Could the blood of camel species help save us from serious diseases? | DW Documentary

What’s known as nanobodies from the blood of camels are at the heart of a medical revolution. Due to their special properties, these nanobodies can be used in a variety of ways, whether in the fight against infectious diseases, in cancer therapy or in the diagnosis of Alzheimer’s disease.

Small antibodies with a big impact: camel blood contains immunological superpowers. It all began in the 1990s with a chance discovery at the Free University of Brussels: students used dromedary blood in an experiment and came across previously unknown antibodies. The university scientists discovered that these antibodies are present in all camel species. And, they have amazing properties. Small fragments can separate from the base of the antibody — without causing any damage and while retaining their full binding capacity.

This was the discovery of the nanobody: a tiny, extremely robust molecule which, due to its small size, can also penetrate areas too small to be targeted by complete antibodies. The nanobody, however, can attach itself with extremely high precision to pathogenic antigens.

This discovery triggered a wave of innovations and shook up the big pharmaceutical companies. In 2018, the first drug based on nanobodies went on the market, designed to combat an autoimmune blood clotting disorder. Numerous potential applications were developed within a very short space of time. Whether in the fight against cancer, in Alzheimer’s diagnostics or to kill pathogenic bacteria – the success of camel antibodies has been so resounding that many medical research centers now have their own herds of llamas or alpacas.

But why do members of the camel family in particular have such immunological superpowers? With the help of camel experts and microbiologists, the documentary sheds light on the surprising abilities of camels and the medical revolution of nanobodies.

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Camels have a reputation for being malcontents. Llamas for being grumpy… But alpacas are best-known for their high-quality wool coats. All the more surprising that the expansive Camelidae family has sparked a medical revolution. Like so many medical revolutions, it began with a coincidental discovery – at the Free University in Brussels. More precisely, in the Department of Applied Biological Sciences. Serge Muyldermans was part of a research team in 1989 headed by Professor Raymond Hamers. Muyldermans today often recounts their historic discovery to students. I will give you the story of the practicals that we did 30, 35 years ago with the students. You all know, if our body is infected with a bacteria our immune system will generate antibodies against those bacteria. And so, the antibodies will bind to the bacteria and they are going to destroy the bacteria. Antibodies are key elements of the immune system. They’re created specifically to detect and eliminate foreign substances – or antigens – that get into our bodies. On the day of the discovery, Professor Hamers’ students were to isolate and identify antibodies in blood. But the class didn’t get off to a very good start… Now, we had our students that refused to donate blood, and they were also afraid of the blood from their colleagues, because it might be contaminated with hepatitis or HIV. And they refused to kill a mouse for a stupid practical. So therefore, Hamers said: Well, you know we have still in our freezers some blood from a dromedary. Blood from the one-humped camel was used instead. The students got to work. But they were in for a surprise. Alongside the classic antibodies, the experiment revealed other antibodies with a much lighter molecular weight. They had only a molecular weight here of ninety thousand, and that was surprising. Because normally that was never seen before in a human, rabbit, mouse or crocodile – you name it. You always have IGGs with a molecular weight of 160 thousand. Professor Hamers’ students had stumbled upon a previously unknown antibody in a living creature. The antibody had just two polypeptide chains, as opposed to the four in classic antibodies, giving it an unusually low molecular weight. The finding then had to be confirmed in repeat experiments. Professor Hamers used fresh blood samples from the Brussels Zoo to replicate the tests: but not just with blood from camels, from llamas and alpacas, too. The results showed that all the animals possessed not only the usual antibodies, but also the newly discovered mini-antibodies. Scientists wondered: Were these just the remains of a primitive immune system or were they functioning antibodies? To find out, the researchers needed not just more blood, but a whole camel. They needed to vaccinate it; in other words, inject it with an antigen – a piece of an