Fuente de la imagen: Cyril Frecillon/Fototeca CNRS
Martin Karpels fue un químico teórico que se propuso explorar los fundamentos de su materia, pero siempre con la vista puesta en las aplicaciones más amplias posibles en el mundo real. Explotó el potencial de las computadoras para simular interacciones entre moléculas a escalas representadas tanto por la física clásica como por la mecánica cuántica. Sus simulaciones de sistemas biológicos complejos revelaron los detalles atómicos de cómo funcionan las moléculas grandes, como las proteínas. Desde sus inicios en la década de 1970, los métodos teóricos desarrollados por Karplus y otros se han ampliado y aplicado enormemente en biología, química, física química y biofísica. El Premio Nobel de Química de 2013 fue otorgado a Karplus, Aryeh Warshel y Michael Levitt por su desarrollo de métodos multiescala. Karplus murió a la edad de 94 años.
Karplus nació en Viena en una familia con una larga trayectoria de científicos, médicos y psiquiatras. En 1938, huyeron del régimen nazi y finalmente se establecieron en el área de Boston, Massachusetts. En la escuela secundaria, desarrolló una curiosidad por la biología, alimentada por su interés en la observación de aves, que incluyó una excursión a Alaska. Publicó su primer artículo sobre ornitología en 1947, cuando tenía 17 años. Ese mismo año ganó el premio Westinghouse National Science Talent Search con un proyecto sobre la vida de las alcas en la costa este de Estados Unidos.
Mientras estudiaba en la Universidad de Harvard en Cambridge, Massachusetts, abandonó su plan inicial de estudiar medicina y, en cambio, obtuvo títulos en química y física en 1951. Deseoso de realizar investigaciones sobre las bases moleculares de la vida, Karpels fue al Instituto de Física de California. Technology en Pasadena, donde aplicó el enfoque de la mecánica cuántica a los enlaces de hidrógeno para su doctorado, bajo la supervisión de Linus Pauling.
Durante dos años en la Universidad de Oxford en el Reino Unido, Karplus se interesó en estudiar las bases teóricas de la resonancia magnética nuclear (RMN) aplicada a la química. En 1955, se incorporó a la Universidad de Illinois en Urbana-Champaign (UIUC), que tenía un programa experimental de resonancia magnética nuclear. Realizó su importante investigación en mecánica cuántica, que condujo a lo que ahora se llama la ecuación de Karplus. Esta ecuación utiliza datos de experimentos de RMN para describir cómo el tamaño de los espines nucleares de grupos particulares de átomos se relaciona con sus relaciones espaciales entre sí. Esta ecuación proporciona información sobre la estructura de sustancias químicas que van desde pequeñas moléculas orgánicas hasta macromoléculas, y se utiliza hasta el día de hoy para determinar la estructura de proteínas, ácidos nucleicos y carbohidratos.
Un traslado al Laboratorio Científico Watson de IBM en la Universidad de Columbia en la ciudad de Nueva York en 1960 le dio a Karplus acceso a las mejores supercomputadoras científicas disponibles en ese momento. Comenzó con estudios sobre la cinética de reacciones químicas e investigó la reacción simple H + H.2 Utilizando las ecuaciones de movimiento clásicas de Newton. Estos esfuerzos son casi una década anteriores a los estudios de mecánica cuántica sobre este sistema, lo que demuestra el poder de métodos clásicos más aproximados en el campo de la química teórica.
Un estudio reciente financiado por la NASA observó hallazgos sobre los procesos moleculares que pueden haber dado forma a los orígenes de la vida. tierra. Una investigación publicada en Nature Communications indica que el ácido ribonucleico (ARN), una molécula que se cree que existió anteriormente ADNno muestra ningún sesgo inherente en la producción de versiones de aminoácidos para diestros o zurdos. Esto desafía las suposiciones de larga data sobre por qué la vida utiliza principalmente aminoácidos zurdos en sus proteínas, un fenómeno conocido como homología.
Rompecabezas de mano molecular
Aminoácidoslos componentes básicos de las proteínas, existen en dos formas especulares: zurdos y diestros. La vida en la Tierra depende exclusivamente del tipo zurdo, aunque no hay una razón clara por la que los aminoácidos diestros no funcionarían de manera similar. Este fenómeno ha desconcertado a los científicos, ya que parece reflejar un aspecto fundamental de la biología. presente el estudiaDirigidos por Erin Chen, profesora de la Escuela de Ingeniería Samueli de UCLA, probaron ribozimas: moléculas de ácido ribonucleico (ARN) capaces de comportarse como enzimas en las condiciones primitivas de la Tierra. Los resultados indicaron que las ribozimas podrían preferir usar cualquiera de las manos, lo que socava la idea de que el ARN prefiere inherentemente ser zurdo.
