CHAPTER 15

Will we stop all diseases?

THE FACEBOOK FOUNDER Mark Zuckerberg recently set up a foundation whose explicit aim is to find cures for all diseases by 2100¹. Will this ambition ever be realised? Why do we get sick? Diseases have always plagued humankind. A disease is defined as a condition that impairs normal functioning and is typically manifested by distinguishing signs and symptoms. They stop us from leading full lives. They are very unequal in their distribution. Some of us get sick, some of us don’t. This can be because we carry variants of genes that make us sick. Or it can be because our lifestyle makes us sick. Or perhaps it’s a combination of both, which is often the case. Some people get sick because of poverty, or just because of bad luck.

Medicine provides us with wonderful treatments for many of the things that ail us, but many diseases are still hard to treat. We all know about the huge effort going on to find new treatments and we often read about ‘breakthroughs’. But what do the prospects look like? Well, the signs are good. We now know more than ever about what goes wrong in the body when we become sick, in some cases right down to the molecules in our bodies that are causing mischief. The goal now is to stop it going wrong or correct it when it does.

The big killer before the discovery of antibiotics was infectious diseases. One idea is that once we stopped being nomadic, and began living in close proximity, infections were more likely to spread among us. This might especially have been the case when we began living with our domesticated animals, as then their germs could spread to us (or vice versa), causing sickness². The symptoms of infectious diseases are often triggered to allow the infectious agent, be it bacterial or viral, to spread. This is one reason why you cough and splutter when you have a cold. The virus makes you sneeze so that it can jump into someone else and breed there.

EDWARD JENNER (1749–1823) PERFORMING THE FIRST VACCINE ON JAMES PHIPPS TO PROTECT HIM FROM SMALLPOX.

Three big breakthroughs limited the devastating effects of infectious diseases: clean water³, vaccines⁴ and antibiotics⁵. In the 19th century, engineers began to devise ways to provide clean water, including filtration methods. Edward Jenner gets the credit for discovering vaccination, when he noticed that milkmaids rarely got smallpox. He figured out (or more likely was told by a farmer neighbour called Benjamin Jesty) that this was because they already had the milder disease of cowpox⁶. This led Jenner to test cowpox on a young boy called James Phipps.

This was the scientific method in action: devise a hypothesis (in this case, that cowpox could protect against smallpox) then test the hypothesis (give someone cowpox and then smallpox and see if they are protected). He gave the boy cowpox and then tried to infect him with smallpox and hey presto he was protected. What had happened was that the boy’s immune system had reacted to cowpox but had caused only a mild disease. Cowpox and smallpox viruses share many features, so when the boy was given smallpox, his immune system had been trained to recognise smallpox, and dealt with it effectively. It was something like a war, where the first encounter with the enemy is a bunch of old guys who are quickly eliminated. Then when the younger, fitter troops arrive in the same uniform they are recognised quickly and eliminated. This was a great advance, as smallpox was an often lethal virus that terrified everyone. Following on from Jenner, many other vaccines were developed using weakened versions of the pathogen you want to prevent, early examples being diphtheria and rabies. We now have vaccines for many diseases.

ALEXANDER FLEMING (1881–1955) WHO DISCOVERED PENICILLIN, ULTIMATELY SAVING HUNDREDS OF MILLIONS OF LIVES.

Antibiotics, on the other hand, kill bacteria on contact. Penicillin was the first of these to be characterised. It was discovered serendipitously (meaning he got lucky) by Alexander Fleming⁷. He noticed that a mould growing on a petri dish with a lawn of bacteria, killed the bacteria. The mould had actually come from a lab near the Fleming lab that was run by an Irish doctor called Charles La Touche. La Touche had been collecting cobwebs in the East End of London to explore if they caused asthma attacks. The cobwebs had captured the fungus penicillium, which makes penicillin to protect itself from bacteria. It was this that somehow blew out of La Touche’s lab and into Fleming’s, killing the bacteria. Fleming called it ‘mould juice’. Antibiotics now save millions of lives every year, although there is a fear that bacteria will evolve a way around them.

We’re also getting better at coming up with ways to beat viral infections, although some viruses remain a problem. Vaccines have been found for viruses such as those causing polio, but not against HIV, the virus that causes AIDS, nor for the virus that causes the liver disease hepatitis C. For these two viral diseases, though, there are drugs that target the virus itself, in a similar way to antibiotics targeting bacteria directly.

