Genetics in Gastroenterology: What You Need to Know, Part 2
Genetic Dominance: Genotype-Phenotype Relationships
In some instances, offspring can demonstrate a phenotype that is outside the range defined by both parents. In particular, the phenomenon known as overdominance occurs when a heterozygote has a more extreme phenotype than that of either of its parents. Indeed, in a few examples, a trait that shows overdominance sometimes confers a survival advantage in the heterozygote (Parsons & Bodmer, 1961).
A well-known example of overdominance occurs in the alleles that code for sickle-cell anemia. Sickle-cell anemia is a debilitating disease of the red blood cells, wherein a single amino acid deletion causes a change in the conformation of a person's hemoglobin such that the person's red blood cells are elongated and somewhat curved, taking on a sickle shape. This change in shape makes the sickle red blood cells less efficient at transporting oxygen through the bloodstream.
The altered form of hemoglobin that causes sickle-cell anemia is inherited as a codominant trait. Specifically, heterozygous (Ss) individuals express both normal and sickle hemoglobin, so they have a mixture of normal and sickle red blood cells. In most situations, individuals who are heterozygous for sickle-cell anemia are phenotypically normal. Under these circumstances, sickle-cell disease is a recessive trait. Individuals who are homozygous for the sickle-cell allele (ss), however, may have sickling crises that require hospitalization. In severe cases, this condition can be lethal.
Producing altered hemoglobin can be beneficial for inhabitants of countries afflicted with falciparum malaria, an extremely deadly parasitic disease. Sickle blood cells "collapse" around the parasites and filter them out of the blood. Thus, people who carry the sickle-cell allele are more likely to recover from malarial infection. In terms of combating malaria, the Ss genotype has an advantage over both the SS genotype, because it results in malarial resistance, and the ss genotype, because it does not cause sickling crises. This complex example of overdominance may be the sole reason that the allele persists in the human population today (Keeton & Gould, 1986).
'Will It Really Work?': Young Sickle Cell Patient Among The First To Start New Gene Therapy
WASHINGTON — For Wedam Minyila, hospital rooms have always meant blinding pain. "Like someone is jamming a knife in me," he said.
But for a brief moment on a recent December morning, Wedam, 19, who has sickle cell disease, allowed himself to believe what his doctors had been telling him for months: This visit could be the first step to a cure. As one of the first patients in the world to undergo commercial treatment for the genetic condition, he could start imagining a future free of excruciating pain.
"I choose to partially believe it," he said the day he was admitted to Children's National Hospital in Washington, D.C., for his stem cell collection — the first major step of the revolutionary sickle cell gene therapy process. "But that also comes with the skepticism of: Will it really work?"
Wedam Minyila spent hours on his phone or sleeping during his stem cell collection, as an apheresis machine drew his blood out of his body, spun out the stem cells and then returned the blood back into his veins.Jason Kane / NBC NewsIt's the same question sickle cell patients nationwide have been asking since the Food and Drug Administration approved two gene therapies that could cure the symptoms of the disease just over a year ago.
Since then, only a few dozen patients nationwide have been able to access it. Paperwork snarls, a multimillion-dollar price tag and patient concerns over serious side effects mean only a limited number of hospitals have treated patients so far.
More than 100,000 people in the United States — 9 in 10 of them Black — have sickle cell disease. The inherited illness causes red blood cells, usually round, to contort into a crescent, or sickle, shape. The sickle-shaped cells often pile up in blood vessels, resulting in excruciating pain, strokes, damage to organs and shorter lives. The new gene therapies, one from Boston-based Vertex Pharmaceuticals and the other from Somerville, Massachusetts-based Bluebird Bio, offer a potential cure.
That's why Wedam pushed past his skepticism — and worked through months of insurance approvals and medical consultations.
"I know what it can mean for me," he said quietly as a team of medical professionals began swarming his bedside. "But until it happens, I'm not really as excited as everybody else."
His mom, Sylvia, watched from the corner of the room, holding her breath. "This is a brand-new thing," she said. "And I never thought that, you know, we would be one of the pacesetters for this. It feels unreal."
But the first step of what she describes as her "miracle" was happening before her eyes: Nurses gave her son a medication to mobilize stem cells normally trapped inside the bone marrow to flow into the bloodstream. A couple of hours later, Wedam was hooked up to what's known as an apheresis machine, which draws blood out of the body and then spins it at high speeds to separate out the millions of stem cells before it returns the rest of blood back into the veins.