Implicaciones para el desarrollo de la vida temprana
La investigación implicó simular las condiciones primordiales de la Tierra, donde las ribozimas estaban expuestas a precursores de aminoácidos. En los 15 grupos evaluados, no se observó un sesgo consistente hacia los aminoácidos zurdos. Este descubrimiento sugiere que la homosexualidad puede haber surgido a través de procesos evolutivos y no como resultado de preferencias químicas por el ARN. El coautor Alberto Vázquez Salazar, investigador postdoctoral de la UCLA, señaló que estos hallazgos implican que el control molecular de la vida probablemente surgió más adelante en su evolución.
Futuras investigaciones sobre los orígenes moleculares de la vida.
Jason Durkin, científico jefe del Centro de Vuelos Espaciales Goddard de la NASA, enfatizó que comprender las características moleculares de la vida ayuda en la búsqueda de vida extraterrestre. El análisis actual de muestras del asteroide Bennu, devueltas por la misión OSIRIS-REx de la NASA, incluye el estudio del uso de aminoácidos. Este tipo de investigaciones pueden revelar más pistas sobre el origen de la homosexualidad y su papel en la evolución de la vida.
Esta investigación fue financiada por la NASA, la Fundación Simons y la Fundación Nacional de Ciencias, y aportó información valiosa sobre uno de los misterios más profundos de la vida.
(Descargo de responsabilidad: New Delhi TV es una subsidiaria de AMG Media Networks Limited, una empresa del Grupo Adani).
Initially, in countries equipped with the necessary laboratory infrastructure, nasal swabs were analysed by polymerase chain reaction (PCR) — a method known for its sensitivity, but also for being slow and expensive. People often endured long waits for tests.
Subsequently, rapid antigen tests gained favour, owing to their speed, low cost and ease of use, despite being less precise at identifying positive cases.
It was a trade-off that public-health officials and individuals grappled with: balancing the need for timely information at an affordable price against the risk of false negatives.
But there was a third way. In countries including Israel, India, the United States and New Zealand, portable tests became available that combined the molecular precision of PCR with the expediency of rapid antigen kits (also known as lateral flow assays).
Like PCR, these ‘isothermal’ tests amplify small segments of the virus’s genetic material to detectable levels. However, they streamline the process by operating at a consistent temperature, eliminating the need for the repetitive heating and cooling cycles of PCR. This not only simplifies the equipment required and eliminates the need for centralized laboratories, but also accelerates the testing process from days to less than half an hour.
“It is providing near-PCR-level sensitivity with antigen usability,” says Nathan Tanner, head of the applied molecular biology division at the firm New England Biolabs in Ipswich, Massachusetts, which produces kits for doing these kinds of constant-temperature (isothermal) test in research laboratories. The main downside, Tanner says, is price: isothermal tests generally cost about US$50 per sample. That’s roughly the same as PCR in most Western countries, but about 5–10 times the cost of rapid antigen assays.
Despite the premium price, these speedy genetic tests secured their place across diverse and critical settings during the pandemic. Care homes, schools, prisons, remote health clinics and even professional sports organizations — sectors in which people were willing to pay more for dependable results — adopted the technology.
Then came the omicron variant. This highly transmissible version of the coronavirus prompted a flood of COVID-19 cases and deaths, leading to a spike in global demand for accurate testing methods in late 2021 and into 2022. Developers of at-home molecular tests seized the moment, ramping up manufacturing capacity and launching intense advertising campaigns.
Daily usage of these test kits soared into the tens of thousands in countries, such as the United States, where the at-home assays were available. But as infection rates declined, so did demand for these products. This downturn was further accelerated by initiatives from various national governments that provided free rapid antigen tests during the omicron surge. The market for more expensive COVID-19 diagnostics collapsed, forcing manufacturers of isothermal tests to shift their focus to other disease areas. Many failed and went out of business.
Consider the cautionary tale of Lucira Health in Emeryville, California — once a leader in isothermal diagnostics. Looking to carve out a new niche for its technology, Lucira pursued regulatory approval for a dual-purpose test designed to simultaneously identify and discriminate between COVID-19 and influenza. In August 2022, authorities in Canada gave this two-in-one test the go-ahead.
But regulators in the United States were slow to provide an approval. According to Lucira’s co-founder and former chief technology officer Debkishore Mitra, the US Food and Drug Administration (FDA) wanted to see extra clinical data, along with product design changes, “for reasons we did not understand”.
