
The University of Zaragoza starts research to search for drugs against covid-19
16 April 2020
Carlos Colás: "I was infected, I have returned to work and I donate my plasma"
20 April 2020Against the clock, researchers from all over the world, including those from Aragon, adapt their lines of work. They speak the same language, that of science, and they are joining forces, reorienting research, looking for what part of their knowledge can point against this coronavirus about which we still know too little.
Getting vaccinated "is like taking your immune system to the gym", wrote Carlos Martín Montañés in a report in Tercer Milenio a few years ago. Vaccines teach the immune system to defend itself against the virus or bacteria for which they are designed, but they get the immune system so fit that they also protect, indirectly, against other infections in addition to the one they are aimed at.
Right now, he doesn't have a minute, not even to count it. You have four months to answer one question: Could the new vaccine against tuberculosis that your group at the University of Zaragoza has been developing for twenty years also protect against the SARS-CoV-2 coronavirus? They still don't have any results in their hands, which is why they need all the calm and prudence in the world to not create false expectations. They have just obtained funding of 318.000 euros from the Covid-19 fund, enabled by the Government to face the emergency with emergency research. Aragón leads one of only fifteen projects approved by the Carlos III Health Institute, which ask for the same thing: short-term solutions.
At this moment, researchers from all over the world, like this group and many others in Aragon, are switching to the AVE route and stepping on the accelerator, They reorient their lines of work and look for what part of their knowledge can be useful here and now, at a very different pace than usual. At the pace of a pandemic.
Having spent twenty years developing a new vaccine (MTBVAC) against tuberculosis – the infectious disease that causes the most deaths in the world – and an alternative to the current one (BCG), could give some advantage in the global time trial to find a useful vaccine against the Covid-19 pandemic.
The development times of a new vaccine, with all its phases and tests in animals before testing it in humans, "reduce an average of 15-20 years," Martín recalled a few weeks ago. "When there is a global alert, everything accelerates and this pandemic is breaking all records: since the WHO was informed of the new virus, SARS-CoV-2 was sequenced in less than 10 days, diagnostic tests were developed in a week "and, at this time, there are 52 vaccine candidates that are being tested in laboratories around the world. If one of the existing vaccines turned out to be useful, a good part of the road would already be covered. And the Aragonese vaccine is already undergoing clinical studies in adults and babies in South Africa.
An express study in primates
The new express study that, led by Carlos Martín, has just been launched will be carried out in macaques, at the Biomedical Primate Research Center (BPRC) in the Netherlands. And if MTBVAC demonstrated a similar degree of indirect protection as BCG against SARS-CoV-2 infection in primates, it would serve as proof of concept to initiate studies in healthcare personnel and nursing home workers, especially at risk due to their direct contact with patients affected by Covid-19.
At the end of March, a clinical trial began in Holland in healthcare personnel in contact with this type of patient to study the protection of the 'historic' vaccine against tuberculosis, BCG, against this coronavirus.
The MTBVAC vaccine, the first based on the human pathogen Mycobacterium tuberculosis, has already demonstrated safety profiles similar to the century-old BCG vaccine in preclinical studies. A very important fact, if this project demonstrates what it proposes, to think about applying it against the coronavirus. Because "even beyond its effectiveness, the most important thing for a vaccine is that it has to be safe," says Nacho Aguiló, coordinator of the MTBVAC immunity team. In addition, it must be able to be manufactured on a large scale and that we can all afford it. "This is a key point - he highlights -. A vaccine that protects very well is of no use if it cannot be produced in quantities of millions of doses on an industrial scale." And, in the face of the pandemic, the ideal would be to vaccinate the entire world population, "to create herd immunity, and this means almost 8.000 billion people."
If BCG, the current vaccine against tuberculosis, whose production has suffered serious shortage problems in recent years, finally demonstrates that it also protects against the SARS-CoV-2 coronavirus, how can we respond to demand? If the vaccine developed in Aragon, MTBVAC, also matched it in this, a response to global demand and vaccination supply would be ensured. In addition, it would be produced in Spain, at the Biofabri plant in Porriño (Galicia), a company of the Zendal group, partner of the University of Zaragoza for the industrial and clinical development of the MTBVAC vaccine.
