Phages saved Irene's life, after she received and rejected four transplanted lungs.
University of Valencia biologist Pilar Domingo-Calap prepares a capsule of coffee in her office in Paterna, northwest of the city. Next to the machine is a small white refrigerator, like those found in hotels. From it, she takes out a bag containing small plastic tubes filled with a liquid that looks like water. They actually contain tens of millions of bacteria-eating viruses known as bacteriophages, or phages. “If you drank this,” she explains to the journalist, “absolutely nothing would happen to you.” But for people suffering from antibiotic-resistant bacterial infections— a global emergency that contributes to five million deaths each year—this colorless liquid can be life-changing.
In 2023, this researcher's team received an email saying: "Let's see when my phage arrives." It was from Irene Nevado, a nurse from Madrid who had been plagued by genetic bad luck since birth. Her parents were unknowingly carriers of a mutation that causes cystic fibrosis , a rare disease that attacks the lungs and other organs. There was only a one in four chance that their children would have the condition. Irene and her brother, two years older than her, were born with it.
Sitting in Domingo-Calap's office, Irene, who will turn 46 this year, tells her story with astonishing optimism and vitality. When she was eight years old, she was infected with Pseudomonas aeruginosa , a respiratory bacterium that complicated the symptoms of her illness. The fibrosis fills the lungs with mucus, nearly impairing breathing. Any movement, such as climbing steps or walking, requires a superhuman effort. "It's like being overturned by a wave," Nevado summarizes.
In 2008, the nurse received a double lung transplant , but suffered chronic rejection, meaning those organs were no good for her. She was put on the waiting list for a second transplant, which arrived in 2019. This time, she suffered acute rejection, which could be relieved with immunosuppressive drugs and antibiotics, but it did not prevent her from suffering severe attacks. By 2023, she was hospitalized with no further therapeutic options. She learned about phages through the Balearic Islands patient association and was able to start an experimental treatment with phage number 10, developed by Domingo-Calap's team in collaboration with doctors from the Yale University Phage Therapy Center in the United States.
The patient completed two 10-day sessions in which the liquid from the phage vials is nebulized and inhaled through the nose and mouth. Since January 2024, her lung capacity has recovered and there is no trace of the resistant bacteria, meaning she will not have to wait for a third transplant. This year, she swam 4,000 meters during the Formentera crossing , a charity event to raise awareness about cystic fibrosis, which affects one in every 5,000 people.
"We believe this is a unique case in the world, given that she has had both lungs transplanted twice," says Domingo-Calap, a 40-year-old from Valencia who works at the Institute of Integrative Systems Biology . Irene Nevado's case has just been published by the American Society for Microbiology in a study co-authored by scientists from the universities of Valencia and Yale, and the doctors who treated the patient at Puerta de Hierro Hospital in Madrid.
This success exemplifies the rise of phage therapy as an alternative against resistant infections. This technique has been known for over a century, and was most widely used during and after World War II in the Soviet bloc. In the West, however, the rise of penicillin and other antibiotics sidelined viral therapy until, a few years ago, it was revived as an alternative to the growing problem of superbugs resistant to many or all known antibiotics. In Spain alone, these infections kill around 4,000 people each year, several times more than traffic accidents.
The theory is that for every known bacterium, there is one or more phages capable of eliminating it. They are highly specific, allowing only those microbes that pose a threat to be eradicated without harming others that are beneficial to health. As Domingo-Calap points out, "phages are everywhere." The researcher has found them in soil, plants, wastewater, and hospitals. One of the places where they are most diverse is in schools, where the researcher regularly takes samples as part of an educational program about these organisms. "Anyone can find a phage; the problem is that not all of them are effective," she summarizes.
