How vaccine was developed Initially, explains Biswajit Ghose

It is in our nature to try to resolve problems using what has worked before. But knowing what worked

It is in our nature to try to resolve problems using what has worked before. But knowing what worked

It is in our nature to try to resolve problems using what has worked before. But knowing what worked before can blend us the insight required for major leaps forward. Our greatest scientists are those who, despite their expertise remain free think differently. By this measure, Charles Janeway, an immunologist working at Yale University, was indeed one of our greatest scientists. He is also said to be ‘one of the most exciting, decent and thoughtful immunologists on the planet’.

Born in Boston in 1943, Janeway studied chemistry and then medicine at Harvard. His path to medicine was influenced by his father, an eminent Harvard pediatrician and a department head of Boston’s children’s Hospital, but Janeway felt that ‘surgery was going to condemn to a life routine procedure and he switched his life to basic research. He switched his life to basic research. He married when young but in 1970, aged twenty-seven, he split up from his wife, when their child was aged one. As a result, he ‘felt lonely for many years’, but gained time and freedom for his research. In 1977 he joined the faculty of Yale, where he met his second wife, Kim Bottomly, also a well-known immunologist.
In 1989, Janeway puzzled over what he called the ‘dirty little secret’ in our understanding of immunity. The problem concerned vaccines and the way in which they were thought to work. The basic principle of vaccination follows the familiar idea that an infection, caused by a virus or bacteria, is dealt with much more efficiently if your immune system has encountered that same virus or bacteria previously. So – the dogma goes – vaccines worked by exposing you to dead or harmless versions of a germ. By provoking your immune system to build up defenses against it, it prepares you to respond rapidly if you encounter the same germ again. This works because the particular immune cells that are activated by a particular germ multiply and persist in the body for a long time, long after the germ has been eradicated, meaning they are ready for action if they encounter the same germ again. And with this, so it seems, one of humankind’s greatest medical triumphs can be explained in just a few lines.

But take one step deeper and it turns out that vaccination has a touch of alchemy about it. The ‘dirty little secret’ is that vaccines only work well when so called ‘adjuvants’ are added. Adjuvants (from the Latin word adiuvars meaning to help) are chemicals, such as aluminium hydroxide, which, as discovered by chance, half vaccines are effective. At one level it seems such a small thing – aluminium hydroxide somehow helps vaccines to be effective – but to Janeway this small technical tip revealed a crack in our basic understanding, because no one can actually explain why adjuvants did this. Understanding vaccination is unquestionably important – nothing apart from providing safe water, not even antibiotics, has ever saved more lives – and Janeway was determined to understand precisely why adjuvant was necessary. In doing so, he uncovered a whole new way of thinking about how the immune system really works.
The use of vaccination as a medical procedure long predates any scientific knowledge of how the process works. The first descriptions of vital life-savers can be found in folklore. Deliberate infections to provide protection – inoculations – were practiced in China, Indian and some African countries, long before any formal medical procedure was established. The scientific story begins however in 1721, when an epidemic of smallpox made the British royal family anxious, especially for the safety of their children. The royals had heard of rural traditions and stories from each other's countries how to inoculate against the disease, but details varied as to how, exactly, the procedure should be performed. Was an application of blister fluid best? Or were hand squeezed smallpox preferable? It was widely known that people only ever got small pox once, and so the real issue was whether or not a small dose of smallpox could be given to someone without it killing them. A test was needed to determine the safety and the efficacy of inoculation before it was used on the royal family – and prisoners seemed to be appropriate for the honour.
The first recorded ‘clinical trial’ in the history of immunity was performed on ‘volunteers’ who had been recruited on the bases that they could either participate in the potentially deadly trial or face the certain death of judicial execution. On 9th August 1721, incisions were made on the arms and legs of six convicts. Skin and pus from a smallpox patient were rubbed in. Another prisoner was given a sample of skin and pus up her nose – needless to say, to her great discomfort. Twenty-five members of the scientific elite witnessed the event, including fellows of the Royal Society (which had been granted its Royal charter in 1662 but still only had vague criteria membership). In accordance faculties and cultivated his passion for experimentation, but he never got to see how his protege blossomed. Hunter died in 1793, three years before Jenner discovered a way to circumvent the acute danger of inoculation while achieving the same effect.
As a country physician who spent most of his life in his small hometown of Berkeley, Gloucestershire, Janner was familiar with fact that milkmaids never get smallpox. His revelatory idea was that perhaps their exposure to cowpox – a mild viral infection that humans could catch cows – provided protection against smallpox, and the pus from non-fatal cowpox blisters might therefore be used for inoculation instead of pus from smallpox victims, which was far more dangerous. His now-legendary experiment was performed on 14th May, 1796. Jenner took pus from dairymaid Sarah Nelmes, who had been infected with cowpox from one of her cows, Blossom, an inoculated his gardner's eight-year old son, James Phipps, James was then given pus from a smallpox patient and he didn’t get ill.
This experiment is often said to mark birth immunology but at the time, Jenner had trouble just publishing his findings. The Royal Society said the observation was merely anecdoted – which it was – and suggested that Jenner should first test many more children before making such bold claims. Jenner did repeat the test on others, including his own eleven - month old son, but never so, he did not try to publish with the Royal Society again. Instead, Jenner self with folk wisdom, each prisoner became ill with symptoms of smallpox for a few days or two, and then recovered. The women inculcated nasally became especially ill, but recovered nonetheless. On 6th September,1721, King George I pardoned the convicted volunteers and they were released. Their immune systems had saved them from two death sentences. The gallows and the pox. 

