There is a growing appreciation among the biomedical community of the value that pigs bring to research. Over the last decade, researchers and clinicians have increasingly seen how useful pigs are in many areas of research – for example, by providing organs for vital human transplants, improving our understanding of a range of diseases including cancer, and other applications like surgical training.
The numerous similar characteristics of pigs to humans, such as the structure of their body, organs and genetics, also make them good choices for exploring and refining scientific techniques, and testing drugs for toxicity and safety, in both the lab and the clinic.
In some cases, pigs can be more appropriate than other more commonly used animals in research, such as mice, and they are an animal that humans have lived and worked with for centuries, with well-understood welfare needs.
Biomedical research is also increasingly making use of a specially bred type of pig called a minipig. The smaller size of these pigs, compared to larger farm pigs, makes them easier to manage in a lab setting, while possessing more fitting characteristics for research, such as their genetics and temperament. One of the most common breeds of minipig used in Europe, especially in pharmaceutical research, is the Göttingen minipig, derived from the crossing of three different breeds – and one of the biggest suppliers is Danish EARA member Ellegaard Göttingen Minipigs.
In this article, we will outline the growing use of pigs as a biomedical research animal in Europe, including the current and emerging areas of biomedical study in which they play an important role. We will also look at what the field of pig research might hold for the future, such as medical and clinical developments to benefit human health, and biotechnologies.
Göttingen minipigs at facility (Credit: Ellegaard Göttingen Minipigs)
Why do we need pigs in biomedical research?
Pigs have a lot in common with humans at the level of organs, genetics, body function and the immune system, so using pigs in research studies can predict similar results in humans, compared to other large animals or the most common research mammal, the mouse (read our feature about mice in biomedical research). For instance, the heart of a pig is very similar to our own in terms of size and structure and so are relevant to human cardiovascular research and can be suitable to use for heart transplant research.
Regulatory bodies demand test data from two different species of research animal for the approval of any new drug. A rodent is usually used and then commonly a larger animal, such as a dog or a monkey, however pigs are now proving to be another viable option. For example, they are more tolerant of certain drugs than both rodents and dogs, meaning they can be more representative of the types of reactions that people will experience.
Modern gene editing technologies mean that pigs can be genetically altered to make them more ‘human-like,’ or humanised, allowing biomedical research that can more accurately mimic the human body. For example, in research at Iowa State University, USA, humanised pigs were designed without essential parts of the immune system, allowing human cells to then be transplanted into their livers. This could then improve drug testing for diseases such as cancer, as well as to develop techniques like skin grafts.
Genetic modification of pigs can ensure the success of organ transplants that otherwise would not be possible, because standard pig organs are rejected by the human body. Additionally, genetically modified pigs can be made susceptible to diseases that wouldn’t usually affect them in the wild, such as Covid-19, to shed light on severe symptoms that researchers cannot directly investigate in people.
Pigs make better medical research subjects than [humanised] mice, because they are closer to humans in size, physiology and genetic makeup
Dr Adeline Boettcher, Iowa State University
Which areas of biomedical research use pigs?
Pigs are being used in more research fields than ever, for instance there is now more available genetic data on the pig genome. In 2019, 82,819 pigs were used for research for scientific purposes in the EU – in comparison there were around 143 million pigs bred as livestock in the EU in the same year.
This growing awareness of the benefits of pigs to research, coupled with advances in technology, has meant that scientists have been able to make increasingly more discoveries in medicine and basic research using pigs. The most commons areas of use are in general surgical training, for testing and assessment for drug toxicity and pharmacology (how medicines work), for studies of the skin (such as wound healing), and exploring new ways that treatments can be delivered to the body.
This section summaries some of these key areas.
Testing drugs, vaccines and medical devices
By law, all drugs and treatments must be evaluated for their safety in animals before they are ultimately tested in humans – if a drug fails at the animal testing stage it will not go forward to human trials. Pigs have therefore been used to assess everything from cancer drugs to medical devices before they enter clinical trials. One recent example of this was a type of ventilator for Covid-19, developed by a team at the University of Oviedo, Spain.
Pigs are also useful for analysing different devices and procedures to treat various diseases, such as injections into the eye for retinal diseases, and exploring optimal or improved ways to monitor body functions – researchers at the Massachusetts and California Institutes of Technology, both USA, recently developed an ingestible sensor that could be monitored as it travelled through the digestive tract of pigs, to potentially diagnose gastrointestinal disorders without the need for invasive surgery.
There is increasing evidence to suggest that pigs are also good models for vaccine research and development since their immune systems closely resemble ours by around 80%. Work at The Pirbright Institute, UK, for instance, has shown that pigs can model the effects of vaccination against human flu, and identified different routes to administering flu vaccines to provide better disease protection.
