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Why are animals used
in rare disease
research?
Why are animals used in rare disease research?
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Rare diseases are defined by the European Union (EU) as those that affect fewer than 1 in 2,000 people globally (and sometimes only a handful of individuals), but although they might be rare individually, collectively they estimated to affect 6% of all people around the world, while 95% of those affected still do not yet have any treatment available. There is now a realisation that this represents a growing health threat and therefore a significant health priority, both in Europe and around the world.
As they are rare – unlike diseases such as many cancers, Alzheimer’s and Covid-19 – usually very little is known about them and there are likely to be few research studies available to help scientists move their knowledge forward. Therefore, research using animals can play a key part in understanding rare diseases and contributing to discoveries that can lead to treatments and cures.
In this feature, we look at the contribution that the use of research animals has made to the understanding and treatment of a range of rare diseases, including key breakthroughs, and the different ways that animals continued to be used to help answer vital questions.
How are animals used in rare disease research?
Because rare diseases are complex and can affect any part of the body, scientists need to study organs like the brain, heart and liver, as well as body systems like the immune or reproductive system. This is why animals are frequently needed. Many rare diseases start in childhood and can affect either only males or females, therefore the sex or age of the animals can also be significant factor in a particular study. Later in this article we will look at some of the different species that are used in studies (see section, Which animals are used in rare disease research?).
There is one common theme for the majority of rare diseases – around 70-80% have a genetic basis, where certain genes have become faulty. This means a key way that animals can be used, to investigate what may cause a particular disease, is to introduce a specific gene of interest into the animal and assess the effects on its body and how these faults can be fixed or prevented. This can work the other way round as well, where animals showing certain symptoms or features characteristic of a disease can be analysed to see how their genes may differ to a healthy animal.
Any studies at this stage are part of basic research, which might not have a direct translatable application to treating diseases in the clinic, but is nonetheless essential to provide the scientific basis for understanding a disease in all its fundamentals and complexities.
Within this field, genetic manipulation of animals, such as mice and rats, is a crucial tool for ‘humanising’ these animals to make them have features that are similar to people, and mimic the human disease condition. This humanising can be done by inserting something like a fragment of human DNA, or a tumour into them, so that the mice react in a similar way to a human. For example, several types of humanised mice species have been bred with certain genetic differences to a normal mouse and only exist for the purposes of the research into a specific rare disease. At a later stage, such as when testing drugs that are intended for humans, this means that the animals are more likely to show the same reactions as us and can provide important insights into the drug’s safety and effectiveness.
Humanised animals can also help to improve treatments that are already being used in humans, such as by identifying how to reduce the damaging side effects of drugs, or identifying a more specific target area for the drug in the body to increase its effectiveness. Trials for a potential drug, or treatment, tend to always start with rodents (most commonly mice and rats), before progressing to larger animals in smaller numbers (such as pigs, dogs and monkeys) if that drug passes the initial tests.
Sometimes a drug will not pass this preclinical stage of testing due to its failure to reach the threshold of effectiveness – and not because it does not work – and this applies to both studies in animals and methods that do not involve animals. Finally, only when a drug has been confirmed to be safe and effective by these previous tests can it advance to human trials. Animals therefore continue to be an established part of the process from understanding a rare disease all the way through to treating it.
Research mice housed in cages (Credit: Understanding Animal Research)
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Statistics on rare diseases
There are varying estimates for how many rare diseases there are, in part because of the different definitions of a rare disease in different regions – it is classed to affect fewer than 1 in 2,000 people in the EU. It is thought there are more than 7,000 rare diseases, or potentially even more than 10,000, affecting between 3.5 % and 5.9% of the global population – which amounts to up to 446m people – 30m in Europe.
In addition, in a term known as the ‘diagnostic odyssey’, the average time that someone with a rare disease can expect to be diagnosed is 5.6 years, in large part because of the differing opinions and consensuses of different healthcare professionals, and the multiple appointments involved.
The EU has therefore put in place strategic objectives (see Box How is the EU tackling rare diseases?) aimed at improving patient access to the diagnosis, information and care of rare diseases.
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Rare disease breakthroughs & discoveries
Childhood diseases
Around 70% of all rare diseases arise during childhood, in part because many rare diseases are also genetic (and are therefore present from birth), for example, conditions such as Batten disease (see Zebrafish and Dogs sections below) and spinal muscular atrophy (see Mice section below).