inactivated virus, for example. Then they had to wait and see if the animal’s immune system would produce a response… using these unusual mini-antibodies. The scientists had to improvise – the zoo animals couldn’t be tapped a second time. We didn’t have any more money, so we had to ask our technician, who was a Moroccan, to take a few antigens in his luggage and visit his uncle in the Atlas Mountains to immunize the dromedary of his uncle. He was a farmer, his uncle. It was immunized during Ramadan, the summer holidays, at New Year – a few times. So, it was a year and a half before we had the immune blood. How did the dromedary’s immune system react? Did it produce mini-antibodies specifically targeting the intruder? The scientists were eventually able to test the animal’s blood. The method, shown here, used a color reaction, to make the antibody’s recognition of the antigen visible. If there was no reaction, that would have meant the camel couldn’t produce an immune response to the antigen, to the vaccine. There’d be no point in continuing. The sample began to turn yellow a half an hour into the experiment. about a half an hour into the experiment. The answer was clear: the mini-antibodies worked! Antibodies attach themselves to an antigen to trigger an immune response and eliminate the intruder. But Serge Muyldermans made a crucial discovery when he looked at the very tip of the camel antibodies – a variable part that can adapt to any kind of virus, bacteria or other antigen, and attach itself to it. Muyldermans showed that the antibody’s tip could be separated from the rest without harming it. The miniscule antibody fragment proved not only to be ultra-resistant, but its binding capabilities remained fully intact. The tip is what’s known as a nanobody: a structure that no longer acts to trigger an immune response but whose size, resistance and binding properties make it an extremely promising tool for medical science. You never forget something like that. It’s like the birth of your first child. It’s unforgettable. His ‘baby’ was soon ready to leave the university lab and enter field research. But first Serge Muyldermans and colleagues Raymond Hamers and Cécile Casterman patented their discovery in 1993, giving them the sole right to commercial development for 20 years. Then they published their discovery in the science journal “Nature”. The debut for the small camelid antibody with a detachable head. Researchers and laboratories around the world responded. Among them a lab in Marseille, France. Structural biologist Alain Roussel began studying the new antibody as soon as he found out about it. It’s here in Marseille that the first nanobody structure was modelled, in parallel with our colleagues in Brussels. We could see the shape that gives the molecule its properties. More precisely, there were three large loops, a bit like three fingers that could grasp the antigen. He knows even more now, thanks to progress in scientific modelling. But it’s been confirmed, at an atomic level, that the nano tip’s binding power is as precise and effective as that of a classic antibody. This nanobody, like many proteins, is composed of various areas that are more or less flat, hollow and bumpy. And these hollows and bumps mirror the bumps and hollows of the antigen. The two molecules fit into one another, thanks to the perfectly complementary shapes of their surfaces. And if we take a closer look at this interaction, if we look at its atomic structure, we can see that the atoms really do touch each other. And it’s these relatively strong bonds between an oxygen atom and a nitrogen atom that bind the entire antibody onto the antigen. The surface complementarity is in nanometers. We’re talking ten to the power of minus ten meters. That’s the magic of natural biology. The tip is atomic high-tech aboard a miniscule vehicle, ready for use at any time. The stuff scientists dream of. And a discovery that required a large dose of luck. The history of science is full of accidental breakthroughs or research that produced unexpected results. From aspirin to dynamite, X-rays and the structure of DNA – all these coincidental discoveries came from a mix of good luck and ingenuity. A recurring phenomenon known as serendipity. And the origin of this term is, for this antibody, quite surprising. It refers to a 16th century Persian fairy tale that recounts a journey made by the three princes of Serendip – and how they were able to precisely describe the characteristics of a camel that had traveled the route before them. The combination of chance observations and insight resulted in… serendipity. And now, once again, the camel is the star. But the discovery of the camelid nanobodies also raised many questions: Could they actually be used on humans? What therapeutic applications could be developed and marketed? Serge