Just a few weeks ago, it was published in the scientific journal 'Plos Pathogens', in a work done at 'normal' speed, that "MTBVAC produces large metabolic changes in the cells of the immune system that trigger the phenomenon of trained immunity", Raquel Tarancón, the first signatory of the article, then explained. Specifically, it has been shown that, in addition to immunizing against tuberculosis, MTBVAC puts the immune system in such shape that it protects against other bacterial respiratory infections, such as pneumococcal pneumonia. What we all want now is for it to be shown that it also protects against this coronavirus that has put us in check.
We desperately search for a vaccine because "the appearance of the disease would be prevented and we could return to a situation of absolute normality, without worrying about this coronavirus, as is the case with other diseases for which there is a vaccine and which in the past were the source of devastating pandemics." says Aguiló.
Vaccines are in all probability the health intervention that has saved the most lives in the history of humanity, "and this is something that we were forgetting," Aguiló reflects. "This crisis is going to be a humbling cure for humanity in many ways, including this one. We are already seeing what happens when we do not have a vaccine for a disease, how destructive it can be."
Adapted and applied
Darwin already said it: the species that survives is not the most intelligent or the strongest, but rather the one that best adapts to change. Faced with Covid-19, an entire planet is in a hurry to find a shield to defend us and therapeutic weapons to attack the infection when it has already occurred: vaccines and drugs. In all corners of the world there are researchers who, agilely adapting their means, are applying their knowledge and know-how. In a very short time, some of them have parked and refocused their research to contribute and work in a common front against Covid-19.
We need to improve the prevention, diagnosis and treatment of Covid-19, but also adopt the most appropriate measures by predicting the evolution of the pandemic with mathematical models, protecting ourselves from contagion and applying our imagination to combat the shortage of protective equipment, tests, respirators... And, also, think about the consequences of confinement, to alleviate them. In all of this are the men and women of science, an 'essential' that should not only be in times of emergency, but always.
Sometimes it is done with resources and at the forefront of national research, such as the study of the tuberculosis vaccine, and on other occasions interdisciplinary collaborations marked by agility emerge on the fly.
Emergency science
With express permission from the rector since the confinement began, up to fifty researchers and technicians have been able to access and use the infrastructure, equipment and laboratories of the University of Zaragoza. The password: Covid-19.
Last week, Pilar Lobera, Gema Martínez, Francisco Balas and Jesús Santamaría accessed the Aragón Nanoscience Institute (INA) to test the effectiveness of different barriers, combining layers of various materials, against the hated coronavirus-laden droplets that They are contagious when inhaled. The experiment responded to the request for collaboration from the young doctoral student in Biomedical Engineering Marta Baselga, who, together with the surgeon Antonio Güemes, is developing a project at the Aragón Health Research Institute to respond to a shortage, "the pressing lack of masks, in number and quality, for health personnel who care for patients with Covid-19". The idea: to design masks that efficiently filter the air, are safe and, very importantly, easily sterilizable "so that they are reusable and can be used indefinitely." And, furthermore, using medical products available in any hospital center: respiratory therapy masks. First they joined them with anesthesia filters and turned to Itainnova to validate the tightness of that union. Today, this 'invention' is already used in the Clinical Hospital, included in the protocol for the use of PPE (Personal Protective Equipment) as a resource in case of a shortage of FFP3 masks.
It was the improved version, "with new adapters to incorporate interchangeable filters", which passed through the INA. It is already on its way to certification and, if the tests are passed, to manufacturing by the Aragonese company in the biomedical sector Dima.
From INA they needed a quick answer to know if various materials combined in layers in the filter worked or not. And they designed a "very wild experiment, a non-approved test but that allowed us to offer interesting and, above all, useful results because, at this moment, if the result arrives in six months, it is of no use to anyone," says Santamaría. Since the SARS-CoV-2 coronavirus travels in droplets of 5 or 6 microns, they subjected the filters "to accelerated exposure with a mist (an aerosol) highly loaded with violet-tinged particles and we simulated a person's breathing." What happens inside the mask when a drop passes through capillary flow was also studied. Joaquín Coronas' team made permeation measurements, "very necessary to evaluate the resistance to air flow through the mask, because the person has to breathe." The electron microscope was even used, where Laura Casado "looked at the structure and porosity of the different materials to compare it with those of commercial masks," explains Santamaría. Quite a deployment that can be done "when you have a research network, with infrastructure and experienced personnel, who know how to do things and respond."