One childhood disease where significant progress has been made is Hunter syndrome – which affects the body’s ability to break down sugars, leading to impairments, such as delayed growth and stiff joins, and a life expectancy of 10 to 20 years.
A stem-cell based therapy is to be trialled in young children, based on research at the EARA member the University of Manchester, UK. Earlier studies in mice had shown that the therapy could successfully correct the condition and some of its effects on the brain, and the trial has the potential to dramatically improve treatments for children over their lifetime. It is hoped the new therapy will remove the need for weekly enzyme replacement therapy, as it is based on inserting a gene that will allow the body to create a working lysosome enzyme produced by the body’s blood cells.
Mice have also played a long-term role in the development of therapies for congenital athymia, where children are born without a thymus gland and are therefore susceptible to seemingly harmless infections. After three decades of research, a therapy was used to treat patients so that they lived well past the average life expectancy of two to three years, and was approved as a treatment by the US Food and Drug Administration in 2021.
Rare cancers
Perhaps surprisingly, rare cancers make up a significant number (20%) of all cancers and include sarcomas (that begin in the bones and tissue), oesophageal (throat) cancer, hepatocarcinoma (liver) and certain types of leukaemia, which affect the blood and bone marrow.
We’re very excited by the preclinical studies we carried out in mice, which showed the potential to correct disease in the body and normalise brain pathology.
Prof Brian Bigger, University of Manchester, UK
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Measuring a tumour in a mouse
(Credit: Netherlands Cancer Institute)
Chronic myeloid leukaemia (CML) is one such rare cancer that develops slowly over a person’s lifetime, but thanks to medical advances can now be kept under control with the right treatments.
Studies in mice were an instrumental part in finding the protein abnormality that causes CML. The precision medicine Gleevec was developed, by Oregon Health & Science University, USA, to just target this protein abnormality in cancer cells in mice (not targeting all cells, like most chemotherapy drugs), and was later used to reduce cancer growth in CML patients.
Other species, including dogs, rabbits and monkeys, were also involved in the development of Gleevec (and its rapid approval by the US Food and Drug Administration), by shedding light on how the drug behaved in the body and potential toxicities.
There are several different types of rare cancer that start in childhood, including neuroblastoma that mainly affects children under five-years-old and starts in nerve cells called a neuroblast, often in the adrenal glands located on the top of each kidney.
Several studies in mice have contributed to improving survival rates and developing treatments with less severe side effects, for example a team at the University of Gothenburg, Sweden, were able to find an effective drug that worked against one of the two gene mutations that cause neuroblastoma.
Mice were also used in a study of the rare eye cancer retinoblastoma (which mainly affects young children) at the St Jude’s Research Hospital, USA, to confirm that the cancer’s cause was not a series of mutations, like most cancers, but the loss of a single gene – explaining why it develops so quickly.
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Genetic diseases
Genetic diseases, such those that are more generally familiar – cystic fibrosis (affecting the lungs), haemophilia (blood) and muscular dystrophy – arise either because of a faulty gene or genes, DNA damage, or a combination of genetic mutations and environmental factors. Sometimes, the mutations can develop throughout a lifetime, while in other cases they are already inherited.
An example of the latter is sickle cell anaemia (or sickle cell disease), which affects the red blood cells and blocks blood flow due to the presence of a faulty gene. It is a lifelong condition that can only be cured with a bone marrow transplant, but requires a genetically similar donor. Researchers have therefore investigated alternative approaches, including the use of CRISPR gene editing to modify the red blood cells of people with the condition – which was safety tested in mice before it could progress to human trials (CRISPR itself was developed using animal research).
As well as using genetically altered mice, other treatments for sickle cell disease hold great potential such as producing cells of interest from human stem cells, which have the ability to develop into any type of cell, and then transplanting these into animals to grow and develop.
A variation on this approach has been used at the University of Alabama at Birmingham, USA, which also previously developed the first mice that could be used to study sickle cell anaemia. By making mouse skin cells develop into stem cells, the researchers successfully made these mice models produce healthy, functioning blood cells and the diseased animals showed no symptoms.
The blood condition haemophilia, also known as the ‘Royal Disease’ because it ran in the family of certain royal lines, is where the ability of the blood to clot is severely hampered, leading to excessive bleeding. It is now known to be caused by a change in one gene in the X chromosome, that is inherited and passed down through generations.
