Desert Warrior is a historical action film directed by Rupert Wyatt, who co-wrote the screenplay with Erica Beeney and David Self. The story sees an Arabian princess team up with a bandit to confront a ruthless emperor, who ruled that all women were to join his army of concubines. This movie went way under the […]
Sickle cell disease is the scourge of a person’s red blood cells. The inherited blood disorder, which disproportionately affects people in sub-Saharan Africa and India, can cause unbearable pain, “crises,” and extreme exhaustion. And until recently, there was no curative treatment. Now approved gene therapies for sickle cell disease (including sickle cell anemia, the most extreme form) and its milder cousin, beta-thalassemia, show enormous promise.
The therapies work by deactivating or replacing a hemoglobin gene so that a person’s body makes a healthy form instead of the telltale sickle-shaped red blood cells that define sickle cell disease or averting the red blood cell deficiency that causes beta-thalassemia.
At some point, all humans produce two forms of hemoglobin, the red blood cell protein that binds oxygen so it can be transported throughout the body: a fetal form, which is more efficient at extracting oxygen in the womb, and an adult form. After we’re born, our body switches from producing the fetal form to making the adult form.
After years of research, scientists figured out that by turning off BCL11A—a gene known to suppress fetal hemoglobin production—they could coax the body of a person with sickle cell disease to continue making healthy hemoglobin. Companies have now developed gene therapies that target this gene. In clinical trials, people who received the treatment were functionally cured of their condition—those with sickle cell disease saw a complete resolution of their pain during the study period, and those with beta-thalassemia didn’t need blood transfusions or bone marrow transplants.
On April 18 a Breakthrough Prize in Life Sciences—one of the $3-million Breakthrough Prizes, sometimes referred to as the “Oscars of science”—was awarded to Swee Lay Thein and Stuart Orkin, who led efforts to identify the BCL11A gene and to show that shutting it off could restore healthy hemoglobin production, setting the stage for treating these devastating blood diseases.
Scientific American spoke separately with Orkin, a professor of pediatrics at Harvard Medical School and an investigator at the Dana-Farber Cancer Institute and Boston Children’s Hospital, and Thein, a senior investigator at the National Institutes of Health, about what happened in the work that led to their prize and how these treatments can be made more accessible to the people who stand to benefit the most.
How did you come to study sickle cell disease? And did you realize early on that fetal hemoglobin would be a good therapy target?
ORKIN: I started out in the 1980s working on the genetics of [beta-thalassemia]—that is, what mutations lead to the deficiency of hemoglobin in that disorder. The hope was that we would learn how a red [blood] cell is made and how genes are regulated. We didn’t really learn that, but we learned a lot about mutations and disease. Even prior to that, we knew the deficiency of beta-globin [a component of the adult hemoglobin protein] in [beta-thalassemia], and the [effects of a] mutation in sickle cell disease can be alleviated by expressing more fetal hemoglobin.
We knew that, from family studies in some very rare individuals who had a lot of fetal hemoglobin, if you raise the level of fetal hemoglobin high enough, you can basically ameliorate those disorders—plus, fetal hemoglobin is perfectly fine to substitute for adult hemoglobin [for carrying oxygen]. As early as genes were cloned back in the early 1980s, one of the goals was to see if we could reverse the switch and make fetal hemoglobin expressed at a high level in adult cells as a treatment [for beta-thalassemia]. The problem was, we didn’t understand the process at all—that’s what’s consumed the past 15 to 20 years or research—or how to reverse it.
Why do our cells switch from making fetal to adult hemoglobin in the first place?
ORKIN: We do that because, in utero, having a fetal hemoglobin is better at extracting oxygen from the mother’s circulation, and it has a higher affinity, so it takes oxygen from the circulation to the developing [fetus]. But it turns out the difference between fetal hemoglobin and adult hemoglobin in that affinity is relatively small, so having fetal hemoglobin as an adult doesn’t matter. If you ran a marathon on the top of Mount Everest, it might make a difference. You might have trouble releasing the oxygen, but under normal circumstances, it’s not a problem.
How did your work lead to the discovery of the BCL11A gene involved in sickle cell disease and beta-thalassemia?
THEIN: The discovery of BCL11A was the result of more than two decades of work driven by a deceptively simple clinical observation: Why do some people with beta-thalassemia have remarkably mild disease, while the majority require lifelong blood transfusions?