Dr. Andrew Campell stepped to Wedam's bedside as the first of the light orange liquid containing his stem cells began collecting in an IV bag hanging next to him.
"You are one of the few in the country and even in the world, you know, taking this big step — gene therapy," said Campbell, director of the hospital's Comprehensive Sickle Cell Disease Program. "It took a lot of bravery, because I know this is still very new in the process."
Wedam looked unfazed. "I had to," he said. "There's not something I could really pass up. So I didn't really have a choice."
A learning curve for hospitalsIn coming months, Wedam's cells will be shipped to a lab in Tennessee, where technicians will use a gene-editing tool called CRISPR to modify a gene in the stem cells so they produce red blood cells that are less likely to sickle and block blood flow, resulting in pain crises.
Wedam will need intensive chemotherapy to wipe out his existing stem cells and make room in his bone marrow for the gene-edited cells, which a team at Children's National Hospital will reintroduce into his bloodstream intravenously.
"To be able to deliver a therapy that is a cure and is going to keep him out of the hospital and is likely going to extend life, this is amazing," said Dr. David Jacobsohn, Children's National's chief of blood and marrow transplantation. "It's very, very powerful what we're able to provide now compared to five or 10 years ago."
Wedam, second from right, does a puzzle with his family. His younger brother Wekem, left, was also diagnosed with sickle cell disease. NBC NewsEven so, Jacobsohn acknowledged few patients have begun the gene therapy treatment. At Children's National — which was ahead of the curve after it participated in Bluebird Bio's clinical trials — only 10 people, including Wedam, have initiated or finished the process. That's out of a pool of about 1,500 patients with sickle cell disease that the team treats in the Washington area.
"At first, leadership in the hospital, they were super excited. They said: 'We have dozens and dozens of patients eligible. We need to build more beds!' And my feeling is eventually we will, but it's not going to happen right away," he said. "It's been a learning curve for the hospitals, and it's been a learning curve for the insurance companies."
Jacobsohn said his team is ramping up to start one or two patients on the treatment per month — a pace he called "exciting."
"Remember, this is a very high-risk treatment requiring high-dose chemotherapy with potential for complications," he said. "So it's not something that we would want to ramp up too rapidly."
The monthslong treatment Casgevy from Vertex Pharmaceuticals comes with a list price of $2.3 million. Bluebird Bio's Lyfgenia is listed at $3.1 million. Neither includes the cost of care to stay in the hospital or for chemotherapy.
To manage the hefty price tag, insurers have implemented extensive pre-authorization procedures. Both drug companies told NBC News they have yet to see an "ultimate denial" for their drugs.
The procedure is resource-intensive for the limited number of hospitals authorized to deliver it, requiring multiple days in the hospital for the stem cell collection and, months later, multiweek hospital stays for chemotherapy and the reintroduction of the stem cells, Jacobsohn said. In between, the stem cell processing lab needs several months to genetically alter the cells and perform safety checks before it sends them back to the hospital for infusion.
For patients like Wedam, there are other considerations, too. The intensive chemotherapy lasts four days and makes patients extremely ill and susceptible to infection. Many develop ulcerating sores in their mouths, throats and esophagi that make eating nearly impossible. Longer-term, the chemotherapy raises the risk of cancer and infertility.
For all of those reasons, only a single patient has completed the process at City of Hope Children's Cancer Center in Los Angeles. Dr. Leo Wang, a pediatric hematologist-oncologist at the center, says he expects that number to rise rapidly in coming months after the "early adopters" start showing success.
"We're very hopeful that uptake will increase and become more acceptable to people who are maybe a little bit more risk-averse," Wang said. "And we've already seen that where we'll have patients come and ask us about it and say, 'Well, I'd really like to talk to somebody who's been through this already and get their perspective, and then maybe I'll be interested in doing that.'"
'God, you did this for me'That's one of Wedam's motivations for becoming an "early adopter." "If all of those people could see me and see that it works, they'll have some hope," he said. "Even if it's a tiny bit."
The disease has robbed him of his ability to do much of anything, including getting out of bed. But the idea of a cure has him dreaming of some day becoming a filmmaker.