Muyldermans preferred to leave the answers to others. I was too much of a scientist. And I didn’t want to get involved in projects leading to commercial products. I wasn’t interested. I stuck to academia. Muyldermans has never looked back. Though he did keep two alpacas from the adventure. Their only duty now is to keep the grass in his orchard trimmed. This is Paco and that’s Pablo. Paco and Pablo are two cartoon characters, two rogues that are always escaping. And as these two are always escaping from the meadow, they earned the names. It was in Belgium that nanobodies’ potential applications were first explored – and some astonishing capabilities came to light. Antonella Fioravanti conducts research at the university where the nanobodies were first discovered. In 2014, she began to focus on a disease that is rare but still lethal: anthrax. It’s caused by Bacillus anthracis, a complex and relatively understudied bacterium. The first time we hear about anthrax is in the Bible. It was the fifth plague of Egypt, just to say that it has always been there. This illness really affects all warm-blooded animals, including us. So, it’s spread everywhere in the world. And there are three different ways to get this infection: by skin, respiratory, and in the gut. And then the infection goes systemic in the blood and then it’s really, really difficult to treat it. Anthrax infection via the respiratory system is particularly deadly. So deadly in fact, that it inspired biological weapons projects in the Second World War. It’s nearly two weeks since the first anthrax attacks in the United States. And circumstantial evidence is now emerging that’s leading the authorities to investigate possible links between the anthrax and Osama bin Laden’s network. Five people in the US actually died from letters laced with anthrax in 2001. So how can we protect ourselves? Pathogenic bacteria. So, this is a Level 2+ security biolab. And what does anthrax even look like? This is what a colony of Bacillus anthracis looks like. So here I’m going to harvest the spores from a colony. And then I’m going to resuspend them in appropriate media where they’re going to grow again. She was interested in one specific characteristic of the bacteria. This is Bacillus anthracis. It’s a long-shaped bacilli. It makes chains made of different bacteria. They are covered by an armor that is made of little pieces that are proteins. It works like an exoskeleton. And if you remove the armor, the bacteria get extremely elastic and are not stiff anymore. So I came to the idea: what if I can destroy this armor? Her thoughts turned to the nanobodies discovered by her university colleagues. Might they be able to use their miniscule size to infiltrate the bacteria’s armor, like tiny missiles? That called for… a llama! The protein that makes up the bacteria’s armor was injected into the beast. After a few months, the llama had created nanobodies specifically targeting this protein. Fioravanti then introduced the nanobodies to the anthrax bacteria. The results were astonishing. Those are the non-treated cells. You see they have this smooth shape. But when you treat them with the nanobodies, they start really to wrinkle and then they will collapse. They were able to stop the protein that makes the armor. And without the support of its exoskeleton, the bacterium falls apart. So it’s really like the nanobodies are the key to the story. Going between the armor and disassembling it – just the nanobody made that possible, because of the size. That success prompted her to test the nanobodies in vivo: in other words, on living mice. The mice were infected with anthrax and then given the nanobodies twice a day for six days. Well, I really thought they were going to die. Honestly, me and my colleague Philippe, we were doing the experiment. And then the mice started to get better, to get better and better. And, on Sunday morning, I got this call from Philippe: They’re alive! They’re alive, while the control group are all dead! I remember, really, I started jumping. I was in my pajamas having breakfast and I started jumping like with tears, because like: Oh my God, we saved some things. This is huge! It works! So this was one of the best days of my life. This opens up really a lot of lines of research, and also the opening of new possible treatments for other bacteria that have such an armor. This is huge. But it’s in the Belgian city of Ghent where nanobodies have enjoyed their most spectacular success. This is the headquarters of Ablynx, a startup founded in 2001 to develop applications for camelid nanobodies. A scientific success story. The discovery of a special type of slow antibodies in camelids sparked decades of innovation and it led to the foundation of Ablynx in 2001. At that time, the slow antibody was renamed a nanobody, and the startup company had 10 employees. For over 15 years, Ablynx explored potential applications for various types of diseases. Investors gradually began seeing the advantages of using camelid nanobodies. And in 2018, they hit the jackpot. Sanofi buys Ablynx for 3.9 billion euros. 