Posted on by Dr. Francis Collins
A lot of young people are driven—driven to get a good education, land a great job, find true love, or see the world. But, today, I want to honor the life of a young man who was driven by something even bigger. Andrew Lee was driven to cure kidney cancer—not only for himself, but for others as well.
I knew and loved Andrew. And so did the legion of doctors, nurses, researchers, and other team members who had the privilege of fighting cancer with him over four very challenging years. Andrew was 19, just finishing his freshman year of college, when he received a devastating diagnosis: stage 4 kidney cancer, a rare type called Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). There is no known cure for HLRCC, and doctors estimated his survival at about a year at best.
Still, Andrew and his family weren’t about to go hide somewhere and wait for the end. They began a journey that led him to take part in at least seven clinical trials, including ones at Yale University, New Haven, CT; Georgetown University, Washington, DC; and the NIH Clinical Center, Bethesda, MD. Experimental treatments slowed down the cancer, but sometimes made him terribly sick. Yet, Andrew always remained optimistic and cheerful. If a trial didn’t help him, maybe it would help someone else.
Andrew’s generosity didn’t stop there. Inspired by his father’s gift of a totally awesome 2015 Liberty Walk Nissan GT-R, he founded the Driven To Cure (DTC) nonprofit and traveled the country in his orange sports car to raise funds for kidney cancer research. According to the National Cancer Institute, nearly 63,000 Americans are diagnosed with kidney and renal pelvis cancers each year.
Andrew figured out how to put the “fun” in fundraising, drawing crowds at car shows and raising more than $500,000 in donations in just three years. His efforts were recognized by the Foundation for the NIH’s Charlie Sanders Award, which I had the privilege of presenting to him last fall.
But I think it was Andrew’s humanity that touched us the most. He always had time to share his story, to encourage another child or adult struggling with a frightening diagnosis. He’d give thrills to kids at The Children’s Inn at NIH when he rumbled into the parking lot with his 700 horsepower GT-R. At car shows, throngs of people were drawn in by the turbocharged ride and then captivated by the young man with the bright smile and compelling story. Andrew wrote: “I realized that the vehicle of my dreams was also the vehicle which gave me the opportunity to make a difference; to do something bigger than myself.”
Still, on the personal level, kidney cancer proved relentless. Options for treatment eventually ran out. As the disease progressed, Andrew and his family had to make another difficult transition—choosing to celebrate life, even in the face of its approaching end. He needed a wheelchair, so family and friends came up with one, keeping in mind one of Andrew’s last wishes. When Andrew needed 24-hour care and pain control, he was admitted to the NIH Clinical Center Hospice Unit, where comfort could be provided and his loved ones could gather around. That even included getting government permission for a visit from his dog Milo! Surrounded by friends and family, he died peacefully on April 21.
Andrew made friends with everyone—especially kids at The Children’s Inn. One special buddy was Isaac Barchus, who has a rare autoinflammatory disease called CANDLE Syndrome. When he was back home in Omaha, NE, Isaac enjoyed challenging Andrew to long-distance video games, especially FIFA Soccer.
Although Isaac can walk, it can be very painful, so he sometimes turned to an old, beat-up wheelchair to cover long distances. But not anymore. When Isaac turned 15 on June 7, Andrew’s father Bruce Lee fulfilled his son’s wish for the future of his wheelchair. He presented Isaac with Andrew’s wheelchair, which had now been painted the same orange color as Andrew’s GT-R and emblazoned with the feisty slogan on Andrew’s personalized license plate—F CANCR. What a cool birthday gift!
During his final weeks and days, Andrew and his dad often listened to the Andy Grammer song, “Don’t Give Up on Me.” Andrew’s family never gave up on him, and he never gave up on them either. In fact, Andrew never gave up caring, loving, and believing. He wouldn’t want us to either, as his favorite song reminds us: “I will fight, I will fight for you; I always do until my heart is black and blue.”
Yes, Andrew, our hearts are black and blue from losing you. But we won’t give up on all you stood for in your short but inspiring life. Race In Peace, dear Andrew.
