Meet the Drug Hunters: the scientists determined to cure rare diseases

Andy Martin explores the world of the resolute few who persistently pursue the cure for conditions which even doctors and pharmaceutical companies have given up on

Tim Guilliams (left) and David Brown, co-founders of Cambridge-based biotechnology company Healx (Onur Pinar Photography)

David Brown was running out of time and money. Having started his career at ICI Pharmaceuticals, he had been recruited as the head of the chemistry department for Pfizer and the drug he had come up with to treat angina (or coronary hypertension) was in clinical trials. The trials weren’t going well.

“Sildenafil citrate” (as they called it) had shown some signs of efficacy, but not enough. It was barely distinguishable from a placebo effect. The study in Aberystwyth, in the summer of 1993, was his last shot. After the closure of their coal mine, the local miners were willing to have a go at anything that paid, such as volunteering for drugs trials. They would come in one day, take their pills and stay overnight. Then the following day they had to fill out a questionnaire followed by an interview with the research associate, when she asked that crucial question: “Any other unusual effects to report?” Once one guy mentioned the erections everybody else chimed in. They’d all had them.

For Brown, a self-professed “drug hunter”, it was a eureka moment. Angina is the result of a restricted blood flow to the heart. Brown had been thinking about “vascular relaxation” and how to get more blood pumping through certain parts of the body. He had an “intuition” that he had found the solution – at least where other parts were concerned. When he heard about the result he chewed it over with his team, then rushed into the medical director’s office with his new idea but was promptly given the brush-off. They were out of time. The trials were obviously a failure. His budget was too tight. The director was calling it a day. A full eight years of hard work down the drain. Brown went to the door, pushed it shut, turned back to the director, and uttered a sentence that would not be out of place in a Tarantino movie: “I’m not leaving this office till you give me the money.”

“Most people would have given up,” he says when I went to see him last week at the Healx offices in Cambridge. He is now 69, has tried to retire twice, but has been drawn back again into drug hunting. “Sometimes you have to stick to your guns. I trusted my intuition.” After an hour of persuasion and stressing the huge potential market, he got a green light for new clinical trials, specifically aimed at male impotence or erectile dysfunction. After initial tests in Bristol, involving blue movies and a “rigiscan” (designed by Dr Mike Allen), the men were allowed to take the pills home for one week only. They were supposed to give back unused portions of the drug, but one patient sent Brown a letter instead. “I am sorry that I have not returned the tablets,” he wrote, “but this is the first time in 25 years that my wife and I have had a good sex life.” The drug would become known under the brand name, Viagra, which has a strong claim to being the most famous drug of all time. Total sales for Viagra since that summer’s day in Aberystwyth amount to more than $35bn (£26.6bn).

We sometimes use the word “serendipity” to describe this kind of scientific breakthrough, a happy result seemingly achieved through blind chance. But Brown doesn’t like to use that word. It wasn’t chance. What they were doing and what Healx is doing now in a much more systematic, data-driven way, is “repurposing”. You take a drug that is being used to treat one condition and you redirect it towards another one. Repurposing promises to come up with new treatments for hitherto untreatable and often fatal rare diseases.

The phrase “rare disease” is, in a way, radically misleading. Taken as a whole, rare diseases are not rare. There are approximately 7,000 of them. Around the world right now, an estimated 350 million people are suffering from a rare disease. One in every 17 people has a rare disease. And 95 per cent of them lack any kind of treatment. What will typically happen if you or your child has such a disease is you will walk into a doctor’s surgery, and you will assume the doctor can finally come up with the correct diagnosis. Then she will turn to you and say, “There is nothing we or medical science can do for you. You’re on your own. Sorry.” You and your child are basically stuffed. Three hundred and fifty million of you and all medical science is saying to you is, Tough!

There is a ruthless logic behind this seeming indifference. There are just not enough of you and your fellow sufferers with this or that disease to justify the investment that would be required to find the medicine that would cure you. I spoke to two men, one in the US, one in the UK, both fathers of children with rare diseases, who have both been through parental hell.