Flu season then arrived, and Lucira’s massive manufacturing infrastructure, built up during the omicron COVID-19 wave, sat largely idle. “It was a frustrating and confusing period of time,” says Mitra. Lucira ultimately ran out of money and filed for bankruptcy on 22 February 2023. A mere two days later, the FDA issued emergency authorization for the company’s combined flu and COVID-19 test.
“If this was not a tragedy, I would definitely consider it a comedy,” Mitra says.
Lucira’s efforts were not for naught, however. Although the company no longer exists, its test lives on, and is now marketed by the pharmaceutical giant Pfizer, which purchased Lucira’s assets at a bankruptcy auction in April 2023. For around $50, anyone can buy the Lucira by Pfizer COVID-19 & Flu Home Test. And that product could soon have competition.
Building on technological advances made in response to COVID-19, many companies are now developing isothermal genetic tests that can diagnose a wide array of respiratory diseases, sexually transmitted infections and more. These products aim to provide precise and prompt diagnostic information, enabling people to quickly seek appropriate medical treatment.
“We are in a new era,” says Wilbur Lam, a paediatric haematologist and biomedical engineer at Georgia Institute of Technology, Atlanta. “The pandemic has really brought point-of-care and at-home testing into its own.”
The challenge now, he adds, lies in pinpointing the most relevant clinical applications and, crucially, in establishing sustainable business models for diagnostic-test providers. Both are essential steps to ensure that these technologies continue to improve disease management in a post-pandemic world.
In the loop
Isothermal methods were developed in the early 1990s, shortly after the invention of PCR. But the main technique now in use emerged at the turn of the millennium. That’s when researchers at Eiken Chemical, a manufacturer of clinical diagnostic tools in Tokyo, described how to eliminate the need for thermal cycling1.
From left to right: the Lucira by Pfizer test and isothermal tests by the firms Detect and Aptitude.Credit: Nathan Frandino/REUTERS; Detect, Inc.; Black Bronstad
There were two key components to the method, known as loop-mediated isothermal amplification (LAMP). These were the use of more primers — short, single-stranded pieces of DNA that help to jump-start the gene-amplification process — and a special kind of DNA-extending enzyme.
A typical PCR reaction uses two sets of primer, which require repeated bouts of heating and cooling to bind their targets and extend copied DNA strands. But the Eiken team demonstrated that increasing the number of primers and using a specialized enzyme allowed the LAMP method to extend DNA at a constant temperature. It worked best at around 65 °C, and produced a single, ladder-like block of DNA, with dumb-bell-shaped rungs that double back on themselves again and again.
There are other isothermal techniques, some of which are found in commercially available COVID-19 tests. But many are protected by intellectual-property rights, says Paul Yager, a bioengineer and diagnostics inventor at the University of Washington in Seattle. By comparison, the foundational patents surrounding LAMP have all expired. What’s more, LAMP works well with minimal sample preparation on crude specimens, such as nasal swabs. These advantages “seem to drive people into the arms of LAMP”, Yager says.
Even with the same core technology underpinning them, the LAMP-based tests on the market are not all the same. They differ in terms of proprietary reagents and in how assay results are identified. Methods for detecting LAMP readouts include fluorescent probes, pH-induced colour shifts, electrochemical assays and CRISPR-mediated recognition strategies. Despite these differences, all of the tests generally achieve comparable levels of accuracy and performance.
A more important distinction, therefore, lies in aspects of the device design that substantially affect the user experience. Although certain products require compact, reusable pieces of hardware to interpret results from disposable test cartridges, others — including the Lucira by Pfizer test — offer the convenience of fully integrated, single-use kits.
According to Mitra, Lucira adopted this all-in-one design strategy because it thought the up-front cost of equipment would turn off would-be buyers. “That was our vision from day one,” he says. At their high point during the pandemic, at-home test readers cost upwards of $250.
But prices have come down drastically — for around $50, it’s now possible to buy a machine from a company such as Aptitude Medical Systems in Goleta, California, and then spend just $25 on an individual test (less if bulk purchasing). Aptitude’s platform also has another advantage: it’s compatible with saliva. Saliva samples are simpler to collect than nasal swabs, and so the likelihood of an error during sample acquisition is lower.
But even $25 exceeds what many people are willing to spend on a test, and not all medical-insurance companies cover the cost. Rapid antigen tests now retail for just $5 or less. And although certain at-risk groups, such as people with a compromised immune system, might be willing to shell out the extra for the diagnostic accuracy of isothermal tests, most people are not.