3.9 billion euros. An amount equivalent to the promise held in the tiny nanobodies. The first actual use was a drug Sanofi began selling in 2019: Caplacizumab. A drug to battle an auto-immune blood disorder that’s very rare but fatal in 90% of cases if left untreated: aTTP. Nathalie suffers from the disease: acquired thrombotic thrombocytopenic purpura. But today, thanks to Caplacizumab, she’s in the clear. She’s returning to the hospital for a check-up with Professor Coppo, an aTTP specialist. Did the treatment work? Yes, very well overall. Everything’s really back to normal now. We’ll just need to check every three months… Probably for the rest of your life… I started to get bruises on my body that appeared for no reason. They started on my legs and then gradually…. little by little they started moving up. I thought I bashed into something and not realized because I’m very active. I’m a primary school teacher. I also do yoga and my children are very young. I’m always moving around. It happened over a couple of weeks. But then I thought: “It’s not OK, something’s wrong” because the bruises started to appear on my arms and I had a huge one on my hand. I thought to myself: “There’s something wrong”. It’s a disease that’s linked to the formation of small clots in the vessels of most organs, typically the brain and the heart, but also the digestive tract and the kidneys. If we do nothing, the organs fail, and the patient dies. The nanobodies seek out the blood proteins involved in the disorder and attach themselves. They replace the platelets that cause the blood clots and prevent them from clumping. The camelid nanobodies make it possible to attack the disease’s inner workings. Since we’ve added Caplacizumab to plasma exchange and other immune-suppressive treatments, patient response is not just faster, it’s also long-lasting. That’s what’s new. Thanks to this we can now stop plasma exchange much sooner than before. Currently we estimate that with the addition of Caplacizumab, we can cut treatment time in half. The nanobodies are now such an integral part of medical research that their origin in the camelid immune system is often overlooked. But what gave camels these unique superpowers? Near Vienna, Austria, Pamela Burger studies the genetics of the very ancient Camelidae family. She‘s a specialist on the origins of the camelids, which have undergone surprising changes during their evolution. Camels originated in North America, and it was maybe like 40 to 45 million years ago. At the very beginning they were very small, like a goat. And over the millions of years they developed into different camel types, larger, smaller. But, around 15 million years ago, they split into the two lineages: namely the New World camels and the Old World camelids. And the New World camelids migrated to South America, which are represented now by the llama, the alpaca, the guanaco and the vicuña. And the Old World camels migrated via the Bering Land Bridge to Asia, and from there then to Africa. The evolution of the nanobodies is also a very, very old development. It must have been older even than 15 million years ago, because both camel lineages have it. So this system, these nanobodies, must have developed before the split of these two lineages. They have developed over the millions of years very successful mechanisms to fight against diseases. Their long evolution has left its mark on the species. But why camelids in particular? I would just say it’s by chance. A lot of evolutionary things happen by chance, trial and error. So, something that has been successful survived and evolved. And if it was too much of a cost to keep, then it would have been abandoned again by the species. But why other mammals would not have developed the same strategy, I don’t know. Camelids may still harbor other secrets, but for now they’re sharing the benefits of their immune system with humans. These alpacas frolicking near Paris belong to the Institut Pasteur. They play an active role in some major research. Immunologist Pierre Lafaye is the shepherd to this small research herd. I got interested in camelid antibodies about 20 years ago because of Professor Hamers’ work in Brussels. People first thought it was funny that we were working with alpacas, but now it’s become so important that everybody understands. I’m vaccinating them against various proteins, against Alzheimer’s in particular. Once they’re vaccinated, we take a blood sample to continue our work in the lab. Then we leave the animals alone for a couple years. Ok, we’re done. Now two years of peace