Michael Tranfaglia had not heard of “Fragile X” before until his first son, Andy, was born 29 years ago (his daughter, aged 27, also has the mutation, but is not affected by it). Tranfaglia was a psychiatrist and pharmacologist in Boston, Massachusetts, but has trained himself up to be a specialist in Fragile X, so-called because of a damaged X-chromosome. “Looking through an ordinary light microscope, you can actually see the bent or broken tip on the chromosome,” Tranfaglia says. The disease wasn’t identified until 1969 and it is estimated to affect one and a half million people worldwide. It produces autism with effects on intellectual development.

Tranfaglia and his wife took Andy to see a number of paediatric neurologists when they noticed he was “not hitting any of his milestones”. There was no history of the condition in their family so it took a long while before the diagnosis came back. Since then the Tranfaglias have co-founded FRAXA, dedicated to funding and furthering research into the condition. Two big companies, Roche and Novartis, both tried and failed to come up with answers. “We spent $25m and we still don’t have a blockbuster,” Tranfaglia says.

The underlying financial reality is that a lot of huge pharmaceutical companies are in jeopardy because the old business model no longer works

“Black Bone disease” causes spinal collapse around the age of 30. There are only 80 sufferers in this country, perhaps as many as half a million around the world, and both Nick Sireau’s two sons – Julien, 18, and Daniel, 15 – have the condition. The first doctor to see his first child suggested that he had been having too much red cabbage. Subsequent doctors told him there was nothing to be done. He was told, “Don’t go home and search for it on the internet – you won’t like it.” Sireau, who lives in Cambridge and has no scientific background, ignored the advice and has since dedicated himself full-time to fund-raising and research into Black Bone disease.

“Alkaptonuria” (to give its technical name), or AKU, was initially identified by Sir Archibald Garrod in 1902 and it was the first disease to be clinically proven to be hereditary (it conforms to the Mendelian theory of recessive gene inheritance). One sufferer said it was like wearing chainmail “on the inside”. It was Sireau himself who came up with the name Black Bone, largely because when he tried to set up an account at NatWest with the name “Alkaptonuria” they prohibited it on the grounds that it sounded too much like Al-Qaeda. Sireau explained that on account of a defective enzyme, victims of the disease accumulate surplus homogentisic acid (HGA), which ultimately produces “ochronosis”, a black pigmentation of the bones (and shows up as black spots in the eyes). Following recent research, Sireau was able to zero in on an ingredient in an ICI weedkiller, “nitisinone”, that has been shown to break down HGA, and talk the company that owns it into letting him test it out. “But,” as he says, “no one is going to fund a study that will take 20 years.” The Medical Research Council, for example, rejected Sireau’s application. The EU, however, has been more sympathetic and he is currently sifting test results.

We love to hate pharmaceutical companies. The phrase “Big Pharma” implies that there are a few fat cat corporations making a fortune out of ill health and screwing the NHS and other similar institutions around the world while they are at it. While not entirely justified, this broad brush picture leaves out a lot of crucial details. The underlying financial reality is that a lot of huge pharmaceutical companies are in jeopardy because the old business model no longer works.

New drugs, if they work, are actually the exception (Getty/iStock) (Getty Images/iStockphoto)

Here is the reason that big pharma charges a billion or two for every new “wonder drug”: most of the time, science fails. We tend to remember the successes; we conveniently forget – infinitely more numerous – the failures. New drugs, if they work, are actually the exception. The reality is that nearly all scientists working within the pharmaceutical industry waste years, sometimes entire careers, testing out new drugs that end up in the bin. Brown says this is true nine out of 10 times. The failure rate is huge.

And then, on the tenth time (if you’re lucky), you come up with one that works. It has cost the drug company typically £200m to produce when you add it all up. Is that the cost to the health service? No: they get charged more like ten times that, £2bn or more, to cover the costs of the other nine drugs that went nowhere. We are mainly paying for failure.