Economic considerations
Price sensitivity explains why the firm Detect, another isothermal-test developer that made waves in the early days of the pandemic, stopped offering its at-home COVID-19 diagnostic test about a year after its launch. The company, which is based in Guilford, Connecticut, instead opted to concentrate on making a LAMP-based platform that could be run in physicians’ offices rather than in people’s homes.
Although the technical aspects of testing in either setting are comparable, the commercial implications of this decision are considerable. Detect is able to leverage an established path for test reimbursement, particularly in the United States, where insurance companies seldom cover the expenses of at-home diagnostics but do reimburse tests ordered by physicians. “The economics just make a lot more sense,” says Eric Kauderer-Abrams, co-founder and chief executive of Detect.
Tests run in physicians’ offices can be less convenient for would-be users, however – especially those who are loathe to seek medical attention. That is why many researchers continue to push for wider adoption of at-home molecular tests.
Enabling people to test at home holds particular promise for the diagnosis of sexually transmitted infections. Personal fears and societal taboos often present obstacles to effective screening and treatment for these infections. With at-home diagnostics, “people can do it in the privacy of their own homes”, says Deborah Dean, an infectious-disease specialist at the University of California, San Francisco, who previously collaborated with Lucira to study prototype LAMP tests for gonorrhoea and chlamydia2. “They don’t have the stigma of going to a clinic, and having everybody else in the waiting room wondering why they’re there.”
Juliet Iwelunmor sees opportunities to harness the power of LAMP testing in low-resource settings. A global-health researcher at Washington University School of Medicine in St. Louis, Missouri, Iwelunmor is leading an initiative to introduce LAMP testing for human papillomavirus (HPV), a leading cause of cervical cancer, in Nigeria, where she grew up. An estimated 3.5% of women in the country harbour HPV infections, but less than 15% of the population are ever tested. Iwelunmor’s goal is to reduce the per-test cost to below $5. “We’re trying to make LAMP as cheap and easy as possible,” she says.
Other efforts are aiming to bring LAMP-based assays to sub-Saharan Africa for two mosquito-borne viral diseases: Zika and chikungunya.
The benefits of LAMP testing can also be seen in countries with greater resources but fragmented health-care systems. A notable example is the Home Test to Treat programme, which launched in 2023 with funding from the US National Institute of Biomedical Imaging and Bioengineering (NIBIB) with the goal of distributing free Lucira by Pfizer test kits to vulnerable communities across the United States. Those who test positive for the viruses can then receive free telehealth consultations and, when appropriate, have antiviral treatments such as Paxlovid (nirmatrelvir and ritonavir) or Tamiflu (oseltamivir) delivered to their homes or local pharmacies.
Before the advent of at-home molecular testing, a definitive diagnosis of influenza relied on a PCR assay, with lab confirmation often required to initiate treatment with Tamiflu — a drug that is most effective when administered shortly after the onset of symptoms. Few people ever get tested, however, and antivirals are an underused weapon.
The distribution of Lucira by Pfizer tests, paired with telemedicine services, removes this barrier. “It allows them to receive care without going to a clinician’s office,” says Apurv Soni, a digital-health researcher at the UMass Chan Medical School in Worcester, Massachusetts, who is leading the analysis of the Home Test to Treat clinical data.
The dual-purpose LAMP test offers the unprecedented ability to quickly differentiate between two respiratory viruses that often present with similar symptoms, yet require distinct treatment approaches. “That’s a tremendous advantage,” Soni says. “You can pick up infections early on and initiate the appropriate treatment in a timely manner.”
So far, the Home Test to Treat programme has distributed LAMP tests to tens of thousands of study participants, identifying infections early and providing antiviral medication to many individuals — evidence, according to NIBIB director Bruce Tromberg, of the technology’s public-health benefit. But will that be enough to convince consumers and insurance providers to pick up the diagnostic tab when the government is not footing the bill? “This is one of the key questions,” Tromberg says. “Now that we’ve created a consumer awareness, will it be sustainable?”
Mitra left Lucira in November 2022 and no longer works on isothermal diagnostics. He now leads technology development at a cannabis-testing firm called Hound Labs, in Fremont, California. Despite his shift away from LAMP testing, he continues to closely monitor the industry that his innovations helped to unleash.
“My hope is that at-home testing becomes routine and regular beyond the pandemic,” Mitra says. Yet his tenure at Lucira has imbued him with a pragmatic outlook on the adoption of isothermal tests. He recognizes that the intricacies and bureaucratic hurdles in health-care systems often dictate the use of new technologies more than their clinical merits alone. “Technology,” Mitra observes, “never gets used in a vacuum.”