Remembering Andrew Lee (Foundation for the National Institutes of Health)
NIH Cancer Patient Receives Humanitarian Award (The NIH Record)
Driven To Cure (Silver Spring, MD)
Video: Fighting Cancer With a 700-hp Nissan GT-R (The Drive)
Video: Andy Grammer—”Don’t Give Up On Me” [Official Lyric Video] from the film Five Feet Apart
Hereditary Leiomyomatosis and Renal Cell Cancer (National Library of Medicine/NIH)
Kidney (Renal Cell) Cancer (National Cancer Institute/NIH)
CANDLE Syndrome (Genetic and Rare Diseases Information Center/NIH)
Treating CANDLE Syndrome (National Institute of Allergy and Infectious Diseases/NIH)
Posted on by Dr. Francis Collins
Forty-five years ago, when I was a first-year medical student, a lecturer introduced me to a young man with sickle cell disease (SCD). Sickle cell disease is the first “molecular disease”, with its cause having been identified decades ago. That helped me see the connection between the abstract concepts of molecular genetics and their real-world human consequences in a way no textbook could. In fact, it inspired some of my earliest research on human hemoglobin disorders, which I conducted as a postdoctoral fellow.
Today, I’m heartened to report that, thanks to decades of biomedical advances, we stand on the verge of a cure for SCD. While at the American Society of Hematology meeting in San Diego last week, I was excited to be part of a discussion about how the tools and technologies arising from the Human Genome Project are accelerating the quest for cures.
The good news at the meeting included some promising, early results from human clinical trials of SCD gene therapies, including new data from the NIH Clinical Center. Researchers also presented very encouraging pre-clinical work on how gene-editing technologies, such as CRISPR, can be used in ways that may open the door to curing everyone with SCD. In fact, just days before the meeting, the first clinical trial for a CRISPR approach to SCD opened.
One important note: the gene editing research aimed at curing SCD is being done in non-reproductive (somatic) cells. The NIH does not support the use of gene editing technologies in human embryos (germline). I recently reiterated our opposition to germline gene editing, in response to an unethical experiment by a researcher in China who claims to have used CRISPR editing on embryos to produce twin girls resistant to HIV.
SCD affects approximately 100,000 people in the United States, and another 20 million worldwide, mostly in developing nations. This inherited, potentially life-threatening disorder is caused by a specific point mutation in a gene that codes for the beta chain of hemoglobin, a molecule found in red blood cells that deliver oxygen throughout the body. In people with SCD, the mutant hemoglobin forms insoluble aggregates when de-oxygenated. As a result the red cells assume a sickle shape, rather than the usual donut shape. These sickled cells clump together and stick in small blood vessels, resulting in severe pain, blood cell destruction, anemia, stroke, pulmonary hypertension, organ failure, and much too often, early death.
The need for a widespread cure for SCD is great. Since 1998, doctors have used a drug called hydroxyurea to reduce symptoms, but it can cause serious side effects and increase the risk of certain cancers. Blood transfusions can also ease symptoms in certain instances, but they too come with risks and complications. At the present time, the only way to cure SCD is a bone marrow transplant. However, transplants are not an option for many patients due to lack of matched marrow donors.
The good news is that novel genetic approaches have raised hopes of a widespread cure for SCD, possibly even within five to 10 years. So, in September, NIH’s National Heart, Lung, and Blood Institute launched the Cure Sickle Cell Initiative to accelerate development of the most promising of these next generation of therapies
At the ASH meeting, that first wave of this progress was evident. A team led by NHLBI’s John Tisdale, in collaboration with Bluebird bio, Cambridge, MA, was among the groups that presented impressive early results from human clinical trials testing novel gene replacement therapies for SCD. In the NIH trial, researchers removed blood precursor cells, called hematopoietic stem cells (HSCs), from a patient’s own bone marrow or bloodstream and used a harmless virus to insert a sickle-resistant hemoglobin gene. Then, after a chemotherapy infusion to condition the patient’s existing bone marrow, they returned the corrected cells to the patient.