Studies in dogs that naturally had a type called haemophilia B led to the development of a gene therapy that later went to human trials, from research at Auburn University, USA, while a factor from the blood of pigs has historically been used as a treatment for specific types of haemophilia (such as haemophilia A), to successfully stop bleeding episodes in severe cases.
Brain diseases
Creutzfeldt-Jakob Disease (CJD) which affects behaviour, memory, co-ordination and vision, can see life-threatening complications develop within a year of people showing symptoms. The disease has been investigated experimentally in monkeys and mice (such as in a 2008 study by EARA member the Mario Negri Institute, Italy), by giving the animals the human prion protein – the abnormal version of this is thought to cause CJD, or the same prion gene defects. The condition can be either genetic or environmental.
Many people with another genetic brain disease, Rett syndrome, which causes mental and physical disability, can live to adulthood, but certain complications such as pneumonia and problems with heart rhythms, can mean some die during childhood. Mice have been important for testing gene therapies for Rett syndrome, particularly by allowing researchers to study it in females, since it affects females more than males.
For some neurological diseases, the fruit fly has proved to be a valuable species, playing a considerable role in not only our understanding of how these diseases work, but also in the discovery of rare diseases. It was thanks to investigating a specific gene mutation generated in fruit flies that researchers at Baylor College of Medicine, USA, first identified Mitchell syndrome (previously a mystery) to understand how it caused progressive loss of various body functions, including movement and hearing, in people with the mutation.
In turn, through investigating potential treatments for the syndrome, again using fruit flies, members of the same team were then also able to apply their insights to other neurological diseases such as multiple sclerosis (which is more common, but includes the common feature of brain inflammation).
Meanwhile, in a study led by EARA member Uppsala University, Sweden, researchers concluded that routinely used blood-thinning drugs could be a hugely beneficial option for people with cerebral cavernous malformations (abnormal groups of blood vessels in the brain that can lead to bleeding, resulting in seizures), by studying mice with mutations that reflected the human condition, as well as human tissues.
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CRISPR genome-edited mice (Credit: CNB-CSIC, Spain)
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Lots of neurological phenotypes in humans can be assessed in fruit flies, including seizure, motor skills, aging and neuroinflammation.
Dr Hyunglok Chung, Houston Methodist Hospital, Texas, USA
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Fruit fly brain (Credit: MPI of Neurobiology/Friedrich)
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Which animals are used in rare disease research?
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Mice
As the most used species of animal in biomedical research, it is no surprise that mice have been used to study many different rare diseases. Some types of leukaemia, which affect the blood-forming tissues, such as the bone marrow, are rare, including acute myeloid leukaemia (accounting for 1% of all cancers) and prolymphocytic leukaemia (less than 1% of chronic leukaemias, with a life expectancy of less than two years for certain types). For these, humanised mice (see How are animals used in rare disease research?) have been used to explore bone marrow transplants as a treatment, as well as develop immunotherapies that work by getting the body’s own immune system to kill cancer cells.
The fact that mice can be easily genetically manipulated to carry specific genes, or have their genes edited, has paved the way for treating various diseases, including familial hemophagocytic lymphohistiocytosis (FHL), a disease of the immune system commonly affecting young children. See also the video below from EARA member the Jackson Laboratory, USA, about how they use mice to explore genetic mutations involved in different rare childhood diseases, as well as translating these findings to the clinic.
Research led by EARA member the Max Delbrück Center (MDC), Germany, used CRISPR gene editing to repair the defective immune cells in mice as well as in blood samples taken from two babies with FHL, to dampen the immune response and return it to normal.
Meanwhile, scientists at ICVS, University of Minho, Portugal, studied Machado-Joseph disease (MJD) – also called spinocerebellar ataxia type 3 – that affects muscle control and in the severest cases limits life expectancy to around 35 years. The team genetically engineered mice to express a protein that is responsible for the rare genetic disorder, and by using these mice to test possible treatments, found that an existing drug for depression could reduce the severity and slow the progression of MJD.
Mice can also be engineered to study cystic fibrosis (CF), a condition that results in thick mucus building up in the lungs and digestive system. The mice used have the CTFR gene that is responsible for the condition and this allows researchers to investigate the faulty mechanisms that cause the mucus to thicken abnormally, as well as ways to prevent common features such as lung damage (see also Pigs section below).
