex partners experienced an improvement in immune resilience over the next 10 years.
Immune resilience and aging
The researchers found that the proportion of people with optimal immune resilience tended to be highest among the young and lowest among the elderly. The researchers suggest that, as people age, they are exposed to increasingly more health conditions (acute infections, chronic diseases, cancers, etc.) which challenge their immune systems to undergo a “respond-and-recover” cycle. During the response phase, CD8+ T cells and inflammatory gene expression increase, and during the recovery phase, they go back down.
However, over a lifetime of repeated challenges, the immune system is slower to recover, altering a person’s immune resilience. Intriguingly, some people who are 90+ years old still have optimal immune resilience, suggesting that these individuals’ immune systems have an exceptional capacity to control inflammation and rapidly restore proper immune balance despite the many respond-and-recover cycles that their immune systems have faced.
Public health ramifications could be significant. Immune cell and gene expression profile assessments are relatively simple to conduct, and being able to determine a person’s immune resilience can help identify whether someone is at greater risk for developing diseases, how they will respond to treatment, and whether, as well as to what extent, they will recover.