Aragón exports diagnostic kits
R&D 'made in Aragón' has also responded to the pandemic. In the month of January the company Certest Biotec I was already preparing a test to diagnose that new coronavirus that had caused almost 7.800 infections in China and an enormous demand for these kits in the Asian market. Previous experience in developing tests for other types of coronavirus allowed development times to be accelerated. In March it obtained the CE marking and, currently, its Viasure SARS-CoV-2 Real Time PCR Detection Kit covers national demand and 20% of the 50 kits manufactured per day are exported to around 60.000 countries. In two hours, and from a biological sample of the patient, such as mucus or saliva, it is checked if it is positive in the virus genome sequence. Detection of the virus is based on real-time polymerase chain reaction (PCR), identifying and amplifying a DNA sequence of the virus in clinical samples.
At this moment, "we are developing recombinant antigens and monoclonal antibodies," explains Carlos Genzor, founding partner and technical director of Certest Biotec, "the basic reagents for making immunoassays, whether rapid tests or other types of serological assays."
Because, to diagnose SARS-CoV-2 there are two main methods: one based on detecting the genetic material of the virus (qRT-PCR tests) and others based on the immune response of infected people (the so-called rapid or serological tests. ) Each one has its advantages and disadvantages, explains researcher Jesús Gonzalo, from the Mycobacteria Genetics group. "The qRT-PCR test is much more specific, but it is only useful at the beginning of the infection; when the immune system has controlled the virus, then it is no longer useful." For its part, "the opposite happens in the serological test, it is much less specific, but a positive result in this test tells us that the patient has developed defenses against the new coronavirus and, therefore, it is useful in later stages of the disease." infection. The ideal is to use both, but this is only viable if the infrastructure, personnel and means allow it. And what we are doing is helping, to the extent of our possibilities, the qRT-PCR test. can be done to as many people as possible.
Specifically, they are designing a solution that can serve as a means of transport for samples taken from the patient and, simultaneously, as a virus inactivation solution. Because each step is important and there are researchers thinking about each step. In this case, protecting the fragile RNA when transporting the samples to the laboratory - "if the RNA is damaged, the test gives a false negative and we run the risk of saying that a person is not infected when in reality they are." "explains Gonzalo – and also protecting healthcare personnel, by achieving immediate inactivation of the virus, as soon as it is collected, instead of having to take the tubes with the samples, which may contain SARS-CoV-2, to biosafety facilities. from the hospital to inactivate them. They hope that this new method can be implemented on a massive scale.
Recycled knowledge
Who was going to tell the biochemist Jesús Gonzalo that the composition of that solution that he learned at the MacGill University-Hospital of Montreal (Canada), during a stay in 2004, when he was doing his thesis, would be useful now, 16 years later. "I have recycled what I learned at that time so that other students like Juan Calvet Seral and Ernesto Anoz Carbonel can learn valuable knowledge. This highlights the importance of generating knowledge in universities and the need to invest in research." In the face of the pandemic, communication between Zaragoza researchers is flowing, Gonzalo notes that "it has been wonderful and exciting to see that we all speak the same language and join forces in this fight."
A Covid test like that of pregnancy
"I am optimistic. We will get something good from this: unity," says Jesús Martínez de la Fuente. He is happy to see how large institutions, such as the Higher Council for Scientific Research (CSIC), have been able to join forces: "It is something very unique that had not happened until now." He has just obtained funding from the CSIC's Global Health Interdisciplinary Technology Platform, money that comes from important donations from companies like Mapfre. "The CSIC has brought together more than 150 research groups with the potential to fight Covid and we are coordinating, based on emails and 'telcos', remotely, to address the different aspects of the pandemic."
In this 12-month project, endowed with 800.00 euros, the Institute of Materials Science of Aragon (CSIC-Unizar), to which this chemist expert in nanomedicine belongs, joins forces to develop new diagnostic devices for the disease. Covid-19 to the Institute of Advanced Chemistry of Catalonia and the Institute of Microelectronics of Barcelona. The Aragonese part is funded with 180.000 euros.
As soon as the reagents and necessary equipment arrive, Martínez de la Fuente will return to the laboratory to take a look at the diagnostic device for tumor markers in which They have been working for seven years. "The challenge now is to adapt it for Covid and, above all, to have portable, easy-to-use and low-cost equipment. Quite a challenge, but we are very excited."
It is a device very similar to a pregnancy test, based on throat or nose samples. "The main difference is that it uses gold nanoparticles with special optical properties," he explains, "that cause them to generate heat after being irradiated with a laser beam." The heat produced burns the nitrocellulose of the strip and, in 10-15 minutes, the result of the test is 'seen': yes or no.
