1st Place: Carla Monté
Teacher: Mrs. Margarita Sihuro
School: La Vall
Location: Sabadell, Spain
Rewriting Immunity: The Promise and Dilemma of CAR‑T Therapy in Systemic Sclerosis
One ordinary morning, the word CAR‑T stopped sounding like science fiction at home. My mother, a clinical trial nurse, told me that her hospital was about to begin the first CAR‑T treatment in Spain for a patient with systemic sclerosis. Suddenly, terms like “risk-benefit” became real decisions. Until then, they were words I saw in academic papers; that day, I understood that behind every acronym stands a person choosing between fear and hope. If genetics lets us reprogram the immune system, how far are we truly ready to go?
Systemic sclerosis is a severe autoimmune disease in which the immune system attacks small blood vessels, leading to fibrosis of the skin and internal organs. In its diffuse form, it can affect the lungs, heart, or kidneys, sharply reducing life expectancy. B lymphocytes play a central role, producing autoantibodies and sustaining chronic inflammation. When conventional immunosuppressants fail, tissue damage continues. At that stage, “resetting” the immune system stops being a metaphor and becomes a potential lifeline.
CAR‑T therapies are a form of ex vivo gene‑engineered cell therapy. They were originally developed for blood cancers such as acute lymphoblastic leukemia (Maude et al., 2014) and have recently expanded into autoimmune diseases (Schett et al., 2023). The process involves collecting a patient’s T cells, genetically modifying them in the lab to express a chimeric antigen receptor (CAR) that recognizes CD19—a molecule on B cells—and then reinfusing them. Once back in the body, these modified cells systematically eliminate B cells, erasing those that drive autoimmunity and creating a kind of “immune reboot.”
In systemic sclerosis, the rationale is solid. Recent clinical evidence suggests that CD19‑directed CAR‑T therapy can induce deep, sustained remissions in severe autoimmune cases, including diffuse systemic sclerosis (Müller et al., 2024). Researchers have reported sharp declines in autoantibodies and significant improvements in function and quality of life after treatment (Wang et al., 2024). Still, these studies involve few patients and short follow‑up periods. The data are promising but not yet definitive.
The potential benefits are striking: one infusion capable of achieving remission when all else has failed. Yet the risks are substantial. Cytokine release syndrome and neurotoxicity, already familiar from oncology, can occur here too (Neelapu et al., 2018; Schett et al., 2023). Long‑term safety remains uncertain, and because this therapy re‑engineers immune cells, ongoing monitoring is essential to detect delayed effects or immune instability.
Another obstacle is cost. In Europe, CAR‑T treatments can exceed €300,000 per patient, and their manufacture requires highly specialized centers. Such constraints risk deepening healthcare inequality: cutting‑edge therapies reachable only by a few. Similarly, ethical tensions arise over consent, uncertainty, and fairness—how to ensure patients understand both the promise and the experimental nature of the treatment (Henderson et al., 2021).
While I was reading the latest papers, my mother described what was happening in her ward: teams checking protocols again and again, intensive monitoring, nurses standing by for a real‑time first infusion. It wasn’t a cinematic triumph. It was quiet, technical, and human. The patient had no other options and understood that taking part meant walking into the unknown, but also lighting a path for others. Weeks later, she was back home under careful observation, clinging to the hope that her immune system had finally found a new balance.
If I ever developed an aggressive, treatment‑refractory diffuse systemic sclerosis, being young and otherwise healthy, I would probably take that same leap. Not out of fascination with innovation, but because the disease’s progression would leave little time for fear. For an older patient or someone with milder illness, the decision might differ, and that’s what makes medicine as much about people as it is about science.
CAR‑T therapy represents more than a technical victory; it captures the moment when genetics and humanity meet at a crossroads. We have learned to reprogram lymphocytes—but the greater challenge is learning to use that power with wisdom. Perhaps progress is not measured only in molecular precision, but in the courage to act, the humility to question, and the empathy to remember that behind every cell we modify, there is a person hoping for a second chance.
CITATIONS/REFERENCES
Henderson, G. E., Churchill, L. R., Davis, A. M., Easter, M. M., Grady, C., Joffe, S., & King, N. M. P. (2021). Clinical trials and the ethics of uncertainty. Bioethics, 35(8), 781–789.
https://doi.org/10.1111/bioe.12901
Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D. M., Bunin, N. J., et al. (2014). Chimeric antigen receptor T cells for sustained remissions in leukemia. New England Journal of Medicine, 371(16), 1507–1517.
https://doi.org/10.1056/NEJMoa1407222
Müller, F., et al. (2024). CD19 CAR T‑cell therapy in autoimmune disease. New England Journal of Medicine.
https://doi.org/10.1056/NEJMoa2308917
Neelapu, S. S., et al. (2018). Chimeric antigen receptor T‑cell therapy—assessment and management of toxicities. Nature Reviews Clinical Oncology, 15(1), 47–62.
https://doi.org/10.1038/nrclinonc.2017.148
Schett, G., Mougiakakos, D., & Mackensen, A. (2023). CAR T‑cell therapy for autoimmune diseases. The Lancet, 402(10416), 2034–2044.