The fight against AIDS has been a particularly successful one. People with AIDS can now expect to live as long as people without it, which is a remarkable success given that it was a death sentence as recently as 20 years ago. HIV is a very cunning virus, as it infects T lymphocytes. These are the foot soldiers of our immune system, making HIV the enemy within. It eventually kills the T lymphocyte as it jumps from cell to cell. This is what causes the immunodeficiency, which in turn leads to all kinds of infections that will eventually kill the patient. Many die from severe pneumonia.

In 2016, 36.7 million people were estimated to have HIV, and 1 million people died. It probably began infecting humans when it jumped into a human from an ape or monkey (who don’t get sick with HIV – they evolved to live with it). The AIDS epidemic in the US officially began on 5 June 1981, when the US Center for Disease Control reported an unusually high incidence of a fungus called Pneumocystis jiroveci in gay men. This was normally only seen in transplant patients who were immunosuppressed. The hunt was then on for what caused it, and in 1983 scientists at the Pasteur Institute in Paris identified HIV as the causative agent. Drug companies then began developing agents to stop the virus dividing, and this led to the discovery of antiretroviral therapies. HIV is a retrovirus – so-called because it has RNA instead of DNA in its genetic material, which is turned into DNA when inside the host T lymphocyte. In our own cells, DNA is turned into RNA.

The first drugs to be developed target the HIV enzyme that performs this reverse transcription – an enzyme called ‘reverse transcriptase’. Three different reverse transcriptase inhibitors in a cocktail are especially effective. A recent study of 88,500 people with HIV from Europe and North America in 18 separate studies has shown that the projected age of death for a 20-year-old with HIV on antiretroviral therapy is now 78 years, which is similar to the general population⁸. This is a tremendous achievement with a disease that has killed so many.

And because of clean water, vaccines and antibiotics, we are now surviving a lot longer than we used to. Vaccines and antibiotics are widely considered the most important of all medical advances because of the numbers of lives they save. We might therefore survive infectious diseases, but we are at risk of many other diseases. Some estimates put the total number of diseases that afflict humanity at around 7,000. Many of these are rare. Some are caused by a genetic abnormality which can either arise spontaneously, or be passed from a parent to a child. An example is cystic fibrosis, where a gene for a protein in the lungs called CFTR is mutated. The job of CFTR is to regulate salt in the lungs. If it’s broken the salt builds up, and this damages the lungs. This in turn promotes infections which cause a lot of the problems in cystic fibrosis.

But the big killers now are heart disease and cancer. The major form of heart disease, which is called atherosclerosis (meaning clogging of the arteries, which ultimately become blocked and stop blood flow to the heart in a heart attack), is caused by a number of risk factors, including smoking, stress and high levels of cholesterol. Cholesterol clogs arteries, causing the heart to stop because blood can’t flow. Cholesterol-lowering drugs like statins are a major advance, as they lower cholesterol and so stop the clogging.

Cancer is caused by mutations in genes, but this time the mutations can be caused by environmental factors, like smoking or UV irradiation from the sun. A chemical reaction occurs, between noxious chemicals in cigarette smoke or by UV light in sun, and DNA. This alters the DNA such that the recipe for the protein to be made is altered. The new protein then causes cancer, by for example causing cells to grow out of control and form a tumour. The genes are usually for proteins that cause cell growth, and the mutant forms go out of control. Others are for proteins whose job it is to suppress tumours from growing (so-called tumour suppressor genes) and when they mutate, the tumour will grow. The tumour cells will spread in a process caused ‘metastasis’. It is often where they lodge and grow (for example in the brain) that kills you.

Therapies to treat cancer involve poisons to kill the cancer cells (called chemotherapy), X-rays to burn it out or surgery to remove it. Doctors have increasingly been winning the war on cancer⁹. Today, 60 per cent of cancers are cured. Five-year survival rates of invasive cancers (the ones that really attack our bodies) have gone up from 45 per cent for patients diagnosed between 1994 and 1999 to 59 per cent for those diagnosed between 2006 and 2011. Currently, 81 per cent survive breast cancer and 91 per cent survive prostate cancer. This is because of earlier diagnosis. The sooner you can start treating cancer the better, as otherwise you are closing the stable door after the horse has bolted. But one breakthrough that is being hailed is that scientists have realised that in some situations your own immune system can kill the cancer cell¹⁰. It can recognise the mutated proteins in the cancer cell as foreign.