Near-term, his ambitions are much smaller — he'd like to attend his college classes in person instead of online.
"Now, I don't really keep up with most of my friends, so I'd be able to make new ones," he said. "I'd be able to learn the material better if I'm in person, asking the teacher actual questions. I just think, being a normal person, doing what a normal person would, I think that is what really excites me."
The disease ravaged the Minyila family for close to two decades. In addition to Wedam, his 14-year-old brother, Wekem, also has sickle cell.
Wedam's younger brother Wekem, left, taught himself how to ride a bike after a stem cell transplant cured his sickle cell disease. NBC News"It's taken almost everything," Sylvia Minyila said. "It's taken our joy."
Wedam, she said, was once a happy boy who loved school and dancing. But once his pain crises started around middle school, she said, he changed.
"He became withdrawn. Anywhere there was bone, he could have pain there," she said. "Anywhere in the house you were, you could hear him moaning. And this is something that I used to think about regularly: 'Am I going to lose him?' Because he was in so much pain."
Until the gene therapy, the only cure for sickle cell disease was a stem cell transplant from a donor. That worked for Wekem after Sylvia discovered she was a match for her younger son. After some scary complications, the procedure was successful.
But antibodies in Wedam's bloodstream prevented the same cure for him.
"I was ecstatic. I said: 'God, you did this for me. But what about my other son?'" Sylvia said, tears rolling down her face. "I wanted the same for Wedam."
She said that when the doctors at Children's Hospital called her just months later to let her know that Wedam might be a good candidate for the new gene therapy, it felt like a double miracle — an answer to her prayers.
"All I kept asking is: 'Is it curative? Is this something that he'll still have to take medications for? Is he going to have pain crises?' They said, 'No.' And I said: 'We're in. We are in.'"
Wedam has seen his younger brother transform since his treatment — even using his new energy to teach himself to ride a bike. The excruciating pain before Wekem's stem cell transplant had made that impossible.
Wekem said he's looking forward to seeing his older brother be healed.
"I feel like it changed the life that he is going to live," Wekem said. "I didn't really think that there was going to be something else that was available to us so he could get treated and cured."
But Wedam remains skeptical. "Maybe 60%," he said of his odds of being cured.
Still, even with the life-threatening complications that may come, he said, if there's any chance of a less painful future, it's worth trying.
NBC News will continue following Wedam Minyila's journey as he begins the next phases of his sickle cell treatment.
Sickle Cell: 'The Revolutionary Gene-editing Treatment That Gave Me New Life'
James GallagherInside Health presenter, BBC Radio 4
Jimi Olaghere thought he would have to wait decades to be freed from his sickle cell disease - but now scientists have engineered his blood to overcome the disease which left him in constant pain.
"It's like being born again," says Jimi, one of the first seven sickle cell patients to have benefited from a revolutionary new gene-editing treatment being trialled in the US. He says it has changed his life.
"When I look back, it's like, 'Wow, I can't believe I lived with that.'"
Jimi, 36, has lived with sickle cell since childhood. "You always have to be in a war mindset, knowing that your days are going to be filled with challenges."
The disease runs in families. It is caused by a genetic mutation that leads to the body making abnormal haemoglobin. This is the protein that is packed into red blood cells and carries oxygen around the body. Red blood cells are normally round and squishy, but mutated haemoglobin can make them rigid and take on their characteristic sickle shape.
Some red blood cells take on the characteristic sickle shape
These sickled cells struggle to navigate the body's blood vessels and get stuck, leading to blockages that stop flow of blood. The risk of heart attack, stroke and organ damage are all higher in people with sickle cell disease. Jimi may need a hip replacement because part of his bone tissue has died after being starved of blood - an irreversible condition called avascular necrosis.
Pain has been a lifelong companion for Jimi. It is like "shards of glass flowing through your veins or someone taking a hammer to your joints", he says. "You wake up in the morning with pain and you go to bed with pain."
But the hallmark of sickle cell disease are the severe pain episodes called crises, which need hospital care and morphine to take the pain away. For years, Jimi was in and out of hospital almost every month. Winters were the worst - as cold weather narrows the blood vessels near the skin and increases the risk of blockages. It is why Jimi moved his family across the US - down from New Jersey to the warmer climes of Atlanta, Georgia.