In a study at Yale School of Medicine, USA, researchers were also able to correct some of the mutations in CTFR in multiple tissues in mice, using gene editing, and found that this treatment led to CTFR partially gaining back its normal function. This has the potential to treat not only CF, by addressing its numerous gene mutations, but other genetic conditions.
Humanised mice can shed light on the gene defects that affect the health and function of the muscles, such as muscular dystrophy and spinal muscular atrophy (they can display similar symptoms to the human condition). Researchers at Harvard University, USA, explored a different approach by successfully transplanting human muscle stem cells into mice with muscular dystrophy, to improve their muscle function and help repair future muscle injuries.
See also the EARA feature about mice.
Zebrafish
EARA member the Luxembourg Centre for Systems Biomedicine (LCSB), at the University of Luxembourg, was able to identify three possible early markers of Batten disease, using zebrafish larvae which had advantages over using mice or other mammals, which do not develop the disease until adulthood.
Meanwhile in work at Sidra Hospital, in Qatar, researchers are using genetically modified zebrafish to gain key insights into the biology and symptoms of a range of rare childhood diseases (including inherited blood disorders such as sickle cell anaemia), in turn paving the way for precision medicines.
For cancer, the benefit of genetic manipulation has led to zebrafish that have specific gene changes linked to the disease. For example, in a study at the University of Birmingham and University of Warwick, both UK, zebrafish were edited to have a so-called GATA2 deficiency – a hallmark of a rare bone marrow disorder that is tied to the development of blood cancer – to shed light on how this deficiency increases the risk of the cancer.
A tumour itself can also be implanted into zebrafish (known as a xenograft) to provide crucial information about how the cancer develops and how the body responds to the disease. Zebrafish cancer xenografts have been widely applied to the study of many types of cancer and have demonstrated their value for rapidly testing the safety and effectiveness of cancer therapies.
See also the EARA feature about zebrafish.
Fruit flies
Although we may seem very different to fruit flies, they in fact share three-quarters of the genes that cause human diseases (and 60% of genes in general). Fruit flies are therefore very useful for genetic studies, particularly when they have the same genetic mutations as humans, or are engineered to express genes of interest to understand how it causes or increases the risk of the disease developing, or is responsible for the symptoms seen in people.
The causes of the rare neurodevelopmental disorders, Harel-Yoon syndrome and Yoon-Bellen syndrome, were both identified as due to specific genetic mutations thanks to studying fruit flies, by researchers at Baylor College of Medicine, USA. Although this gene mutation had been linked to neurological symptoms in humans, it was only by determining the effect in fruit flies that researchers could confirm the cause – paving the way to targeted treatments.
Meanwhile, in a fruit fly study at the University of Sydney, Australia, researchers were able to pinpoint how a mutation underpinned a key mechanism behind episodic ataxia, a condition that severely affects balance and co-ordination.
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Zebrafish larva (Credit: The University of Manchester, UK)
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The animal models provide essential information regarding nervous system function that is not possible to obtain in cell culture systems and allow us to evaluate the effect of treatments on the organism as whole, namely on the movement problems associated with the disease.
Dr Patrícia Maciel, ICVS Minho, Portugal
Fruit flies reach adulthood in just two weeks, so using them in research opens doors to exploring the long-term effects of a disease and how it progresses over a lifetime, which is more difficult to achieve in larger animals and humans.
For example, research at the Institute for Research in Biomedicine and SJD Paediatric Cancer Center Barcelona, both Spain, engineered fruit flies to express a variant of a cancer gene that causes a rare bone cancer called Ewing sarcoma, which has a survival rate of only just over 50% in teenagers, and less than 30% after the cancer has spread to other parts of the body. This resulted in the same tumour development as seen in humans, and was the first time the disease was modelled in an animal, after failed attempts to do so in mice.
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While the use of mice for studying rare diseases is generally the most widespread, zebrafish are increasingly being employed in these studies too, as they can be maintained in very large numbers in the lab, can mature faster than rodents, and, like mice, can be easily genetically manipulated.
Zebrafish have therefore contributed to the study of various genetic diseases, including Batten disease, (see also Dogs below) an incurable disease that results in several symptoms, such as vision loss, seizures and problems with cognition. By using tools such as CRISPR gene editing, researchers can initiate in zebrafish the same gene mutations as people with the condition (mostly children), thereby replicating key aspects and testing the effect of possible drugs.