The idea is that the device is portable and requires very little sample manipulation, for mass analysis in outpatient clinics, mobile analysis points, etc. "We are not going to reach PCR sensitivity levels, but we will be well above the current rapid kits. And it would be one hundred percent national technology."
A technology that, although it is "very mature - it is a patent approved in the European Union, the United States, China and Japan and is licensed to the company Nanoimmunotech - its translation to Covid-19 detection is quite a challenge, but We are obliged to try."
All in one
The Veterinary Faculty opened for them for a few hours last week. At the Veterinary Hospital of the University of Zaragoza, it was tested on an 80 kilo piglet. a respirator prototype that is easy and quick to manufacture, based on industrial or automotive components that are as standard and common as possible, designed by five engineers from the Polytechnic University School of La Almunia. This team of "freelance veterinarians and engineers work intensely with total empathy," recalls Miguel Ángel de Gregorio, researcher at the Minimally Invasive Techniques Research Group. For him, who is also an interventional doctor at the Clinic, "that day, alone in the faculty, was an oasis to abstract ourselves from this apocalypse," which he experiences in the hospital trench. Now there is talk of promoting research and health, "but we'll see where it stays."
We have experience of investigations that fall into oblivion and now they would come in very handy. Adrián Velázquez Campoy, researcher at the Aragonese Agency for Research and Development (ARAID) of the Government of Aragon, already investigated AIDS and SARS (a virus similar to SARS-CoV-2) during his postdoctoral stage in the United States (1998- 2003). He remembers how, when the epidemic was controlled in a short time, "interest stopped, aid decreased and nothing was finished." He believes that "just as we have a military arsenal, we should have an arsenal of resources in reserve for these situations." Now, "a lot of money is invested explosively, and we see that prevention is cheaper than cure, because the cost is, in addition to many human lives, a gigantic economic crisis."
With help of 50.000 euros from the hna Foundation, plus its experience in viruses similar to the current one and the experimental infrastructure of the Institute of Biocomputing and Physics of Complex Systems (BIFI) of Unizar, a project is now beginning that, tracking the interaction of thousands of compounds with two essential proteins for the virus, hopes to find several candidates to become future drugs.
Bureaucracy is flying these days and, at the Aragón Health Research Institute (IIS Aragón), numerous projects and clinical trials are already underway or about to begin to increase knowledge about Covid-19 and generate diagnostic and treatment solutions. of the illness. It has also been released a donation campaignto finance these initiatives.
Among the clinical trials, Aragón participates in solidarity, the World Health Organization's mega-study that involves 90 countries and will include thousands of hospitalized patients to test four treatments.
The inflammatory response of Covid-19 patients to SARS-CoV-2 is one of the things that keeps doctors up at night. Some studies indicate that some severe cases are due to an excessive immune system response.
Knowing better the populations of immune cells responsible for controlling the infection, in order to understand how they respond to the Covid-19 disease, is what the project in which José Ramón Paño, principal investigator of the Clinical Research Group on Infectious Diseases of the Hospital Clínico de Zaragoza, Luis Martínez, immunologist at the Hospital Clínico de Zaragoza, and Julián Pardo, immunologist and Araid researcher at IIS Aragón. They want to "identify biomarkers that contribute to personalizing treatment based on the situation of the viral infection and the immune response profile of each patient," says Paño. Furthermore, "predicting which patients may develop more serious clinical conditions will allow planning and optimization, reducing stress on the health system."
Artificial intelligence also lends a hand to classify, as soon as possible, as soon as they enter the emergency room door, which patients are most at risk of having an unfavorable outcome. To do this, doctors, engineers and mathematicians join forces. "A few years ago, without electronic history, it would have been impossible," says Trinidad Serrano, head of the Clinic's Hepatology section, "but today we have a treasure of data that can help us make decisions, classify and apply the most appropriate treatment." to the patients".
Mountains of anonymized data – from the more than 4.000 people diagnosed in Aragon, plus those from several control groups not diagnosed with Covid, in total about 10.000 patients – are being analyzed in Itainnova "to find relationships, patterns" between the thousands of variables considered per patient: hospitalization data, number of visits to primary care, demographic, anthropometric data, personal history, treatments...