So far, nine SCD patients have received the most advanced form of the experimental gene therapy, and Tisdale presented data on those who were farthest out from treatment [1,2]. His team found that in the four patients who were at least six months out, levels of gene therapy-derived hemoglobin were found to equal or exceed their levels of SCD hemoglobin.
Very cool science, but what does this mean for SCD patients’ health and well-being? Well, none of the gene therapy trial participants have required a blood transfusion during the follow-up period. In addition, improvements were seen in their hemoglobin levels and key markers of blood-cell destruction (total bilirubin concentration, lactate dehydrogenase, and reticulocyte counts) compared to baseline. Most importantly, in the years leading up to the clinical trial, all of the participants had experienced frequent painful sickle crises, in which sickled cells blocked their blood vessels. No such episodes were reported among the participants in the months after they received the gene therapy.
Researchers did report that one patient receiving this form of gene therapy developed myelodysplastic syndrome (MDS), a serious condition in which the blood-forming cells in the bone marrow become abnormal. However, there is no indication that the gene replacement technology itself caused the problem, and MDS has previously been linked to the chemotherapy drugs used in conditioning regimens before bone marrow transplants.
The NIH trial is just one of several clinical trials for SCD that are using viral vectors to deliver a variety of genes with therapeutic potential. Other trials actively recruiting are led by researchers at Boston Children’s Hospital, Cincinnati Children’s Hospital, and the University of California, Los Angeles.
While it’s hoped that genes inserted by viral vectors will provide long-lasting or curative treatment, other researchers are betting that new gene-editing technologies, such as CRISPR, will offer the best chance for developing a widespread cure for SCD. One strategy being eyed by these “gene editors” is to correct the SCD mutation, replacing it with a normal gene. Another strategy involves knocking out certain DNA sequences to reactivate production of fetal hemoglobin (HbF).
The HbF protein is produced in the developing fetus to give it better access to oxygen from the mother’s bloodstream. But shortly after birth, the production of fetal hemoglobin shuts down, and the adult form kicks in. Adults normally have very low levels of fetal hemoglobin, which makes sense. However, from genome-wide association studies of human genetic variation, we know that that actual levels of HbF are under genetic control.
A major factor has been mapped to the BCL11A gene, which has subsequently been found to be a master mediator for the fetal to adult hemoglobin switch. Specifically, variations in a red cell specific enhancer of BCL11A affect an adult’s level of HbF— levels of BCL11A protein lead to higher amounts of fetal hemoglobin. Furthermore, it’s been known for some time that rare individuals keep on producing relatively high levels of hemoglobin into adulthood. If people with SCD happen to have a rare mutation that keeps fetal hemoglobin production active in adulthood (the first of these was found as part of my postdoctoral research), their SCD symptoms are much less severe.
Currently, two groups—CRISPR Therapeutics/Vertex Pharmaceuticals and Sangamo Therapeutics/Bioverativ—are gearing up to begin the first U.S. human clinical trials of gene-editing for SCD within the next few months. While they employ different technologies, both approaches involve removing a patient’s HSCs, using gene editing to knock out the BCL11A red cell enhancer, and then returning the gene-edited cells to the patient. The hope is that the gene-edited cells will greatly boost fetal hemoglobin production, thereby offsetting the effects of SCD.
All of this is exciting news for the 100,000 people living in the United States who have SCD. But what about the 300,000 babies born with SCD every year in other parts of the world, mostly in low- and middle-income countries?
The complicated, high-tech procedures that I just described may not be practical for a very long time in places like sub-Saharan Africa. That’s one reason why NIH recently launched a new effort to speed the development of safe, effective genome-editing approaches that could be delivered directly into a patient’s body (in vivo), perhaps by infusion of the CRISPR gene editing apparatus. Recent preclinical experiments demonstrating the promise of in vivo gene editing for Duchenne muscular dystrophy make me optimistic that NIH’s Somatic Cell Genome Editing Program, which is hosting its first gathering of investigators this week, will be able to develop similar approaches for SCD and many other conditions.