A few months later on 17th April 1722, the Prince and The Princess of Wales – who in five years would become King George II and Queen Caroline – had two of their daughters inoculated. The event was covered by all the newspapers and lead to considerable interest in a reminder that high – profile leaders or celebrities have enormous influence on public attitudes to new scientific ideas.

Even so, the procedure remained controversial, in the part because, some claimed, the intervention went against nature or god- a London preacher spoke in 1722 on the dangerous and sinful practice of inoculation, for example but also because around 2% of people died after being deliberately inoculated with smallpovacjoiniater a twenty-year old man named Edward Janner began three year's training at St George's hospital, London, under John Hunter, one of the most prominent surgeons anatomists in England. Hunter helped Sharpon Jenner's critical published his work in a large print 75 page book. Initially available in just two London shops, the book was released on 17th September 1798 and became a huge success. The term 'vaccine' was coined a few years later by a friend of Jenny to describe the process he had discovered from the Latin word for cow, Vacca. Smallpox became the first disease fought on a global scale and was officially eradicated in 1980.

Jenner always believed that his work could lead to global annihilation of smallpox, but he never had a deep understanding of how vaccination worked. By the time of Janeway's epiphany in 1989, the consensus view was that the presence of a germ in the body triggers an immune reaction because the body is primed to detect molecules that it has not encountered before; in another word, that the immune system works by reacting against molecules that are non – self not from the body. After the exposure to the molecules alien to the body, the immune system is poised to react rapidly if the same nonself molecules are encountered again. But an experiment performed by different scientists working independently in the early 1920s (it is unclear precisely when) didn't fit this simple view of vaccination and this Janeway deeply.

This experiment was performed by French biologist Gaston Ramon and London physician Alexander Glenny. They discovered that a protein molecule made by bacteria which cause diphtheria – toxin – could be inactivated by heat and a small amount of the chemical formalin. Potentially this meant it might be used as a safe vaccine against the disease. To their surprise, however, when the inactivated protein molecule was injected into animals, the immunity it produced was only short-lived. The observation was seen as mildly curious at the time, and largely forgotten, but decades later Janeway reasoned that protein from the bacteria was non-self not part of the human body – and so, according to the consensus view of the 1980s there was no explanation for why it could not work well as a vaccine. How come the pus from cowpox blisters worked well as the vaccine. Janeway wondered whereas protein molecules such as diphtheria toxin, which had been isolated from germ, did not?

Glenny was a workaholic and though-extremely shy and not easy to get on with, he was skilled in organising his research, streamlining procedures so that he and his co-workers could perform huge numbers of experiment with great efficiency. He had no time for proper statistical analysis; results were either obvious and useful, or doubtful and valueless! This attitude go-getting, fast moving as an important factor in his lab's ability to screen on enormous number of experimental conditions, seeking a way to make diphtheria toxin work as a vaccine. Eventually in 1926, Glenny's team found that when diphtheria protein was purified by a chemical process that involved combining it with aluminium salts, it became an effective vaccine. Glenny's explanation was that the aluminium salts help the diphtheria toxin stain the body long enough for an aluminium reaction to develop, but no one knew of any process which can explain how are why this might be. After Glenny, other substances such as paraffin oil were discovered to help vaccines work in the same way that aluminium salt did, and they collectively they became known as adjuvants. But still there are no obvious common features that explain why they worked.

