by Sarah Gray
Angrist is a passionate advocate for the sharing of research results with human participants. He’s written numerous scholarly articles on the subject, including one titled, “You Never Call, You Never Write: Why Return of ‘omic’ Results to Research Participants Is Both a Good Idea and a Moral Imperative.” According to the article’s abstract: “Return of genomic data to those who want it, even if a difficult undertaking and even if the meaning of the data is unclear, engages participants in science and the research enterprise, and positions them to be better stewards of their own health and wellbeing.”
Angrist thinks the real problem with institutions insisting on confidentiality is not the Common Rule, or privacy issues, but simply that they are risk-averse. There’s a history of treating people who participate in research as anonymous. If researchers don’t have to know any personal information about the subjects whose tissues they work with, they don’t have to take any responsibility for those people. Without that responsibility, they can focus all their time on their work rather than on placating participants who might be requesting more information about what they’re doing (a thing Angrist has sympathy for).
There is a tendency to dehumanize research subjects; even calling them subjects is dehumanizing. According to Angrist (and others, including many involved with the Precision Medicine Initiative), those who choose to contribute to these studies should be referred to as participants or partners.
“I think we have come to a place where the term subjects is not only offensive, it’s inaccurate. If you are a subject, you have nothing to say about anything. If you are a participant or a partner, then you do have something to say. And science needs to listen,” says Angrist.
In his field of genomic studies, participants expect to be told what researchers learn about them. Indeed, the incentive that is often offered to prospective participants is a copy of the survey results.
When Angrist was on Duke’s IRB committee, he saw firsthand how restrictive the consent forms could be. He would regularly see protocols that said the investigator would not return information to the prospective participant because it was not clinically actionable—that is, the participant wouldn’t be able to do anything with the information other than know it. “It’s condescending,” Angrist says. “The consent form is already twenty-eight pages long and designed to protect the institution from getting sued. To say also that you will get nothing, and it will be better for you, just feels like an insult.”
So how does one turn around this entrenched culture of keeping information close to the researchers’ vest? Incentives, Angrist says. He thinks institutions that are funding the research, such as the National Cancer Institute and the NIH, could add a little more funding to help researchers figure out how to return results. “Returning results is a concrete way for an investigator to say to a participant, ‘I have some information about you. It may or may not be useful, but if you are interested in receiving it, I am prepared to share it with you.’” In other words, it’s a way for scientists to treat participants as people rather than as cells on a spreadsheet.
To my mind, as long as scientists are pursuing ethical research—which I imagine is the case most of the time—and participants are informed and openly consenting, the barriers seem largely unnecessary. I knew that the researchers I spoke to about Thomas’s gifts were not trying to steal our son’s tissue. Since Thomas was dead, these donations were his legacy. These were his first and last contributions to the world. What good is a legacy if no one in the family can pass it down because we don’t know about it?
CHAPTER FOURTEEN
From Donation to Discovery
October 30, 2015
Five years after Thomas’s death, a lot had changed. What started as a broken heart blossomed into a sense of pride in my son’s accomplishments. His donation exposed me to a world of scientific and medical advancements I would not have even imagined before. I had the privilege of meeting brilliant and kind professionals who are changing the field and saving and improving lives on a daily basis.
Thomas led me to a new career, and his deeper purpose gave me one, too.
At the end of October 2015, the National Disease Research Interchange (NDRI)—the organization that facilitated the donation of Thomas’s cornea to Harvard and his retina donation to the University of Pennsylvania—celebrated its thirty-fifth anniversary with a symposium at the Union League of Philadelphia: “From Donation to Discovery: The Critical Role of Human Tissue in Research.”
Since its founding three and a half decades earlier, not only had NDRI become a leader in the world of recovering and distributing human organs and tissue for research—what they call “biospecimens” in the profession—they had also developed a number of specialized programs to help researchers in specific ways.