Wang, X., et al. (2024). Allogeneic CD19‑targeted CAR‑T therapy in severe autoimmune disease. Cell, 187(18), 4890–4904.e9.
https://doi.org/10.1016/j.cell.2024.06.027
2nd Place: Shiree Lapin
Teacher: Ms. Sam Lapin
School: Acellus Academy
Location: Kansas City, Missouri
“Careful with that butter—heart disease will surely follow.” Such cautions reflect the prevailing dogma that cardiovascular risk lies primarily on our plates. While lifestyle undeniably influences health, genetics exert powerful control over cholesterol regulation and long-term disease risk. As genetic medicine advances, conditions once considered untreatable are increasingly targeted at the molecular level. A quieter revolution is emerging in the world’s most common and deadly conditions: atherosclerotic cardiovascular disease. Researchers have begun testing in vivo gene editing to directly silence the PCSK9 gene in liver cells [6]. This approach aims not only to manage cholesterol but to reduce risk before disease manifests, marking a pivotal moment in genetic application.
Atherosclerotic disease develops when LDL cholesterol accumulates in arterial walls, triggering endothelial dysfunction and chronic inflammation that leads to plaque formation [2,4]. As arteries narrow, the likelihood of myocardial infarction and stroke increases. LDL levels are largely regulated by LDL receptors that clear cholesterol from the bloodstream. PCSK9 modulates this process by binding to LDL receptors and directing them for degradation rather than recycling [1,6]. Therefore, fewer receptors are available, leading to higher circulating LDL levels.
A substantial discovery occurred in 2003, when researchers identified individuals with natural loss-of-function mutations in PCSK9. These individuals exhibited dramatically low LDL levels and reduced cardiovascular risk, yet were otherwise physiologically healthy [1]. This provided rare human genetic validation: long-term reduction of PCSK9 appeared not only effective but safe. The finding catalyzed pharmaceutical development, inspiring monoclonal antibody inhibitors and eventually genome-editing approaches such as VERVE-101.
Unlike antibody therapies requiring repeated administration, VERVE-101 is a one-time infusion. VERVE-101 uses lipid nanoparticles delivering an adenine base editor mRNA plus guide RNA targeting PCSK9. Rather than creating double-stranded breaks, base editing converts one nucleotide into another, reducing unintended genomic damage [3,5]. The intended outcome is durable suppression of PCSK9, sustained LDL reduction, and prevention of cardiovascular disease.
Potential advantages of this treatment are striking. With millions affected worldwide, even modest LDL reductions result in significant decreases in heart attack and stroke incidence [2]. This permanent genomic intervention could eliminate issues of adherence, decrease healthcare costs associated with chronic therapy, and shift cardiology from reactive treatment to preventive genomic medicine.
However, the risks and ethical considerations are substantial. Base editing is irreversible. While safer than earlier CRISPR systems in terms of off-target effects, unintended edits remain possible, and long-term safety data are limited [5,7]. Moreover, editing a gene that influences risk raises philosophical concerns: should we permanently modify the genome to mitigate probabilities? For people with familial hypercholesterolemia—who face very high LDL and early heart problems—the justification can be strong. For those with only moderately elevated cholesterol, the line between benefit and risk becomes less clear.
Accessibility further complicates the equation. Gene-editing therapies often carry high upfront costs, which could limit availability and exacerbate health disparities. Since cardiovascular disease disproportionately affects lower-income populations, unequal distribution of preventive genomic tools could deepen gaps in healthcare. Thoughtful policy will be essential alongside scientific progress to ensure successful integration.
If a family member or I were diagnosed with familial hypercholesterolemia, the prospect of a single intervention offering decades of risk reduction would be compelling. However, if cholesterol levels were only moderately elevated and manageable through established therapies, I would hesitate to pursue irreversible genetic alteration. Until long-term data is obtained, the risk of permanent genomic change would outweigh the benefit. Ultimately, the decision would depend heavily on age, overall health, safety evidence, financial feasibility, and the proportionality of benefit relative to risk.
In vivo PCSK9 gene editing represents more than a novel therapeutic strategy; it signals a shift in medicine toward modifying disease susceptibility itself. As genomic technologies mature, society must determine how far preventive gene editing should extend and under what conditions permanent intervention is justified. The promise is extraordinary, but its integration into healthcare must remain anchored in safety, transparency, and equity. The future of cardiovascular medicine may not lie solely in what we eat or prescribe, but in how carefully we choose to edit the code that shapes biological risk. If PCSK9 editing continues on its current trajectory, perhaps one day your grandfather’s fear of cholesterol will feel as outdated as the myths that created it.
CITATIONS/REFERENCES
1. Cohen, J. C., Boerwinkle, E., Mosley, T. H., & Hobbs, H. H. (2006). Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. New England Journal of Medicine, 354(12), 1264–1272.