In January 1989, Janeway and his wife, fellow immunologist Kim Bottomly, were discussing what happens in the body when you got a cut or an infection. They realised that they could not easily explain how an immune response starts; what actually was the trigger? As Bottomly recalled, they often argued about scientific matters in the car and later forgot what had been said, but this time they were attending a conference in steamboat springs, Colorado, so they had their notebooks with them. The debate stuck with Janeway. For the next few months, he mulled over the problem – how does an immune reaction start? as well as the question work and it was by thinking about the two problems together he had a revelatory idea.

A important clue was that a chemical normally found in the outer coating of some bacteria (a large molecule with cumbersome name of lipopolysaccharide or LPS) had been shown to be an especially effective adjuvant. What if, Janeway reasoned, the presence of something that never have been in your body before was not the sole indication that an immune reaction should occur? What if there to be something else-a second signal-that's needed to kick off and immune reaction, a second signal that can be provided by an adjuvant which might in turn replicate the presence of actual germs? This might explain why protein molecules separated from their originating germ were ineffective as vaccines, but a molecules such as LPS, from the outer coating of bacteria, worked well as a adjuvant.

With great guts, Janeway first presented his idea in now famous paper "Approaching the asymptote? Evolution and revolution in immunology published in the proceedings of prestigious meeting at Cold Spring Harbour, New York, held in June 1989, has a slightly different shape, allowing it to interlock a different foreign molecule. It reaches out from the immune cells surface into its surroundings, and it connects with something that hasn't been in your body before,"it Starches on" the immune cell, which then kills the germ on infected cell directly or sermons the immune cell to help. Crucially, the activated immune cell also multiplies, populating your body with more cells that have the same use fully shaped receptor. Some of the cells stay in the body for a long time which is what gives the same immune system a memory for germs that have been encountered before which is of course, at the heart of how vaccination works.

Importantly, receptors on TT and B cells are not made of bird germs per se; these receptors have randomly shaped ends. Which allow them to lock into all kinds of molecules. The way in which the body ensures as they only latch onto germs in one of the greatest wonders of the immune system, and worked as follows. Each T cell or B cell acquires its receptor which developing in the bone marrow. A shuffling of genes as the cell develops gives each cell a uniquely shaped receptor. But before entering the bloodstream, each individual T cell and B cell is tested in case its receptor is able to bind to healthy cells. Iit is, then the particular T cell or B cell is killed off, because it would be dangerous to have such an immune cell in the body. In this way the T cells, only T cells or B cells that wouldn't attack healthy cells are allowed to depend the body, and by same logic, if a receptor on a T cell or B cell does bind to something that something must be a molecule that hasn't been in your body before. In formal language, this is how the immune system is able to distinguish cells, the components of your body, from non-self anything that is not a part of you. 

In it he suggested that everyone seemed to be studying the immune system as if the knowledge was approaching some sort of asymptote, where future experiments are obvious, technically difficult to perform, aim to achieve ever higher degrees of precision rather than revolutionary in our understanding. As a result, they had all missed something big :- the 'tremendous gap' in our understanding of how immune reactions start. He suggested that distinguishing between self and non-self was not enough, the immune system has to be able to tell when something is likely to be a treat to the body before an immune reaction takes place, and there for the immune system must, he reasoned, be able to detect tell tale signs of actual germ or infected cells. He predicted that there had to be a whole part of our immune system, yet to be identified, with this very purpose, and he even predicted a way it could work.

As we have seen and Janeway pointed out, nobody at this time paid much attention to how an immune reaction started and most (if not all) researchers focused on understanding another aspect to immunity, related to inoculation and vaccination; namely, how the immune system is able to respond two germs faster and more efficiently a second time around. It was known that at the heart of this process are two types of white blood cells called T cells and B cells. This white blood cells have an especially important receptor molecule at their surface, not so imaginatively called the T cell receptor and the B cell receptor. These receptors come from the class of biological molecules known as proteins, which are long strings of atoms that fold up into elaborate shapes well adapted for a specific task in the body. In general, proteins bind or join with other molecules, including other proteins, to complete their tasks, and the precise shape of the protein detects which types of other molecules it is able to connect with, in the same way that two jigsaw pieces interlock by having complementary shapes. The receptors on each individual T cell or B cell what Janeway predicted was that this is not the whole story. Specially, he predicted there must be receptors (which he called pattern – recognition receptors) that are not randomly generated and then selected, but rather have fixed shapes that interlock specially with germs or infected cell (or rather with molecule patterns that are found only on germs or infected cells). Because this appeared a much simpler way for immune cells to detect germs compared with the elaborate process of making immune cells with randomly shaped receptors and then killing off those which might react against healthy cells, Janeway suggested that receptors with fixed shapes probably evolved first to defend against disease, an only letter, when life on earth became more complex, did a more elaborate immune system develop, which include T cell and B cell.