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Our new model may also facilitate drug screening to identify compounds that could slow or halt disease progression, a breakthrough that the 14,000 patients living with this still uncurable disease are eagerly waiting for.
Dr Carole Linster, LCSB, Luxembourg
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Another benefit of zebrafish larvae is their transparent bodies which makes them particularly suited to research into rare skeletal disorders, such as idiopathic scoliosis (abnormal spine curvature arising after birth). Their transparency means that genes linked to the development of such conditions can be easily seen under a microscope, as well as the bones and skeleton itself, to understand the fundamentals of bone formation and where it can go wrong. Adult fish can also develop similar bone complications to people (they have shown osteoporosis-like features, for example), but are also able to repair and renew their skeletal tissue, which can offer insights into possible treatment strategies.
Zebrafish (Credit: Paco López-Cuevas, the University of Bristol, UK)
Female fruit fly (Credit: Evans Lab, University of Sheffield, UK)
Dogs
Like us, dogs are also naturally prone to rare diseases. Some of these canine conditions have many parallels with human ones, and so research in dogs has helped to inform and improve both human and veterinary medicine, and holds the potential to do so for even more diseases in the future. Cancer-driving gene mutations, the biological make-up of tumours, and the spread of cancer (metastasis) all share similarities between dogs and humans.
A rare disease that dogs can get is Batten disease – called neuronal ceroid lipofuscinoses in the canine version (see also Zebrafish). Here, studies in dogs by a US team led by the University of Pennsylvania, have led to new findings about how best to deliver gene therapy to slow the development of the disease in children and in dogs. Studies at the University of Missouri have also looked at how to preserve the function of the retina – a common hallmark of Batten disease is vision loss.
Although hypophosphatasia has been extensively studied in humans, the results of the canine study are significant, as they provide the first spontaneous animal model for the disease, which may also open new avenues for the development of novel therapies.
Prof Hannes Lohi, University of Helsinki, Finland
It was from a study at EARA member the University of Helsinki, Finland, that researchers found that the canine version of hypophosphatasia (impaired mineralisation of the bones and teeth) closely resembles the disease in human babies, and also marked the first report of this condition naturally occurring in dogs. The findings then allowed the team to develop a gene test for the specific dog breed they investigated, to identify the defect before birth.
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Beagle (Credit: UAR)
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Dogs can also suffer from the blood disorder haemophilia (see Genetic Diseases), while another condition that is shared with dogs includes muscular dystrophy (MD, see also Genetic Diseases and Mice), because the gene mutation in human MD matches that in golden retrievers with MD. In an unexpected development of studying a version called Duchenne MD in this breed, researchers at the University of São Paulo, Brazil, discovered a new gene mutation that can protect against muscle degeneration and weakness from the disease, opening new avenues to treatment.
See also the EARA feature about dogs.
Pigs
As a larger research animal, pigs are emerging as a suitable choice for investigating certain diseases, where their similar make-up to us (especially in terms of anatomy, genetics and body processes) make them more suitable to use than a rodent.
While pigs do not naturally get cystic fibrosis (CF) (see also Genetic Diseases and Mice) they can be bred to develop very similar symptoms to the condition, such as lung disease which can naturally develop as a result – the lungs of pigs have been shown to be affected in a very similar way to those of humans. This means that interventions can be tested at an earlier stage than in a patient, in turn allowing researchers to come up with measures that could help to ease symptoms or detect the condition earlier on.
Pigs have also been genetically engineered to develop a disease that mimics CF in newborns, in a study at the University of Missouri, USA – although CF is present from birth, it is not always easy to diagnose it early in life, meaning that treatment does not start at the optimal time.
Meanwhile, the same similarities in body make-up to humans have also meant that pigs have been used to model Huntington’s disease, a rare disorder where the brain’s nerve cells are damaged, and that can affect movement, behaviour and communication, among other effects.
In a study from Emory University, USA, and Jinan University, China, the genome of pigs was edited using CRISPR to insert the human gene that causes Huntington’s. This approach resulted in pigs that showed very similar symptoms to people with the condition compared to rodents, such as difficulties with walking and running with age. In addition, certain brain changes were similar, such as the loss of specific neurons and immune responses.
See also the EARA feature about pigs.
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Group of minipigs (Credit: Ellegaard Göttingen Minipigs, Denmark)
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How is the European Union tackling rare diseases?