Pigs have similar physiology to humans and are infected by the same influenza strains, making them an excellent model to study novel vaccine strategies for respiratory viruses, including Covid-19, which might be used in humans
Dr Elma Tchilian, The Pirbright Institute
Pirbright has also conducted trials on pigs for new Covid-19 vaccines, while EARA members Sanofi Pasteur, France, and Ellegaard Göttingen Minipigs, Denmark, demonstrated the value of using minipigs to study the long-term effects of vaccines against whooping cough, which can be a particularly dangerous infection for babies and children.
As well as this, research in pigs can provide benefits to the health of pigs themselves. For example, the global VACDIVA consortium, co-ordinated by Professor José Manuel Sánchez-Vizcaíno, at EARA member the Complutense University of Madrid, Spain, is currently developing and testing vaccines against African swine fever, a deadly disease affecting pigs and boars.
Minipigs, that have been ‘humanised’ through genetic editing, are increasingly being used for toxicological testing and safety assessment of therapeutic antibodies, as there is a growing interest in antibody-drug development to precisely target cells or molecules related to disease.
Antibodies make up part of the body's immune response against foreign invaders (such as viruses). Humanised minipigs can tolerate human antibodies – otherwise, the antibodies would be rejected by the pig’s immune system as being foreign. These minipigs therefore open the door to the testing of new therapeutic antibodies and minimise the chance that these antibodies will lose their desired effect, or cause possible unwanted side effects.
Using minipigs to develop new antibody-drugs
Göttingen minipig (Credit: Ellegaard Göttingen Minipigs)
Skin disease studies
One of the major research areas that has involved pigs are studies of skin diseases, such as psoriasis, skin reactions (including allergies), understanding how wounds heal, the best way to give dermal treatments (such as an ointment or cream), as well as ways to administer non-dermal ones, for example through an injection into the bloodstream.
Pigs are beneficial to such studies because of the similarity of their skin to ours, in aspects like thickness and composition, allowing more accurate safety assessments to be carried out into chemicals and other potential skin toxicities. This also means pig skin can be used to help with injuries, with a group from Linköping University, Sweden, using pig skin to make human cornea implants, which successfully improved people’s eyesight in a 2022 clinical trial.
Training for surgery
Due to the many similarities shared between the pig and human body – from the teeth and skeleton to organ and blood systems – pigs are one of the standard animals used to train surgeons in often crucial and complicated procedures.
In combination with technology such as simulated training environments and robotics, animals can allow for best performance and practices in surgery, while moving away from training on human patients altogether. This invaluable training is carried out by organisations such as EARA member the Orsi Academy, Belgium, where pigs are put under anaesthetic, with a team of animal caretakers and veterinarians to ensure that their welfare and ethical needs are being addressed and met.
Surgical training (Credit: Orsi Academy)
Genetically modified pigs are very valuable in the study of many diseases, often providing a more accurate picture of human ones – for instance, better reflecting the complexities of what happens in the human body than a standard pig or some other genetically modified research animals.
Gene editing techniques, such as CRISPR-Cas9, allow researchers to introduce modifications into cells and organisms at specific sites to target areas of interest. Some of the diseases that have been studied using genetically modified pigs include Huntington’s disease. In 2019 research led by the Emory School of Medicine, in Georgia, USA, successfully expressed in pigs one of the key genes that causes the disease - to model its neurodegenerative effects - to help study how Huntington's develops and identify possible routes to therapy.
Cystic fibrosis (CF), is another condition that has been well-studied in pigs thanks to gene editing. Pig and human lungs have a close resemblance, and pigs can be engineered to develop some of the same effects of CF, including all the symptoms of lung disease – the main cause of death from the condition. Gene editing in pigs also helps to refine and improve therapies for CF in humans, (since it is caused by a faulty gene) by using them to improve how efficiently the CRISPR-Cas9 gene-editing tool can be delivered to the right place in the body to carry out the gene editing.
Cancer, heart disease and other conditions
Pigs have helped in the understanding of cancer by mimicking how certain diseases and malignancies, such as heart disease and brain tumours, work or react to drugs in humans. Research led by the Technical University of Munich, for example, is using genetically edited livestock pigs to study a range of cancers, including colorectal cancer, osteosarcoma (a major form of bone cancer) and pancreatic cancer.
Research into cardiovascular disease and heart conditions has made use of pigs to provide key insights into their management and treatment – such as in tackling heart failure by helping the heart muscle to repair itself, carried out by scientists at Baylor College of Medicine, in Texas, USA.
This is a potentially transformational strategy to treat human heart failure… [that] can make a substantial difference in the lives of those who suffer a heart attack
Dr James Martin, Baylor College of Medicine
Infection and nutrition studies
Using common waste products from the livestock industry, researchers have also been able to study infections. One example is a team at the University of Sheffield, UK, which investigated how bacterial, viral and fungal infections affected pig eyes and could lead to blindness, and serving as a guide to develop effective antibiotics.
Because what we eat can influence our risk of certain diseases like cancer, pigs can also provide vital clues to healthy (or unhealthy) lifestyles, and allow researchers to study conditions related to diet, such obesity and diabetes. And as a large animal that can be fed a similar diet to humans, pigs are well suited to nutrition studies and research into the microbiome – the community of bacteria within us that is significantly impacted by diet and increasingly recognised as important in everything from digestion to a healthy immune system.