and quiet. The next step: extracting, from those few centiliters of blood, the antibodies the animal has produced in response to the protein characteristic for Alzheimer’s disease. Fewer than a dozen out of several million antibodies. Louis Pasteur developed the rabies vaccine in these buildings in the 1880s. And the institute continues to work on promising treatments, thanks to its alpacas’ mini-antibodies. We can make antibodies against Covid, against Zika, and recently against monkey pox. We can make them against certain brain cells, like nicotinic receptors. My research focuses on Alzheimer’s. We’re trying to extract the antibodies specific to Alzheimer’s – for diagnostic- and, eventually, for treatment. Nanobodies that could recognize some of the disease’s degenerative characteristics – and in this case, nanobodies specifically produced by alpacas. The first stage is to extract the DNA from all the nanobodies in the blood sample, and then introduce it to the bacteria. We have 1 billion bacteria here containing the DNA coding for about 100 million nano-antibodies. Through selection methods, we gradually isolate the ten best nanobodies. The selection is ruthless. They first use a virus that can eliminate 99% of the unsuitable nanobodies. The remaining 1,000 candidates are turned over to a robot which, one by one, tests their ability to identify the Alzheimer protein. The entire process takes around three months. Just two of the original 100 million nanobodies remain standing. The chosen nanobodies are then taken to the Institut du Cerveau – the Paris Brain Institute – to help conduct research into Alzheimer’s. Here, Pierre Lafaye’s antibodies are always eagerly awaited. Especially by Doctor Benoît Delatour, who is exploring new methods of diagnosing the disease. Alzheimer’s directly affects the brain’s neural communication network. The formation of protein deposits, known as amyloid plaques, block the flow of information. But the disease also causes the neurons themselves to degenerate and die. Alzheimer’s initially affects memory before causing irreversible damage in the other areas of the brain. For treatment to be effective, Alzheimer’s must be diagnosed as early as possible. The goal is to detect the amyloid plaques that build up in the patients’ brains from the start. Enter the nanobodies. But their responsiveness must first be tested. It’s quite interesting. The two antibodies really work very well. This one recognizes the amyloid plaques … I’ve done some tagging on a transgenic mouse that’s full of amyloid plaques and you can see they’re all tagged. This really resembles what we see in the brains of Alzheimer patients. The antibody is very precise, it recognizes only one thing. There’s no background noise. It really is perfect. And the other antibody recognizes the second classic lesion of Alzheimer’s disease, neurofibrillary tangles. You can see that all the lesions have been carefully detected. In the hippocampus, which is the memory center for humans and animals, we can also see all the tagged neurons recognized by the antibody. The first experiment was conducted on brain tissue extracted from mice. It will now be repeated on living animals. See the mouse there, under the microscope. The aim is to see if the nanobodies can cross the blood-brain barrier. As its name suggests, it’s a barrier that isolates the brain from the blood. Why? Because the blood carries pathogens, toxic molecules, that mustn’t enter the brain. The downside of this barrier is that important molecules, like antibodies, can’t cross it. Except maybe camelid antibodies. Their small size is the key. You can see, for now, it’s very black. You can just start to make out some shapes appearing in real time. You can see the antibody exit the vessels. It’s crossing the blood-brain barrier. And it will gradually spread and gather at the site of the amyloid plaques. Look! That’s cool, you can see the plaques clearly. All the tagging’s done by the antibodies – but this time in vivo, not a slice. Unimaginable just a few years ago. The technology opens up new opportunities for treating Alzheimer’s disease. These nano-antibodies or nanobodies, clearly have a future. By combining them with elements that can be picked up on an MRI, we’ll be able to carry out early, high-resolution diagnoses on patients, as well as monitor various therapies on the regression of these lesions. These are high hopes in the fight against a disease that afflicts hundreds of thousands each year in Europe and an estimated 10 million worldwide. But nanobodies can go even further and highlight other processes that occur deep inside the human body. Ulrich Rothbauer wants to use the nanobodies’ tiny size to infiltrate living cells and monitor what goes on inside them. A job that requires a slight upgrade to the nanobodies. Nanobodies are