The first panel of the day was called “Advancing the Nation’s BRAIN Initiative.” BRAIN stands for “Brain Research through Advancing Innovative Neurotechnologies,” and the initiative was launched by President Barack Obama in April 2013 to support further understanding of the human brain and uncovering new ways to treat, prevent, and cure brain disorders like autism, epilepsy, schizophrenia, Alzheimer’s, and traumatic brain injury. And the government wasn’t fooling around: the National Institutes of Health invested more than $130 million in BRAIN in the first two years alone.
Why so much interest in the brain? Because every year, approximately one in eighty-eight children in the United States is born with autism or a related disorder, and more than five million older people will be diagnosed with dementia—a number that’s likely to rise as the boomer generation moves into old age. Also on the rise are ALS, or amyotrophic lateral sclerosis (a.k.a. Lou Gehrig’s disease); Parkinson’s; and progressive supranuclear palsy, a degenerative neurological disorder that affects about twenty thousand Americans and for which there is no effective treatment or cure.
Suicide is a significant public health issue as well. It remains one of the leading causes of death in this country: it’s tenth overall, fifth for ages forty-five to fifty-nine, and second for ages ten to twenty-four. Suicide among young Native Americans is nearly twice the national average. Women are three times more likely than men to attempt suicide, but men are four times more likely than women to actually kill themselves.
Here are some of the other sobering statistics for suicide in the United States, according to the American Foundation for Suicide Prevention: a million people attempt suicide every year, and forty thousand are successful. Veterans account for more than 22 percent of suicides. (U.S. Department of Defense guidelines make it very difficult for researchers to gain access to the brains of deceased veterans for the purpose of research, whether death was from suicide or traumatic brain injury.) And 90 percent of people who commit suicide have a diagnosable psychiatric disorder.
Given these upsetting numbers, researchers are keen to investigate the physiological aspects of brain function that might help explain why suicide is such a big problem.
So here’s the big challenge that medical science faces: We all learned in school that the brain is the most complicated organ in the body, which means it remains—even with all our advancements—one of the least understood. There are something like one hundred billion neurons sending about one hundred trillion messages to one another, which makes the brain “one of the greatest mysteries of science and one of the greatest challenges in medicine,” according to the BRAIN Initiative. Given the ambitiousness of the project, NIH is collaborating with scientists and engineers from other government agencies, such as the Defense Advanced Research Projects Agency (DARPA), National Science Foundation (NSF), U.S. Food and Drug Administration (FDA), Intelligence Advanced Research Projects Activity (IARPA), and private partners. It’s a huge undertaking, and these studies require donated whole brains.
On the dais for the first panel at the NDRI symposium were Mark Frasier, senior vice president of research programs at the Michael J. Fox Foundation for Parkinson’s Research; Richard D. Hasz, vic
e president of clinical services at the Gift of Life Donor Program; John Madigan, vice president for public policy at the American Foundation for Suicide Prevention (SPAN/ USA); Dr. Daniel Perl, a man with many titles including director of the Neuropathology Care Center for Neuroscience and Regenerative Medicine; and Thor D. Stein, a neuropathologist with the U.S. Department of Veterans Affairs.
There was also Deborah C. Mash, director of the University of Miami Brain Endowment Bank, which is one of just six designated brain and tissue biorepositories in the country. They’re supporting research into ALS, multiple sclerosis, Huntington’s disease, traumatic brain and spinal injury, developmental disorders like autism and Down syndrome, and mental-health issues like depression and bipolar disorder. Founded in 1987, the bank holds more than two thousand brains, with another five hundred people on the list to donate.
As the experts convened to discuss challenges in acquiring tissue to study, it became clear that recovering brains for research was rather different from acquiring other organs and tissues. For instance, the medical/social interview, now called the Uniform Donor Risk Assessment Interview, wouldn’t have covered the kind of information that scientists looking at the brain need. A person can donate a kidney or skin without anyone needing to know if he or she ever heard voices, but not so the brain. Trying to come up with a uniform list of questions for potential brain donors and their families was a challenge.