The job of the immune system it is to distinguish friend from foe, and a cancer cell is only sometimes seen as a foe. The problem is that cancer is cunning, sometimes called ‘The Emperor of Maladies’. It has ways to switch off the immune attack against it. An important immune off-switch, also called a ‘checkpoint’, is PD1. The level of this protein increases on the tumour and then engages with a protein called PDL1 on immune cells, which are hitting off the tumour cells and trying to kill it. Once PDL1 is engaged by PD1, however, the immune cell is deactivated. It’s somewhat like PD1 acting as a finger to flip the PDL1 switch, turning off all the lights in the immune cell. This led scientists to test checkpoint blockers, actually antibodies designed to stop the PD1 finger from touching the PDL1 off-switch, and so letting the immune cell do its job and kill the tumour cell. These new drugs have seen success where previously there was no treatment that would extend life, notably in the big killers of lung cancer and melanoma.

THE EBERS PAPYRUS, AN EGYPTIAN MEDICAL PAPYRUS DATING FROM 1550 BC. IT DESCRIBES THE USE OF MARIJUANA AS A TREATMENT FOR EYE INFLAMMATION AND HAEMORRHOIDS.

In melanoma the average survival time is around one year, but for some of those on anti-PD1 this has gone up to three years and counting. Some become disease-free. The prospect therefore of coming up with treatments for cancer that might actually cure the disease or at least slow it down is now a real prospect. PD1 is a brand new target which was gone after by scientists and has yielded a brand new medicine.

So we now have a reasonable idea of what causes the two big killers of heart disease and cancer. But there are many other diseases which afflict us for which there is no known cause. The next biggest group are the inflammatory diseases, which include diseases like rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. We also classify neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease as inflammatory, since in those diseases there is an inflammatory reaction in the brain to proteins being wrongly deposited there. In the case of Alzheimer’s disease, two proteins, called beta-amyloid and tau, build up for some unknown reason. In the case of Parkinson’s disease, a protein called alpha-synuclein builds up, again for an unknown reason.

What we do know is the immune system goes rogue in these inflammatory diseases, and starts to attack our own tissues. There are various anti-inflammatory medicines that can be used. Several of these originated in plants, as our ancient ancestors noticed that certain plant extracts could limit inflammation. Nearly all early medicines were derived from plants. Other primates had also noticed the beneficial effects of certain plants. When they have a worm infestation chimpanzees will eat certain plants, such as the Aspilia mossambicensis, which helps expel the worm¹¹.

Inflammation has always been easy to see. It meant you had an infection or an injury. The affected area becomes hot to touch, swollen, painful and red. So the ancients could see it and could rub in a plant or eat it to treat it. The first medicine that we know of ever to be depicted was a hieroglyph on the Ebers Papyrus (1550 BC)¹². It was an anti-inflammatory plant that was used to treat eye inflammation and haemorrhoids in Ancient Egypt. And what was that plant? Marijuana. This is now known to have cannabinoids, active ingredients that suppress inflammation.

The first drug to be actually synthesised in a lab was aspirin, a derivative of salicylates which had been isolated from willow bark and had known anti-inflammatory properties. This was done by the German drug company Bayer, who at the same time made a derivative from morphine which they called heroin, because it made people feel like heroes. Bayer sold heroin for a number of years as a cough remedy, until they noticed that heroin had some rather perturbing other effects.

The main diseases of ageing are actually inflammatory diseases. In many ways, we caused these diseases, because humans who would otherwise be dead from infections now age. Being old looks like a disease: our eyes and ears don’t work well, we have aches and pains, and we mightn’t be able to lead as full a life as we used to. We don’t know what causes these inflammatory diseases of ageing, other than to say that the inflammatory process goes out of kilter and starts to damage our tissues as we age. The pain, redness and swelling happen in whichever tissue might be affected – our joints in the case of arthritis, our digestive system in the case of inflammatory bowel disease and our central nervous system in the case of multiple sclerosis.

There have been advances in treatment, with new targets being found that are then turned off. A good example is a protein called TNF, which is made in inflamed tissues and promotes further inflammation and destruction. Drugs that target it are effective in diseases such as rheumatoid arthritis and Crohn’s disease. These are very high-tech drugs, as they themselves are proteins (in the form of antibodies) that are engineered to act as sponges to mop up the TNF. This slows down disease progression and makes a big difference to patients, although the drugs do not cure them. For a cure we need to find out the underlying cause, which is likely to be a mix of genetic differences and environmental influence, perhaps even a virus yet to be discovered.