Phages can be trained with directed evolution to give them new capabilities, such as operating at human body temperature. Each virus is trained with bacteria extracted from the patient, and those that best eliminate it, or those that cause the least resistance, are chosen. The scientist explains that since 2023, she has treated 15 patients in Spain with these therapies, which are usually administered as compassionate treatment, that is, when no other resources are available. "In many cases, we have managed to make the infections disappear," she emphasizes. Her phage library already contains more than 500 specimens, including some that have shown effectiveness against the 12 most dangerous families of resistant bacteria, according to the WHO, the scientist adds.
These viruses are often administered alongside antibiotics and other treatments. In some cases, they kill resistant bacteria . In others, they attack the efflux pumps that microbes use to capture nutrients, allowing the antibiotics to eliminate them. Alternatively, the phage can attack a receptor on the outside of the bacteria, prompting the immune system to identify and destroy them. In most cases like Irene's, it's never clear whether the phage killed the microbe, nor its exact activity inside the body, as is the case with other drugs, and this has contributed to the widespread use of the therapy so far.
Belgian doctor Jean-Paul Pirnay is one of the world's leading experts in phage therapy. His team has achieved several spectacular cures, such as that of a woman injured in an attack who overcame one of the worst known infections thanks to phage therapy. In recent years, these types of treatments have successfully eliminated infections in liver, kidney, and lung transplant recipients, including a 15-year-old girl with cystic fibrosis and a double lung transplant, he emphasizes. "Every success story is important, and this one is especially so because it occurs in a country like Spain, where efforts are still being made to establish these therapies," Pirnay explains to this newspaper.
Belgium is somewhat independent of the rest of Europe in this field. EU regulations, applied in Spain, stipulate that these types of treatments can only be carried out on a compassionate basis and in specialized advanced therapy centers, equipped with clean rooms and the highest levels of asepsis. The idea is to prevent unapproved and potentially dangerous treatments, although this also hinders work in laboratories like Domingo-Calap's. In Belgium, on the other hand, authorities allow hospitals to formulate these therapies as master formulas, which has facilitated their access to more patients. In 2023, the researcher co-founded a spin-off company on the Valencia campus to apply phages to human, animal, and plant health, in which Mercadona founder Juan Roig recently invested. The researcher believes that Spain should follow Belgium's example. But for now, she is already seeking funding to begin clinical trials with more patients to demonstrate the widespread effectiveness of these therapies.
“In our gut, there are 100 times more phages than bacteria,” explains Bruno González-Zorn , a professor at the Faculty of Veterinary Medicine at the Complutense University of Madrid and an expert in antibiotic-resistant infections. Bacteria have developed resistance mechanisms to many of them. When phages have been tested in large clinical trials, they haven't shown clear effectiveness, he points out. Furthermore, since they can't be properly controlled once they enter the body, a priori, “they can be a little scary.” But that contrasts with the success stories reported in recent years, some very striking, like Irene's, González-Zorn acknowledges.
These viruses can not only be used to treat desperate cases, but also to disinfect operating rooms, vials, and even body prostheses, which are the entry point for many of the most lethal resistant infections. And the same principle can be applied to animals and plants, opening up a new avenue for combating veterinary epidemics and agricultural pests. The researcher emphasizes that multi-million-dollar projects are underway in Spain to establish specialized centers for these therapies. "They are very promising treatments, although we are still in the process of getting to know them better. It's very likely that they will have a niche of their own in the future," says González-Zorn.
Irene Nevado often visits the Valencian laboratory, where she knows almost all of its members. Now that Kaftrio, a new drug effective against cystic fibrosis, has hit the market, her expectations are very high. From her past years, she remembers above all "the loneliness and the wait for that call confirming there's a donor. In addition to all her health problems due to fibrosis and infection, she also suffered from depression after the first rejection. The nurse has created La Vida Espera (Life Waits ), an altruistic initiative to advise and support people awaiting a transplant. "There are cases in which they don't quite decide to request it. My brother died in part because he did so too late. My goal is for everyone who gets a transplant to do so in good condition," she explains.
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