With around 30 million people in the EU living with a rare disease, it has laid out its strategy for combatting this number by improving how patients can access diagnosis, information and care for their disease.
One element to this is ‘building and broadening the knowledge base also through research’, including the funding of hundreds of research projects.
The EU is working to pool different resources so that more professional expertise can be provided and shared, with a key component being a virtual European Reference Network (ERN), where those with expertise in rare diseases across Europe can collaborate to review people’s diagnoses and treatments.
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In addition, the EU Commission’s Joint Research Centre has developed the European Platform on Rare Disease Registration (EU RD Platform) to ensure that data is searchable for those who need it. Similarly, a resource created by EARA member the National Centre for Biotechnology (CNB-CSIC), Spain, is allowing users to explore the different molecular relations between rare diseases, and other clinical data, to improve the transfer of knowledge and identify scope for research collaboration.
Another avenue is support for the development of so-called orphan medicinal products – new drugs for treating rare diseases that receive considerably less investment from the pharmaceutical industry given the smaller numbers of people who require them.
We need a European action plan on rare diseases because the world is changing
– with new technologies, new knowledge, and new opportunities –
and the 30 million people living with a rare disease in Europe cannot be left behind.
Yann Le Cam, Chief Executive Officer at EURORDIS (Rare Diseases Europe)
Are there alternatives to animals in rare disease research?
The study of rare diseases spans many different research fields and employs various types of scientific technique, and animal research will undoubtedly continue to be a core component of this work, to understand how diseases arise and operate, and how they can be treated. However, it can also be complemented by a range of other methods.
Human cells and tissues that are grown and cultured in the lab, for example, can fill some of the role of testing drugs and other compounds as possible treatments. Though they cannot give a comprehensive picture of how the drug will behave in the body, the effect on cells and how they respond can be very useful for informing future directions of research and strategies for treatment – such as whether a particular drug is suitable for investigating further in a living animal and, possibly, humans later down the line.
On a larger scale, cells can be made to develop into organoids that resemble parts of organs or complete organs. This can now be achieved for virtually every organ, whether that is the brain, retina or pancreas, and research groups have increasingly been making use of organoids to model how different diseases take hold, as well as to test drugs. On a more fundamental level, organoids can also give insights into organ development, how cells interact with each other, and much more, to provide the basic information necessary to inform future medical interventions.
By combining the use of rats and organoids, a study at Stanford University, USA, successfully reversed some of the molecular defects of Timothy syndrome, which causes severe neurological complications in newborns. It achieved this by creating brain organoids from human stem cells, which were then transplanted into the brains of the animals.
Before drug tests even take place, computer modelling can help to predict the effect that a drug will have in the body and whether it is suitable to use for people. Computation also has the benefit of allowing researchers to screen many different compounds for their suitability as drugs, and the ease of use, accuracy and speed are often important advantages.
One way that computation can be achieved, and that is gaining popularity in many fields (not just biomedical research), is through Artificial Intelligence (AI). A team at EARA member the University of Zurich, Switzerland, developed an AI that could identify drug targets for cystinosis. This condition is caused by the build-up of the amino acid cystine in different tissues and organs, leading to varied symptoms that can be severe and necessitate organ transplants, such as of the kidneys. The drug targets were then validated by testing them in mice and zebrafish, revealing treatments for the condition with new or existing drugs.
Together with animal research, the techniques outlined here can provide the best possible picture of our knowledge and treatment of rare diseases.
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Midbrain organoids under the microscope (Credit: MPI for Molecular Biomedicine, Germany)
The future of rare disease research
Despite advances in other types of research method, there is no doubt that animal research will continue to be needed in the field of rare diseases. Overall, researchers, doctors and healthcare professionals still know very little about rare diseases, and so to encapsulate as many aspects as possible of a disease’s cause, emergence, progression and effects, studies in a whole, living organism must be carried out to provide the essential information to ultimately develop, treat and prevent these diseases.
Unfortunately, for particularly serious diseases such as Huntington’s, it is likely that procedures used on animals such as dogs and pigs will cause severe pain when the nature of the study makes it unavoidable – but as per EU Directive 2010/63/EU, experiments are always designed to cause the least pain, suffering, distress or lasting harm. In the case of using gene editing to produce genetically altered animals, as above, it is expected they could experience severe and persistent impairments to their health, while some of these animals may be bred but not used, for example when they do not have the desired genetics specified for the study.