I began collecting blood samples from people with unusually mild beta-thalassemia (thalassemia intermedia) and their families. And sure enough, it turned out that most of these milder cases possessed an innate ability to produce high levels of [fetal hemoglobin]. Crucially, our family studies showed that the responsible gene or genes were inherited independently of the beta-globin gene itself and that the inheritance pattern was complex. I was convinced that that there was a substantial genetic component underlying this common [fetal hemoglobin] variation, which I confirmed with twin studies.
Then, genome-wide association studies revealed the involvement of BCL11A, a gene with no previously known role in hemoglobin biology. Our findings were independently confirmed by another group the following year, firmly establishing BCL11A as a key regulator of fetal hemoglobin and, ultimately, a therapeutic target in both sickle cell disease and beta-thalassemia.
ORKIN: Back in 2011, we did an experiment in which we took mice that had been engineered to have sickle cell anemia and disabled the BCL11A gene in those mice—but only in the developing red blood cells—through fancy genetics. The result was that we could completely correct those mice—they were completely well after we knocked out [deactivated] the BCL11A gene. That told us that one gene was sufficient to correct the disease and that it would be a therapeutic target if we could manipulate it. That was 15 years ago. It took several years to figure out where we’d want to do the editing, and just about the time we wanted to ask that question, [the gene-editing technique] CRISPR came on the scene, so, you know, all the stars aligned in just the right way.
Dr. Thein, can you describe some of your research with populations in Malawi?
THEIN:At the time, identifying the genes responsible for elevated fetal hemoglobin relied on a technique that requires large, multigenerational family cohorts with well-documented relationships. Finding such families is no small feat, so when I came across a person with exceptionally mild beta-thalassemia who happened to come from a remarkably large extended family, many of [whose members] were living in Malawi, I recognized it as a rare and significant opportunity.
I organized a field trip to Malawi and, through careful tracing and recruitment, was able to expand the study family to 210 individuals spanning seven generations—an extraordinary resource for this technique.
There was some hesitation among family members initially, which is entirely understandable when people are asked to participate in something unfamiliar. We addressed this through clear, patient explanations of the study’s purpose and what participation involved.
What had begun as a scientific endeavor became, in many ways, a communal one—a reminder that behind every dataset are real people whose generosity and trust make the research possible.
These discoveries paved the way for the first approved gene-editing treatments for sickle cell disease in 2023: Casgevy, made by Vertex Pharmaceuticals and CRISPR Therapeutics, and Lyfgenia, made by bluebird bio (now known as Genetix Biotherapeutics). How many people with sickle cell disease have received these therapies?
ORKIN:The original [Vertex] trial had [about] 75 participants [with either sickle cell disease or beta-thalassemia, and since then, they’ve treated more people. They report that more than 90 percent of the participants who were treated are basically functionally well. In other words, in the case of [beta-thalassemia], they don’t need transfusions anymore, and in terms of sickle cell disease, they don’t get sickle crises, the painful crises.
It really is transformative for these individuals, particularly for the people with sickle cell. Beforehand, it was a miserable disease. They had intermittent pain crises and other complications. And it’s hard to maintain a job if you’re an adult. And what the patients describe is, after they’re treated, they have a new lease on life.
Are the populations most at risk for these diseases likely to receive gene therapy treatment for their conditions? And how can these treatments be made more affordable and accessible?
THEIN:Honestly, in the near term, the answer is probably not.
The gene therapies currently approved by the U.S. Food and Drug Administration are ex vivo. This means harvesting a patient’s own hematopoietic [red blood] stem cells, editing them in a specialized laboratory, and then reinfusing them—but only after the patient has undergone intensive chemotherapy to destroy the existing bone marrow and create space for the edited cells to engraft [settle and begin producing new cells]. The process is physically grueling for the patient, logistically demanding and extraordinarily expensive, costing about $2 million to $3 million per patient. Even in the wealthiest health care systems, access is far from universal.
The scientific community is acutely aware of this, and research priorities are now pivoting toward next-generation in vivo gene-editing approaches where the editing machinery is delivered directly into the body to target the hematopoietic stem cells in situ.
But the challenge that weighs on me most is access to treatment, whether [it is] gene therapy, [a] bone marrow transplant or drugs. The burden of sickle cell disease is heaviest in sub-Saharan Africa and India, precisely where these therapies are currently least accessible. Even if we develop a cheaper, simpler gene therapy tomorrow, getting it to the patients who need it most will still require political will, sustained global health investment, international partnerships and a serious rethinking of how we price and distribute transformative medicines.
What are you working on next?
ORKIN: My group is focused on trying to understand in very exquisite detail the whole mechanism and the process that is involved in the switch [from fetal to adult hemoglobin]. And we’re focused on trying to see if we can develop a way to find small molecules that will do the reversion, if you will, by taking a pill. That would be something that could be distributed much more easily than the current editing therapy.