Amanda and Jimi Olaghere moved south for the warmer weather
The disease has affected every aspect of his life. He is a technology entrepreneur because he couldn't imagine any employer being sympathetic to his frequent hospital visits. To escape from the constant pain, Jimi found "pockets of happiness" in video games and watching Liverpool play football.
His family urged Jimi to take part in other clinical trials or have a bone marrow transplant - which is an option for some people with sickle cell. But he thought they would involve too much time in hospital for the improvement in his quality of life. Instead, he pinned his hopes on a cure that was yet to be invented. He told his family: "One day in the future, probably 20 to 50 years from now, I'm going to get my DNA edited, and it's going to cure my sickle cell."
The future arrived a lot sooner than he imagined.
In late 2019, Jimi read an article about a new clinical trial using gene editing and he immediately emailed the medical team. A month later Jimi and his wife Amanda, who was eight months pregnant, travelled to the Sarah Cannon Research Institute in Nashville to see if he would qualify. When news came back that he had been accepted into the trial, Jimi said it was "the best Christmas present ever". And then he was lucky. The pandemic threatened to disrupt the trial as growing numbers of internal flights were cancelled due to low passenger numbers but he was able to commit to making a four-hour journey by car for each and every session..
In the trial, scientists would genetically engineer his body so he no longer produced that tainted haemoglobin.
First they had to get to the part of the body that manufactures red blood cells - these are stem cells that live in the spongy marrow at the centre of our bones. Then, in January 2020, Jimi was given drugs that flushed stem cells out of his bone marrow and into the bloodstream. He was then plumbed into an apheresis machine to collect the stem cells from his blood.
"You sit there for eight hours and this machine is literally just sucking all the blood out of you," he said.
At the end he was physically, mentally and literally drained and would need a transfusion to replace the blood that was taken. This was the hardest part of the whole process for Jimi and he went through it four times.
Jimi went home to recover after the final donation, but the harvested stem cells were only beginning their journey.
Scientists were about to perform an impressive feat of genetic trickery that would turn back time in Jimi's blood.
When we are still in the womb, our bodies use a different type of haemoglobin called foetal haemoglobin. This grabs hold of oxygen more tightly than adult haemoglobin and is essential for a developing baby to take oxygen out of its mother's bloodstream.
After we're born, a genetic switch is flipped and we start making adult haemoglobin. Crucially, it's only the adult form of haemoglobin that is affected by sickle cell disease.
That genetic switch - memorably named BCL11A - was identified in the mid-2000s. And advances in the field of gene editing meant scientists now had the tools to flip it.
"Our approach is to turn that switch off and increase the production of foetal haemoglobin again, basically turning the clock back," says Dr Haydar Frangoul, who treated Jimi at the Sarah Cannon Research Institute.
Jimi's stem cells were sent to the laboratories of Vertex Pharmaceuticals and Crispr Therapeutics where the genetic editing would take place.
By September 2020, it was time to put the engineered cells into Jimi's body. "It was the week of my birthday, actually. So it was almost like getting a new life," he says.
First Jimi had chemotherapy to destroy the stem cells in his body that were making sickle-blood cells. Then the genetically engineered ones were infused into his body to give him new, and hopefully sickle-free, blood.
The procedure was exhausting, but around two weeks later, Jimi emerged as a completely new person.
"I remember waking up without any pain and feeling lost," he says. "Because my life is so associated with pain, it's just a part of who I am. It's weird now that I don't experience it any more.'"
Dr Frangoul says the data on the first seven patients has been "nothing short of amazing" and represented a "functional cure" for their disease.
"What we are seeing is patients are going back to their normal life, none have required admission to hospital or doctor visits because of sickle cell related complications," Dr Frangoul says.
The same genetic procedure has been performed on a total of 45 patients with either sickle cell disease or another blood disorder called beta thalassaemia, which is caused by malformed haemoglobin. But the full data is still being collated.
Finally free of pain, Jimi feels he can finally be the person he "always felt inside". He says the illness had turned him into more of an introvert because it forced him to stay home and be careful.
"I have this analogy I use. When my son was first born, I saw him looking out the car window and seeing him experience the world for the first time as a new human being. I almost feel the same way. I'm living life as a new person."
And he feels he can finally be the parent he wanted to be. "Just being able to take a walk with my son, that's something I thought I was going to miss out on."
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