THE GERMAN PHARMACEUTICAL COMPANY BAYER MADE THE FIRST EVER SYNTHETIC MEDICINE, ASPIRIN. THEY ALSO MADE HEROIN AS A COUGH REMEDY WHICH WAS LATER WITHDRAWN BECAUSE OF ITS HIGHLY ADDICTIVE PROPERTIES.

As our population ages, we will see more and more Alzheimer’s disease and Parkinson’s disease. Alzheimer’s disease is an irreversible brain disease that slowly destroys memory and thinking skills. Symptoms usually begin to appear after the age of 60. It is named after Dr Alois Alzheimer, who examined the brain of a patient of his who had dementia and noticed clumps (now called amyloid plaques) and bundles of fibres in the hippocampus, the part of the brain most involved in memory. These clumps and fibres kill the nerve cells in the hippocampus, hence the memory loss.

A MACROPHAGE ENGULFING BACTERIA. THESE CELLS DEFEND US BUT CAN ALSO DO MISCHIEF IN INFLAMMATORY DISEASES.

Again it seems to involve the immune system, as immune cells try to clear these clumps, causing inflammation as a kind of collateral damage, killing the neurons in the process. Scientists have searched for genes that might be different in patients with Alzheimer’s disease, and one called APOE-epsilon stands out. Carrying that gene increases the risk of the disease developing, and a recent study has shown that having this gene variant promotes the formation of the clumps and tangles. This might give rise to new drugs to target APOE-epsilon. Drugs that target the clumps and tangles themselves are also in development, although with only limited success so far.

Parkinson’s disease is similar to Alzheimer’s disease, but in this case the clumps are made of the protein alpha-synuclein. This is getting deposited in another part of the brain, called the substantia nigra. This part is involved in the control of movement, and so as the neurons die there movement is affected. Speech is also damaged, as the correct movements to form words are diminished. Treatment for Parkinson’s is limited, and mainly involves trying to replace the neurotransmitter dopamine, which is made in the substantia nigra.

STEM CELLS HAVE HUGE POTENTIAL AS THEY MIGHT ONE DAY BE USED TO GROW DAMAGED ORGANS OR ORGANS THAT HAVE BECOME WORN OUT BECAUSE OF AGE.

But again there is good evidence that immune cell over-activation might be important, and so targeting the immune system and inflammatory process might give rise to therapeutics for Alzheimer’s (for which current therapies are very limited) and Parkinson’s disease. There is in fact a theme emerging of many inflammatory conditions, where an immune cell called the macrophage tries to clear the gunk that is being deposited as we age. The macrophage then gets very irritated and causes inflammation. Other examples include gout, which involves crystals of uric acid being deposited, atherosclerosis (the deposition of cholesterol crystals in the arterial wall) and type 2 diabetes (which involves a protein called IAPP being deposited). The macrophage tries to chew these things up, but a protein called NLRP3 senses them, and this triggers inflammation. Drugs that block NLRP3 are in development by a company I co-founded called Inflazome, along with other companies, and may prove useful in a whole host of diseases. NLRP3 was discovered by scientists interested in macrophages and the inflammatory process, and could turn out to be a very important discovery.

GERTRUDE ELION, WHO WON THE NOBEL PRIZE WITH GEORGE HITCHENS IN 1988 FOR THE DISCOVERY OF MEDICINES FOR GOUT, MALARIA AND HERPES.

So what does the future hold? Medical research is a multibillion-euro activity going on all over the world. It’s being carried out in universities, research institutes and pharmaceutical companies by scientists who are trying to make a difference. A real hero is Gertrude Elion. She shared the Nobel Prize in Physiology or Medicine in 1988 for discovering new medicines for diseases such as gout, malaria and herpes. She has said: ‘When we began to see the results of our efforts in the form of new drugs which filled real medical needs and benefitted patients, our feeling of reward was immeasurable.’¹³ The world spends more that $240 billion every year on biomedical research. This, however, is inclined to be skewed towards the diseases that afflict the Western world, such as heart disease and cancer, with infectious diseases such as malaria and TB (which have high mortality) being more neglected. This is partly commercial: pharmaceutical companies want to make profits, and these are driven by diseases that afflict more affluent countries. Sometimes a pharmaceutical company will give up on some diseases because they are deemed too difficult to crack, as happened recently with Pfizer announcing that they were halting internal work on diseases of the brain such as Alzheimer’s disease.