By studying the pig microbiome in the gut, the PIG-PARADIGM project, involving researchers from Denmark, the Netherlands and USA, is addressing the global health threat of antibiotic resistance by advancing understanding of how to prevent resistant bacterial infections in piglets and reduce the need for antibiotics.
Göttingen minipigs at facility (Credit: Ellegaard Göttingen Minipigs)
In biomedical research, stem cells – which have the ability to develop into many different specialised cell types – are a promising technology that can be used to do everything from studying diseases to making regenerative medicine (replacing diseased cells with healthy ones). Pigs tend to have stem cells that are similar to humans, such as in the colon, again increasing the chance that they can be successfully applied to humans.
Researchers at the University of Maryland, USA, demonstrated for the first time in 2020 that pig stem cells, when injected into pig embryos, could solely lead to the development of the gut and liver – raising the possibility of growing human-specific organs in pigs. And in pig research carried out at the University of Georgia, USA, which provided new insights into stroke, transplanting stem cells into the brain was found to improve harmful stroke symptoms.
Stem cell research has the potential to benefit pigs too – 2022 research led by The Roslin Institute at the University of Edinburgh, UK, for example, showed that pig-derived stem cells can provide an almost limitless supply of the cells to help combat infectious diseases affecting pigs.
This novel technique could help improve understanding of how infectious agents interact with the immune system of farmed animals, which ultimately can contribute to prevent disease spread and pandemics, improve animal welfare, and reduce the use of animals in research
Dr Stephen Meek, The Roslin Institute
Although stem cell research has historically been more established in mice, monkeys and human cells in the lab, the increasing potential of pigs makes it likely that more efforts and practices to implement their use will emerge in the future.
Organ transplants and donation
Organ transplants are becoming increasingly possible, thanks to the dramatic advances in biomedical knowledge and medical expertise. However, a shortage of human organs available for patients needing a transplant is a growing concern.
It is now likely that animal-to-human transplantation (xenotransplantation), using genetically modified pig organs such as the heart, kidneys, liver and lungs, will be regularly possible in the near future, saving countless lives.
By modifying pigs to have a similar genetic background to humans, researchers can also prevent pig organs from being rejected during transplantations, increasing the availability of organs for crucial medical procedures and make transplants a reality for more people.
A kidney transplant (the most in-demand organ for transplants) was the first successful xenotransplantation from pigs to humans, in a surgery carried out by doctors at New York University (NYU) Langone Health, USA, in 2021.
[This research gives] new confidence that it’s going to be all right to move this into the clinic
Dr Robert Montgomery, NYU Langone Health
The heart and blood system of pigs and humans work in a remarkably similar way, making hearts from pigs by far the most explored and used in these types of procedures, compared to other animal organs. Another major milestone in animal-to-human organ transplantation was achieved using a genetically modified pig heart, with the patient surviving for two months following the procedure - longer than ever achieved before. This operation was conducted as a last treatment option for the patient, who would otherwise have died from terminal heart disease.
Researchers at Yale School of Medicine have also recently managed to revive hearts from dead pigs to further increase the amount of potential organs for transplants and donations, while 2016 work at the University of California, Davis, USA, developed pig embryos with human cells as a way to grow human organs in pigs.
The solutions that pig organs are now providing for organ transplant has led to plans for their regulatory approval, including for clinical trials of xenotransplantation by the US Food and Drug Administration (FDA). Clinical trials are needed to test and evaluate how well a medicine or therapy works in the general population, with the goal of establishing it as an approved treatment – provided it is shown to be beneficial and safe.
Can pigs replace the use of dogs and monkeys in some research?
There is evidence that pigs are becoming more favoured over other types of large research animals, such as dogs, which have historically been used as a standard animal model in areas such as training for surgery and cardiovascular research. In brain research, scientists are increasingly using pigs to study brain diseases - sometimes instead of mice. Pigs are also being viewed as an alternative to monkeys in some areas of pre-clinical research, such as in the testing of treatments for therapeutic antibodies (see the Minipigs box above).
As the use of pigs continues to grow and replace other animals in research across Europe and worldwide, it seems likely that they will open new doors to what researchers can study and achieve, particularly for human medicine and biotechnologies.
As with all species of animal used for research in Europe and elsewhere, consideration of their welfare is required by law to minimise any pain they experience during research, and the principle of the 3Rs (Replacement, Reduction, Refinement) is applied to lower the number of animals used where it is possible. In surgical training, for example, where pigs are commonly employed, measures such as organ harvesting after procedures can help to reduce the need for additional pigs in other training settings.
For all live models we implement the 3R principle of Reduction, Refinement and Replacement as much as possible. Meaning that before any animal is used for a training or a research purpose, we make efforts to find a replacement alternative.
Marieke François, Orsi Academy veterinarian
Banner image courtesy of University Medicine at Johannes Gutenberg University of Mainz