The simpler system of fixed pattern – recognition receptors that Janeway predicted form of the system called innate immunity, by the contrast with the aspect of our immune defence that accounts for its memory of past infections, which called adaptive immunity. The term 'innate immunity' was already used before Janeway – to describe early – defence mechanism provided by Shēn, mucus and the immediate actions of immune cells move into cut or wound – but the subject was given only a few pages in text books, including best selling one written by Janeway himself. What made Janeway's ideas revolutionary was that he essentially changed the immune system's mission statement. Before, Janeway, the raison de'etre of immune system was to react against things that have never been in your body before. But Janeway said ki said that the immune system must respond to things that have not been in your body before – and are from germs.

In hindsight it is blatantly necessary that immune system has to do more than merely react to things that have never been in your body before. Things such as food, harmless gut bacteria or dust from the air – all not part of the human body – pass no danger and should not trigger an immune reaction. George Bernard Shaw put it in 1930 sciences never solve one problem without raising ten more problems. Leaving aside the biggest problem Janeway's Idea faced, which was lack of experimental evidence to support them, there was a theoretical problem too, germs increase in number rapidly. Just how fast germs multiply is mind boggling. One virus infected-human cell can produce hundred new virus particles. This means that just three copies of a virus going through four rounds of replication – taking a few days or so leads to 300 billion new virus particles. It is not just viruses that behave like this, bacteria divide every twenty minutes in optimal conditions, which means one bacterium can produce 5 billion trillion (5 × 10²¹) bacteria in a single day – something like the number of stars in the universe. In practice, germs can't multiply to such an extent with the human body because this level of growth requires an unlimited amount of resources, but even so, germs reach enormous numbers fast, for quicker than our mealy average of about two offsprings per couple's life time. This leads to a crucial problem with Janeway's Idea; each time a germ reproduces, it acquires random changes in its genes – mutation – and through these changes it seems likely if not inevitable that some will lose the molecular signature detected by the immune system. In other words – in the whole population of viruses or bacteria, some of them will by chance – because there are so many – have acquired a genetic change which alters the parts of the germ which the pattern recognition receptor was designed to lock onto. Microbes lacking the 'molecular pattern' would escape detection by the immune system and multiply readily.

Janeway realised this and he predicted that the pattern recognised should be the product of a complex and critical (process) in the microorganism. In other words, the tell tale structure of a germ would have to be something so critical to its life cycle that it would be exceptionally difficult, if not impossible, for the germ to alter it. Janeway had evidence that germs survival and also vulnerable to attack because a feature such as this what allows penicillin to work. every time one bacterium divides, it needs to build a cell wall or envelope or encap – sulate its two daughter cells. Importantly, the process is so complex that bacteria cannot easily change it. Penicillin works by interfering with the last stage of the process. As a result there is not any simple genetic mutation that would allow bacteria to escape penicillin's affects. True, bacteria can become resistant to the antibiotic by making their cell walls with a very different process, but it is not easy, penicillin remain effective against a huge number of microbes : it locks onto bacterial protein molecules involved in an essential and complicated process.

One scientist recalls that when Janeway presented his paper the audience was 'intrigued but not convicted'. Another recalls that the 'community was not ready for Charlie's thinking. Standing before any of the world's greatest immunologist, Janeway had the confidence to claim that everyone had missed a hugely important part of how the immune system works, even though, as he put it himself, experimental verification – is not available. Quite simply, at the time, nobody could say if Janeway's idea were revolutionary or fanciful bunkum.

Janeway's paper was all but forgotten hardly referred to in an other scientific paper for the next seven years. But it touched one person – 4,500 – miles away – who would, against all the odds, bring Janeway's idea out of obscurity. In autumn 1992, a student in Moscow University, Russia, Medzhitov read Janeway's paper and it changed his life.

Biswajit Ghose

Biswajit Ghose

Guest Writer

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