Soon, it is expected to have a deep learning tool that draws conclusions. He works on it, "day and night," says Rafael del Hoyo, head of the Artificial Intelligence and Cognitive Systems team at Itainnova, the team he forms together with Rocío Aznar, David Ignacio Abadía and Gorka Labata, plus Luis Mariano Esteban, mathematician at Unify. For him, "working directly with the heroes of this crisis, the doctors who are on the front lines of fire, is exciting and personally rewarding."
How do we get out of this?
Mobility restrictions, quarantines, social distancing, cessation of non-essential activities, mandatory masks, rapid tests... Countries have adopted various measures to contain the pandemic. Have the right decisions been made? The science of networks and complex systems, as well as computer science and data science, have a lot to say.
Mathematical models predict the path of a hurricane or tropical storm, and also "the theory of complex networks has proven to be a very effective tool when developing mathematical epidemiological models to simulate processes of the spread of infectious diseases using different scenarios." hypotheticals – highlights Yamir Moreno, theoretical physicist and head of the Networks and Complex Systems Group at BIFI – The development of computing and data science has also contributed to expanding our knowledge about the structure of populations and contact networks. through which these diseases spread".
But an epidemic is not a storm or a hurricane. "Factors such as our behavior patterns, mobility and the way we relate in society or with other individuals decisively influence its evolution."
Yamir Moreno has put the city of Boston into the computer, entire. Well, not its inhabitants, but real data on the flow of their movements, provided by the Data for good program of Cuebiq Inc., a company that collects the locations of mobile phone users and aggregates them anonymously. Furthermore, in the study carried out by his team of researchers from Unizar, the Carlos III University of Madrid, the Massachusetts Institute of Technology and the ISI Foundation, in Italy, census data from the Boston area have been analyzed to construct a statistically equivalent population , precisely, to that area. Boston on the computer, come on. And on this so similar to reality, they apply a model of the spread of epidemics and you can see what effects taking one measure or another has. It is research designed "to be useful in decision-making", to help evaluate the impact of social distancing strategies adopted in different countries and to prepare for a hypothetical second wave.
These were the conclusions, published openly under a Creative Commons license, available to the authorities who want to hear them and to the scientific community: the complete confinement of the population in the face of an epidemic like Covid-19 is not a strategy that will solve the problem. problem if active measures are not taken after it, such as large-scale diagnostic testing, remote monitoring and isolation of people with symptoms and tracing their contacts.
What has happened so far reveals, in his opinion, that "we were not prepared. That is undeniable. And I am not just referring to Spain, but to most countries in general." And since predictions are his thing, he predicts what his models indicate: "That, in almost all scenarios, a new wave of infections is very likely." Will we react late again?
"We are working more intensely than ever, in an extraordinary collaborative environment"
The Barcelona Supercomputing Center (BSC) directed by Aragonese Mateo Valero is also on the front line against the coronavirus. "We have dedicated ourselves to the fight against Covid-19," he declares. "In addition to the resources used by our researchers, we give priority to external projects dedicated to studying this disease so that they can also use it. It is mainly used by groups that search for drugs and analyze medical images". Personally, he perceives that "they are working more intensely than ever and in an environment of extraordinary collaboration between research groups from all countries."
In this unique moment, "it's the first time that technology can be a big part of a solution to the pandemic." The BSC has "three main lines open in relation to the Covid-19 pandemic: search for drugs and vaccines, creation of tools to assist doctors in the diagnosis and choice of treatments and creation of tools to monitor the exit from confinement and prevent new large-scale outbreaks, like the one we have experienced. On all these fronts "we use supercomputing, the extraordinary talent of our researchers and our extensive network of contacts, because we work in close collaboration with laboratories, hospitals and experts around the world."
Valero specifies that, "in the search for drugs and vaccines, we work in collaboration with specialized laboratories and centers, such as Irsi Caixa, Cresa, IQA, Grífols, etc. and with genomics experts from around the world. Our role is to collaborate in understanding the virus and use this knowledge to perform simulations of different drugs and antibodies trying to attack the virus. This computer process performs a first screening of possibilities that saves laboratories a lot of time and, therefore, shortens the time necessary to create a drug or vaccine.
Now that there is "a significant amount of clinical data on Covid-19 patients, we are also collaborating with hospitals and health centers to collect clinical histories and images and look for patterns that may be useful in making diagnoses and assisting clinicians in treatment decisions.
And, to help the authorities manage the pandemic, "we are carrying out projects such as models based on large amounts of data from different sources, to predict the spread of the virus, or studies that relate the measures taken by the Administrations with their impact on Covid-19 and on citizens".