In addition, families need to feel comfortable with the decision to donate, since they also make a decision about what kind of funeral to have. Some family members may wish to see the decedent one final time at an open-casket funeral. Facing the death can help some people believe it and come to terms with it. Initially, there was concern from both families and funeral directors that a brain-recovery incision would alter the appearance of the decedent and force a difficult decision on a family in this position: “Do we donate a brain for research, or do we have an open-casket funeral?” OPO professionals wanted to make it possible to do both.
Rebecca F. Cummings-Suppi, L.F.D., C.T.B.S., is manager of tissue recovery and preservation at Gift of Life Donor Program in Philadelphia and is also a licensed funeral director and embalmer. She spoke about this challenge at the 2014 American Association of Tissue Banks annual meeting. Becky and her team developed a brain-recovery technique that involved making an incision from ear to ear at the back of the head where the skull meets the spine. I was touched by the pride she took in caring for both the needs of a grieving family and the research protocol.
“I don’t believe in putting anything of value in the ground. Whether it’s a diamond ring that can be passed down to another generation, or if it’s tissue for transplant or for research,” she told me. “That’s how cures happen.”
The second panel that day focused on research for rare diseases—which, generally speaking, don’t have relevant animal models such as mice. (Even common disorders, like age-related macular degeneration, have this problem, because mice don’t get this disease, so there’s no way to study it in them. That’s why researchers like Patricia D’Amore at Schepens Eye Research Institute at Harvard need human tissue to complete their work.)
NDRI’s Rare Disease Initiative collects donated tissues, organs, and blood as well as DNA and cell lines for more than one hundred rare conditions. Some of these include amyotrophic lateral sclerosis, or Lou Gehrig’s disease—a progressive degenerative disease that targets nerves in the brain and spinal cord and causes progressive muscle weakness and paralysis until the patient is no longer able to breathe on his or her own. (Perhaps the most famous sufferer, aside from the New York Yankee great after which it gets its nickname, is physicist Stephen Hawking, who has managed to survive for many years beyond the usual life expectancy for this brutal disease). Also included is Lewy body dementia—also known as dementia with Lewy bodies—a disease named after scientist Friedrich H. Lewy, who identified the abnormal protein deposits in the brain that disrupt normal functions such as perception, thinking, and behavior. (The late comedian Robin Williams was found to be suffering the early stages of this disease when he took his life in 2014.) Another disease included is sickle cell disease, a genetic condition characterized by abnormal hemoglobin in the red blood cells. (At the moment, only a stem-cell transplant can cure this otherwise lifelong condition, and life expectancy is between forty and sixty years in the United States, which is nevertheless up from fourteen years just forty years ago.)
Notable among the veteran scientists on the dais for this second panel was the smiling face of a teenage girl. That’s because the discussion centered in particular on NDRI’s partnership with the Cystic Fibrosis Foundation and Vertex Pharmaceuticals, which together have developed the first-ever medications to treat the underlying cause of cystic fibrosis rather than just its symptoms. The young woman’s name was Mara Cray; she was a patient.
Cystic fibrosis (CF) is a life-threatening genetic disease that affects thirty thousand children and adults in the United States and seventy thousand people worldwide. CF causes a buildup of thick, gluey mucus in the lungs, pancreas, and other organs. The mucus in the lungs clogs air passages and traps bacteria, which can lead to severe infections that damage the lungs. In the long run, the damage can be such that the only option is a lung transplant. Today, the life expectancy of a person with CF is under forty years. In the 1950s, it was fewer than six.
The Cystic Fibrosis Foundation was founded in 1955 by a group of parents whose children had the condition. At the time, CF kids were not expected to live long enough to enroll in grade school. In 1980, the Cystic Fibrosis Foundation created a research development program to speed up the search for a cure. That move contributed to the discovery, in 1989, of the CF gene, the first major step in understanding the disease at its root. The Cystic Fibrosis Foundation has been behind just about every drug invented to treat the disease.