THEIN: My current research is centered on small molecules, particularly those that can prevent or abort the severe pain crises that remain one of the most debilitating and undertreated aspects of sickle cell disease. These crises represent a profound unmet clinical need, and finding effective, accessible interventions for them would make an enormous difference to patients’ daily lives.
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Artwork showing normal red blood cells (round) and red blood cells affected by sickle cell disease (crescent-shaped). KATERYNA KON/SCIENCE PHOTO LIBRARY/Getty Images
President Donald Trump has invited executives from some of the biggest U.S. companies — including Tesla CEO Elon Musk, Apple CEO Tim Cook, BlackRock’s CEO Larry Fink, and Boeing CEO Kelly Ortberg — to join his trip to China this week, according to a White House official.
Also expected to join Trump’s delegation for meetings with Chinese President Xi Jinping are Blackstone’s Stephen Schwarzman, Cargill’s Brian Sikes, Citigroup’s Jane Fraser, Coherent’s Jim Anderson, GE Aerospace’s H. Lawrence Culp Jr., Goldman Sachs’s David Solomon, Illumina’s Jacob Thaysen, Mastercard’s Michael Miebach, Meta Platforms executive Dina Powell McCormick, MicronTechnology’s Sanjay Mehrotra, Qualcomm’s Cristiano Amon and Visa’s Ryan McInerney, the official said, speaking on condition of anonymity because the list has not been announced.
A spokesperson for Cisco said CEO Chuck Robbins had been invited by the White House to join the trip but is unable to attend due to the company’s earnings schedule.
The executives will join Trump on the trip during which he has said he hopes to secure a series of business deals and purchase agreements with Beijing.
The summit agenda is expected to cover trade, artificial intelligence, export controls, Taiwan, and the Iran war, with both sides entering the talks after weeks of escalating tensions.
Notably absent from the attendees is Nvidia CEO Jensen Huang, who said last week in an interview with CNBC’s Jim Cramer that “We should let the president announce whatever he decides to announce … If invited, it would be a privilege, it would be a great honor to represent the United States.”
General Motors, Disney, and Alphabet are also companies with interests in China that the White House did not list as having executives expected to attend.
On Friday, Citigroup’s Fraser told CNBC’s Leslie Picker that “I think it’s very important to see engagement” between the two economic superpowers.” Adding, “we all need that engagement to be occurring.”
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U.S. President-elect Donald Trump greets Elon Musk as he arrives to attend a viewing of the launch of the sixth test flight of the SpaceX Starship rocket on November 19, 2024, in Brownsville, Texas.
FEMA Administrator: President Trump nominated Cameron Hamilton, a former acting administrator of the Federal Emergency Management Agency, to be FEMA’s permanent leader on Monday. He was pushed out of the acting role a year ago after he did not endorse eliminating the agency, which Mr. Trump had suggested. Mr. Hamilton, a former Navy SEAL, is likely to face opposition from Democrats because he lacks experience in disaster response.
Reflecting Pool: Federal records show that the no-bid contract to repair the Lincoln Memorial Reflecting Pool and paint it blue now costs $13.1 million — more than seven times the amount President Trump initially said it would.
China Trip: Mr. Trump will be joined by 16 top executives in China this week, including Elon Musk and Tim Cook.
Trump nominates an ousted FEMA leader to run the agency again.
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Cameron Hamilton campaigning in 2024 during his unsuccessful run as a Republican for a congressional seat in Virginia.Credit…Amanda Andrade-Rhoades for The Washington Post, via Getty Images
President Trump on Monday nominated Cameron Hamilton, a former member of the Navy SEALs, as administrator of the Federal Emergency Management Agency, seeking to install the organization’s first permanent leader of the president’s second term.
If confirmed by the Senate, Mr. Hamilton would rejoin the agency a year after serving a brief stint as its acting administrator. He was ousted from that role days after he testified to Congress that FEMA should not be eliminated, an idea that Mr. Trump and Kristi Noem, then the homeland security secretary, had floated early last year.
The cost of repairing the National Mall reflecting pool is far more than Trump initially said.
President Trump said that his handpicked contractor would charge only $1.8 million to repair the Lincoln Memorial Reflecting Pool and paint it blue.
The actual cost is now more than seven times that, after the Interior Department nearly doubled the size of the contract late last week, federal records show.