While moving forward in this fast-paced field, it is important that we remain ethical, but also remain bold on behalf of the millions of patients with genetic diseases who are still waiting for a cure. We must continue to assess and address the very serious ethical concerns raised by germline gene editing of human embryos, which will irreversibly alter the DNA instruction book of future children and affect future generations. I continue to argue that we are not ready to undertake such experiments.
But the use of gene editing to treat, perhaps even to cure, children and adults with genetic diseases, by correcting the mutation in their relevant tissues (so-called somatic cell gene editing), without risk of passing those changes on to a future generation, holds enormous promise. Somatic cell gene editing is associated with ethical issues that are much more in line with decades of deep thinking about benefits and risks of therapeutic trials.
Finally, we must recognize that somatic cell gene editing is a profoundly promising approach not only for people with SCD, but for all who are struggling with the thousands of diseases that still have no treatments or cures. Real hope for cures has never been greater.
 NIH researcher presents encouraging results for gene therapy for severe sickle cell disease. NIH News Release. December 4, 2018
Sickle Cell Disease (National Heart, Lung, and Blood Institute/NIH)
Cure Sickle Cell Initiative (NHLBI)
John Tisdale (NHLBI)
Somatic Cell Genome Editing Program (Common Fund/NIH)
NIH Support: National Heart, Lung, and Blood Institute; Common Fund
Posted on by Dr. Francis Collins
Whether by snail mail, email, or social media, it’s the time of year for catching up with family and friends. As NIH Director, I’m also fortunate to hear from some of the amazing people who’ve been helped by NIH research. Among the greetings to arrive in my inbox this holiday season is this incredible video from a 15-year-old named Aaron, who is fortunate enough to count two states—Alabama and Colorado—as his home.
As a young boy, Aaron was naturally athletic, speeding around the baseball diamond and competing on the ski slopes in freestyle mogul. But around the age of 10, Aaron noticed something strange. He couldn’t move as fast as usual. Aaron pushed himself to get back up to speed, but his muscles grew progressively weaker.
Posted on by Dr. Francis Collins
It might have been 25 years ago, but Karina Davidson remembers that day like yesterday. She was an intern in clinical psychology, and two concerned parents walked into the hospital with their troubled, seven-year-old son. The boy was severely underweight at just 37 pounds and had been acting out violently toward himself and others. It seemed as though Ritalin, a drug commonly prescribed for Attention Deficit Disorder, might help. But would it?
To find out, the clinical team did something unconventional: they designed for the boy a clinical trial to test the benefit of Ritalin versus a placebo. The boy was randomly assigned to take either the drug or placebo each day for four weeks. As a controlled study, neither clinical staff nor the family knew whether he was taking the drug or placebo at any given time. The result: Ritalin wasn’t the answer. The boy was spared any side effects from long term administration of a medication that wouldn’t help him, and his doctors could turn to other potentially more beneficial approaches to his treatment.
Davidson, now an established clinical psychologist at the Columbia University Irving Medical Center, New York, wants to take the unconventional approach that helped this boy and make it more of the norm in medicine. With support from a 2017 NIH Director’s Transformative Research Award, she and her colleagues will develop three pilot computer applications—or digital platforms—to help doctors conduct one-person studies in their offices.
Posted on by Dr. Francis Collins
For a remarkable journey through the front lines of clinical research, I’d like to invite you to join me in viewing First in Human, which premieres tonight at 9 p.m. ET on the Discovery Channel. This three-part docuseries, to be aired August 10, 17, and 24, provides an unprecedented look inside the NIH Clinical Center here in Bethesda, MD, following four of the many brave patients who’ve volunteered to take part in the clinical trials that are so essential to medical breakthroughs.
You’ll learn about what it’s like to take part in an experimental trial of a new treatment, when all standard options have failed. You’ll see that the NIH Clinical Center and its staff are simply amazing. But keep in mind that you don’t have to travel all the way to Bethesda to be part of outstanding, NIH-funded clinical research. In fact, we support clinical trials all across the country, and it’s often possible to find one at a medical institution near your home. To search for a clinical trial that might be right for you or a loved one with a serious medical problem, try going to ClinicalTrials.gov, a web site run by NIH.