invisible. Since we can’t see them, we must make them visible. We link the nanobodies with a small fluorescent protein to make a chromobody. The fluorescent nanobody then makes it possible to navigate within cells and observe some of their biological processes ‘live’. These are dynamic processes taking place inside living cells. And that’s where the chromobody has the additional advantage of functioning in living cells. The cell’s processes can be displayed and the dynamic modifications within can be visualized in real time. Inside the cell, the chromobody binds itself to its target. It traces the target’s contours and reveals its movements. We can see the chromobody, the signal of a chromobody that has bound itself to the HIV virus. We can observe in fine detail how this HIV virus attaches itself to a cell’s plasma membrane and is then discharged to infect neighboring cells. Chromobodies are already used today to study the effect of certain drugs on cells. In particular, for cancer treatments… Here you can also see a chromobody in a living cancer cell. The chromobody collides with the nuclear membrane, so we can observe the division of this cancerous cell. It’s an important process. For example, if we want to now develop a drug that prevents cancer cells from dividing, we can test them in this cell line. We will know immediately at what moment and in what quantity the drug stops this cancerous cell. And we can see it in real time. This helps us choose medicines at a very early stage and saves money in the development of new active ingredients. Nanobodies offer the greatest hope in cancer treatment. Over 18 million new cancer cases are diagnosed every year, and nearly 10 million people die from the disease. Most current cancer treatments lack precision. Chemotherapy attacks not only cancerous cells, but healthy ones, too. Researchers are looking for more targeted therapies. And nanobodies have become a new, precision weapon in the fight against cancer. The number of potential applications is growing. Some are designed to inhibit a tumor’s growth while others destroy the cancer cells – a strategy adopted by Belgian startup Precirix. It relies on nanobodies’ special ability to bind onto other molecules to form a bond with a radioactive isotope. The treatment is still in the test phase, but some potential uses are already being assessed in clinical trials. Here, in a first stage, the nanobody is being added to a tracer that is very slightly radioactive. Its mission: to seek out diseased cells and attach itself to them. Here we see an axillary lymph node with a high uptake. And here we can see the breast lesion, with also a very good uptake of the tracer. The nanobody’s target is a protein called HER2 that’s a characteristic of certain types of cancer. For us, it’s very important to know if there is a high HER2 expression in the tumor and in the metastases of the tumor, in the metastatic lymph nodes. Because we know, in that way, if this patient will respond to therapy. Another advantage, as it allows the treatment to be tailored to the nature of the cancer. However, the researchers’ long-term goal is to equip the nanobodies with a far more powerful radioactive payload. So, the nanobody is present in the tumor. But if you couple the same nanobody with a therapeutic radioisotope, you would irradiate the irradiate the tumor and the cancer cells – so, specifically targeting the tumor cells while sparing the healthy tissue that you want. The small size is very beneficial for this approach. Once you administer it to a patient, it diffuses through tumor tissue very fast. On the other hand, of course, you’re working with a very potent radioisotope for therapeutic use, and you don’t want the fraction that is not bound on the tumor to stay long in the body. And, because of the small size, it will clear out very fast from the body, which is perfect for the safety. Now the young startup must complete the extensive series of required tests to get its treatment approved. We do the clinical studies to prove that our drug is safe and effective – all the way from the camel, if you want, to the patient. And that whole journey will take more than ten years. Nanobodies have the potential to revolutionize therapies and diagnostic procedures, now and in the future. The growing number of companies offering custom-made nanobodies is proof in itself. Along with their physical and chemical benefits, these single-domain antibodies are also especially light and inexpensive to produce. These practical and economic advantages make them affordable for many research labs, stimulating innovation. Camelids may look very unassuming. But they’re masters at miniaturizing antibodies, which has made them into the kings of biotech. Something no one could have predicted. And a fact that should cheer camels and llamas alike.