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The U.S. Senate has confirmed Steve Pearce to steward about 245 million acres of federal land and 700 million acres of underground minerals as director of the Bureau of Land Management. Pearce, a Republican former U.S. representative from New Mexico, faced opposition from conservation and hunting groups for his past support of privatizing public lands. During his confirmation hearing, though, Peace pledged he would not pursue sales of “large swaths” of federal holdings. The 46-45 vote along party lines confirmed a large bloc of nominees to energy and environment positions, including Pearce.A third federal appeals court has rejected the Trump administration’s policy of detaining U.S. residents who entered the country illegally years ago and holding them without bond. The majority opinion in the split ruling from the U.S. Court of Appeals for the Sixth Circuit is the first by a federal appeals court to affirmatively find that not only does the policy rest upon a misinterpretation of immigration law, it also violates the Fifth Amendment’s guarantee to due process. Both questions are likely to reach the Supreme Court.
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Senate Republicans on Monday defended their plan to include $1 billion for security funding for President Trump’s ballroom project as they prepared to take up a politically charged budget bill that faces stiff opposition from Democrats.
Returning to the Capitol for the first time since the components of the spending plan were made public, top Republicans said the security money was necessary given the threats to the president, and claimed that none of it would be used for the ballroom itself. The president has said private donations will pay for the ballroom, which he has estimated to cost $400 million, though some Republicans want tax dollars to go to it as well.
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James Comey, the former F.B.I. director, took aim at President Trump during his first interview since being indicted over his social media post of seashells on a beach, told MSNOW it was a “little bit humorous” to have “this obsession by this 80-year-old man with me.” He also took a swipe a Joseph Joseph diGenova, who was recently tapped to oversee investigations of Trump enemies, quipping that the 81-year-old ex-prosecutor had not served in government “since Duran Duran was on the charts.” Comey, targeted for his investigation into the 2016 Trump campaign’s connections to Russia, lamented that his successor, Christopher Wray, had not spoken up about Trump and his appointees at the F.B.I. Comey said he hoped Wray and others have not been “chilled” by Trump — whom he called “an empty narcissist.”
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Cameron Hamilton attending a hearing at the Capitol last year as the acting administrator of the Federal Emergency Management Agency. Credit…Oliver Contreras/Agence France-Presse — Getty Images
Necessary for a presidential candidate to be able to read or even write even a congenital idiot can run for the presidency of the United States of America and serve if you were elected “
Edgar Rice Burroughs
Proverbs 27:22
New Living Translation
22 You cannot separate fools from their foolishness, even though you grind them like grain with mortar and pestle.
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EVIL PEOPLE
They had been long accustomed to do evil. They were taught to do evil; they had been educated and brought up in sin; they had served an apprenticeship to it, and had all their days made a trade of it. It was so much their constant practice that it had become a second nature to them. – Matthew Henry
“When a clown moves into a palace, he doesn’t become a king, the palace instead becomes a circus. — Turkish proverb,”
Hmmmmm…History is repeating itself yet again!
Isaiah 59:14
New Living Translation
14 Our courts oppose the righteous, and justice is nowhere to be found. Truth stumbles in the streets, and honesty has been outlawed.
Jeremiah 5:21
New Living Translation
21 Listen, you foolish and senseless people, with eyes that do not see and ears that do not hear.
This sounds just like today’s World although it was written about Israel in Babylonian captivity.
History repeats itself
Isaiah 59:9-15
New Living Translation
9
So there is no justice among us, and we know nothing about right living. We look for light but find only darkness. We look for bright skies but walk in gloom. 10 We grope like the blind along a wall, feeling our way like people without eyes. Even at brightest noontime, we stumble as though it were dark. Among the living, we are like the dead. 11 We growl like hungry bears; we moan like mournful doves. We look for justice, but it never comes. We look for rescue, but it is far away from us. 12 For our sins are piled up before God and testify against us. Yes, we know what sinners we are. 13 We know we have rebelled and have denied the Lord. We have turned our backs on our God. We know how unfair and oppressive we have been, carefully planning our deceitful lies. 14 Our courts oppose the righteous, and justice is nowhere to be found. Truth stumbles in the streets, and honesty has been outlawed. 15 Yes, truth is gone, and anyone who renounces evil is attacked.
The Lord looked and was displeased to find there was no justice.
Film and Writing Festival for Comedy. Showcasing best of comedy short films at the FEEDBACK Film Festival. Plus, showcasing best of comedy novels, short stories, poems, screenplays (TV, short, feature) at the festival performed by professional actors.
Cameron Hamilton attending a hearing at the Capitol last year as the acting administrator of the Federal Emergency Management Agency. Credit…Oliver Contreras/Agence France-Presse — Getty Images
A. R. Bernard: one of many
James' World 2 