Medical research begins with efforts to understand how living systems actually work, and from there moves on to figure out what happens when they are broken. The Medical Research Council in the UK funded the work that led to the discovery that DNA was a double helix which contained the information to make proteins. Changes in this information are the basis for genetic diseases. Genes could also be engineered to make important medicines like insulin for diabetes, so the Medical Research Council’s money was very well spent. In general, scientists try to find a target to fire drugs at to treat diseases.

Many new medicines are in development, and there is great optimism. All that fundamental research is yielding new insights which will give rise to new medicines. We might have a situation where in the future, the main diseases that currently afflict us will be either prevented, slowed or cured. What might we then die of? Boredom? Will new diseases emerge or old ones come back to haunt us? We don’t know. The recent emergence of the Ebola virus, which can now be vaccinated against, was a lesson in not being complacent. We must also be watchful for bacteria becoming resistant to antibiotics, returning us to the days of infectious diseases killing us by the millions – a frightening prospect.

We also have several brave new things to consider. One especially exciting area is technology to correct defective genes. This is a system that was originally described in bacteria, which chops up and manipulates foreign DNA in viruses. It is a key part of the bacterial immune system which fights viruses by targeting the virus’s DNA. Scientists (notably Jennifer Doudna, Emanuelle Charpentier and Feng Zhang) then realised that this same machinery could be used to target any DNA, and even fix broken DNA as occurs in mutated genes. The technology is called CRISPR, and many labs are now testing it in different contexts¹⁴. It’s been possible to correct a mutated gene that causes heart disease¹⁵. This correction was performed in a human fertilised egg, which means that if that egg were allowed to develop, the resulting human would now not get that particular form of heart disease. This holds great promise, as it might be possible to correct broken genes for many diseases, including diseases that cause blindness or muscle atrophy, and in fact a whole host of genetic diseases.

COMPANIES ARE OFFERING TO TAKE STEM CELLS FROM YOUR BONE MARROW, STORE THEM, AND THEN USE THEM IN YEARS TO COME TO BUILD A NEW YOU.

Stem cell research is another prominent area causing much excitement. We know that the fertilised egg contains all the information to make all the organs in your body. A Japanese scientist named Shinya Yamanaka found that putting in genes for four proteins, Oct3/4, Klf4, Sox2 and c-Myc, would reprogramme the cell and make it into what effectively is a fertilised egg¹⁶. This is called the ‘OKSM protocol’, which perhaps should stand for ‘OK, So Make Me!’

These genes somehow wind the tape back for that cell (say a skin cell), and it effectively turns back into the fertilised egg. Remember, all the cells in our bodies have all the DNA you need to make a full human, since they are descended from that fertilised egg whose DNA just kept on getting copied. What makes each specialised cell type different is that some genes can be turned on and others off. So a skin cell makes proteins that say ‘I’m a skin cell’ and a liver cell makes proteins that say ‘I’m a liver cell’. But if you put in OKSM, the skin cells revert back to being an undifferentiated stem cell. Almost back to the egg. It might then be possible to grow for yourself new nervous tissue that will repair a broken spinal cord, or a new kidney if yours have become damaged.

Companies are offering to take stem cells from your bone marrow, store them, and then use them in years to come to build a new you. A bit like replacing a part in a car engine, maybe we will be able to replace the parts that break or become old. Maybe we can defy ageing and live for ever. An important question though, is, How will we pay for all these new medicines? They are, and will be, expensive. The anti-cancer medicines that wake up our immune systems are currently costing up to €100,000 per patient per year in Ireland. Who will pay? Will governments cover the cost? Will we have a situation of inequality, where only the rich will be able to afford treatments, with the poor getting sick as they have always done? This is the case to some extent currently, especially with infectious diseases in Africa, which are treatable now, but where people can’t get access to the medicines they so badly need.

Maybe the thing to do is to keep reminding people that, for most of us, there are three things needed to prevent diseases starting in the first place. We know that good diet, exercise and sleep will help ward off many of the diseases mentioned above. If we can correct the genes that might put us at risk of these, then the diseases may never start in the first place. Perhaps we should all follow what Jonathan Swift, the writer of Gulliver’s Travels, wrote: the three best doctors are Dr Diet, Dr Quiet and Dr Merryman. Maybe laughter is the best medicine after all.