2. Ference, B. A., et al. (2017). Low-density lipoproteins cause atherosclerotic cardiovascular disease. European Heart Journal, 38(32), 2459–2472.
3. Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A., & Liu, D. R. (2016). Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature, 533(7603), 420–424.
4. Libby, P. (2021). The changing landscape of atherosclerosis. Nature, 592(7855), 524–533.
5. Gaudelli, N. M., et al. (2017). Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature, 551(7681), 464–471.
6. Musunuru, K., et al. (2021). In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature, 593(7859), 429–434.
7. Rees, H. A., & Liu, D. R. (2018). Base editing: precision chemistry on the genome and transcriptome of living cells. Nature Reviews Genetics, 19(12), 770–788.
8. Seidah, N. G., et al. (2014). The PCSK9 revolution and the potential of gene editing. Circulation Research, 114(6), 1022–1036.
3rd Place: Dragoș-Andrei Drăghici
Teacher: Ms. Codruța Dorina Burlea
School: Colegiul Național ”Octavian Goga”, Sibiu
Location: Sibiu, Romania
Zolgensma – Efficiency vs. Equity
Is a cure that cannot be reached by many a cure in reality, or just in theory? This paradox essentially describes the case of Zolgensma, a biologically transformative drug that is economically beyond the reach of many eligible patients.Spinal Muscular Atrophy (SMA) is a genetic disorder in which the lower motor neurons of the spinal cord and the central nervous system degenerate, resulting in symmetrical muscle weakness. It is an autosomal recessive genetic disorder caused by the absence of the survival motor neuron 1 gene. SMA affects one in every 10,000 newborns and, in rare circumstances, adults (Fernandes et al., 2024). It causes severe physical disability, respiratory difficulties, orthopedic issues such as contractures and scoliosis, and shortened life expectancy, as it has been regarded to be one of the leading genetic causes of premature death in children (Infante Cantú & Rodríguez Rivera, 2024).
Onasemnogene Abeparvovec, also known as Zolgensma, is a gene therapy drug approved by the Food and Drug Administration in 2019 to treat children younger than two years of age with SMA. It has to be administered in a single intravenous infusion using an adeno-associated virus serotype 9 (AAV9) vector that crosses the blood brain barrier to provide a functional copy of the SMN1 gene (Thielen et al., 2022).
However, despite its proven effectiveness, Zolgensma has sparked an international debate regarding its price (Thielen et al., 2022). Based on the estimate of the Department Pricing and Valuation of Amsterdam, its minimum sustainable price is €1.7 million, which is slightly lower than the current price of €1.9 million, making it one of the most expensive drugs ever marketed (Pacione et al., 2019). The healthcare systems are thus faced with the dilemma of innovation versus accessibility. Can a life-saving drug be considered an innovation if only a few people can afford it?
The most important issue is the concept of opportunity cost. If €1.9 million is allocated to one patient, what other treatments will receive less funding? From a utilitarian viewpoint, the allocation of healthcare resources should aim to maximize health outcomes, even if this implies allocating more resources to less expensive treatments that benefit more people. This logic is already in use by most systems through the cost-effectiveness threshold expressed in the form of cost per Quality-Adjusted Life Year (QALY), where treatments above the threshold are often regarded as inefficient use of public funds (Drummond et al., 2015). On the other hand, egalitarian theories state that patients with rare diseases should not be discriminated against just because their treatment is costly (Aartsma-Rus et al., 2021). Neither approach, taken alone, solves the dilemma, since utilitarianism might overlook rare disease patients, and egalitarianism might overlook population-level effects. Though there are trade-offs in spending a lot on a single patient, it doesn’t mean that expensive treatments should not be provided at all. The government has to strike a balance between efficiency and equity so that funding rare diseases doesn’t compromise funding preventive care or treatments for more common conditions.
Zolgensma supporters claim that the drug has a unique single-dose regimen that makes it a better choice than the other disease-modifying therapy, Spinraza, which was approved in 2016, and needs to be injected every four months intrathecally, meaning continuous long-term spending (U.S. Food and Drug Administration [FDA], 2016). Unlike Spinraza, whose costs are spread over time, Zolgensma’s front-loaded spending may be cost-effective over a person’s lifetime, but in a public healthcare system, where there are yearly budget constraints, big one-time spendings, such as this one, are hard to justify.
If I or a loved one were diagnosed with SMA, the issue would no longer seem theoretical, but urgent. Knowing that immediate intervention could save or improve a life, I would be willing to take any risks it may pose. However, given that my country does not invest heavily in its healthcare system, access would likely be limited or depend on seeking treatment abroad, using personal funds, or even organizing public fundraising. In such cases, it is difficult to justify a reality in which access depends more on national wealth than on medical need. A reality in which a baby from a wealthy country has access to gene therapy while a baby from a poor country does not.
In the end, the problem is not whether Zolgensma is effective, but whether modern healthcare systems are organized in a way that ensures that innovation is available to all, not just those who can pay for it.