In the mid-2000s, clinical trials began on the first oral medication that targets the mutated protein responsible for CF. In 2012, the FDA approved ivacaftor (Kalydeco) for certain CF patients over age five. In 2015, the FDA approved Orkambi, a two-drug combo of ivacaftor and lumacaftor, for about one-third of CF patients over age twelve. It was a huge breakthrough for the treatment of this disease, presenting the possibility for the first time of CF patients living out something closer to the life span of someone without CF.
This most recent milestone occurred in large part thanks to an effort begun by the Cystic Fibrosis Foundation with an assist from NDRI. In 2006, NDRI began receiving donations of diseased lungs from CF patients who received transplants. The donations were transported to Vertex, a global biotechnology company that studied the tissue to develop two new drugs designed to combat the disease at its biological root. Since CF, like other rare diseases, has no correlative in the animal world, to really make advances in treatment, researchers needed human tissue.
“We needed a relevant pharmacology model to assess our drugs,” said Eric Olsen, Ph.D., Vertex vice president and CF franchise leader. “Airway cells derived from the native tissue provided by NDRI allowed us to better understand” how the drugs might work in patients with CF, he told the panel.
Chris Penland, Ph.D., director of research at the Cystic Fibrosis Foundation, has said: “The most important contribution that NDRI makes is their ability to reach out into the community and acquire tissues to help drug discovery efforts. Almost every primary cell used in the research to make these discoveries was from a lung NDRI acquired.”
You could draw a direct line between the donation of those lungs by people who had no choice but a lung transplant and future CF patients who may be saved from ever needing one.
For example, Mara Cray. She has been just one direct beneficiary of those sixty years of research and about two hundred donated CF lungs.
In parallel to all this research using donated lungs, in 2014 NDRI launched a five-year initiative called the Molecular Atlas of Lung Development Program (LungMAP), which is funded by the National Heart,
Lung and Blood Institute and the NIH. For this project, NDRI is looking specifically for pediatric lungs in order to study pediatric lung diseases—ones that develop in utero and in early childhood.
That’s a tall order, but had it been available when Thomas died, he might well have been eligible to donate. It would have been a privilege to be a part of this project.
Perhaps the most ambitious program that NDRI supports by providing human tissue is the genotype-tissue expression (GTEx) program, which was launched in October 2010 by the National Institutes of Health’s Common Fund.
As I learned from the Duke study, gene expression has a huge impact on a person’s health. The federal government decided to create a massive data bank to study how that expression affects genes and correlates to various genetic diseases.
The National Human Genome Research Institute (NHGRI) described it in terms even I could understand: “Each cell in the human body contains a complete set of genes, yet not every gene is turned on, or expressed, in every cell in the body. To function properly, each type of cell turns different genes on and off, depending on what the cell does. For example, some genes that are turned on in a liver cell will be turned off in a heart cell.”
What GTEx sought to do, as NHGRI explained, was put those two ideas together to study how gene expression is regulated in different organs in the body, which would go a long way toward explaining the “underlying biology of many organ-specific diseases.”
Spearheaded by NDRI’s leadership team, NDRI set out to collect thirty-three different kinds of tissue from approximately 160 deceased donors.
NDRI started receiving donated tissue for GTEx in July 2011, from approximately six deceased donors each month. (One of the guidelines for the GTEx project was that recovery had to occur less than six hours after death. NDRI averaged just three to four hours for most of their recoveries, well under the target.) Two years into the effort they had collected thirty-three different types of tissue from 175 donors, for a total of sixteen hundred samples. Scientists in the GTEx project then studied the DNA and RNA from those samples, focusing largely on the tissue types they deem most valuable: fat, heart, lung, skeletal muscle, skin, thyroid, blood, tibial artery, and nerve.