The classic scientific approach to devising new medicines is, paradoxically enough, designed to fail. Broadly, it corresponds to the “conjecture and refutation” model that the philosopher Karl Popper set out in the decades after the Second World War. He insisted that any scientific proposition worth its salt had to be “falsifiable”, that is, you had to be able to prove, in principle, that it might be wrong. It had to be possible to assemble evidence that could either verify your original hypothesis or invalidate it. On this basis, Popper denounced the whole of psychoanalysis and Marxism as unscientific, a form of quasi-religious dogma, because they simply did not allow for any evidence that could negate their fundamental assumptions.

DNA is like the master copy of a movie in the vault. But if you want to show the movie in the local theatre you have to copy it, which is when it gets translated into protein

Michael Tranfaglia

Traditionally, pharmaceutical science begins by targeting a specific condition. It comes up with theories of causation, the core pathology behind the symptoms. Next, it identifies a drug that might, theoretically, impact on the cause. After that you have the trials, which take years, on animals, and finally on humans. The whole process is immensely slow, laborious, expensive, and rarely comes to fruition. This is the so-called “target-based” approach, because it relies on making an accurate guess upfront on how to target a disease.

But, you might well ask, what about gene replacement therapy? Isn’t that going to fix everything once and for all? Short answer: no. Back in the 1990s and the early 2000s, when science was finally mapping out the human genome, there was a utopian idea that once the map was complete, all you would have to do is take out the old broken gene (rather in the way that you can take out, say, worn-out plugs in a car engine) and stick in a new sound one to take its place, and hey presto, problem solved. But it hasn’t worked out like that. Results have been disappointing. As Brown says, “human biology is so complicated”. “Gene expression” means that a single faulty gene carves out a labyrinthine pathway through the body. And it is the whole pathway that needs to be fixed. DNA gets transcribed into RNA – messenger molecules – which produces a much more complex “transcriptome”.

Gene replacement therapy cannot easily fix a disease caused by a faulty gene, for as David Brown points out, ‘human biology is so complicated’ (Getty/iStock) (iStockphoto)

Having studied the way Fragile X works for more than two decades, Michael Tranfaglia says: “DNA is like the master copy of a movie in the vault. But if you want to show the movie in the local theatre you have to copy it, which is when it gets translated into protein.”

A hopeful parent once asked him: “Does that mean we should be feeding them peanut butter? Tranfaglia replied: “If only it was that easy.” In the case of Fragile X, for example, only a single protein is missing, but that protein regulates a hundred or a thousand other genes. Discovering a genetic mutation doesn’t in itself lead to any new treatment.

But now there is an alternative, a new way of doing medicine. Brown and Tim Guilliams, who co-founded Healx in 2014, call it “Biotech 2.0”. The old way is good science but bad business. And therefore very bad for sufferers. Biotech 2.0 is the core of what Healx does.

Guilliams, 35, has a PhD in biophysical neuroscience from Cambridge, but went on to specialise in the use of AI for drug discovery. He set up the Cambridge Rare Disease Network to connect the millions of sufferers who have no approved treatment. “A large part of what we do is to work with patient groups,” he says. “They are an inspiration, but also a valuable source of data. We realised that they are the experts in the disease. They are the most committed and motivated.”

This is where the paths of Nick Sireau, Michael Tranfaglia and Healx have intersected. The old-style pharmaceutical industry is just not interested in people like Tranfaglia and Sireau and their rare diseases. They can’t afford to be. But Brown and Guilliams are. Their new science and business model fits in a way that the classic approach does not. Both Tranfaglia and Sireau and their associated patients groups have partnered with Healx in the quest for new treatments for Fragile X and Black Bone disease. “It’s a shortcut,” says Tranfaglia.

We’re not in the business of inventing new molecules. Why invent new ones when there are old ones that can help right now at a fraction of the cost

David Brown

The key insight behind the second-generation bioscience paradigm is that devising new drugs in the traditional, targeted, conjecture-and-refutation way, is inefficient. Far better to make use of existing drugs. They’ve already been tested over the years. They are already well tolerated by the human body. No need for expensive, long-winded trials. Healx reckons it is “de-risking”. The new data-driven approach, or “computational biology”, is “hypothesis-free”, no longer “target-based”. “We don’t even care about the gene,” says Brown. “We look at the transcriptomic fingerprint of the disease and the fingerprint of the drug. You can work back to the mechanism from there.”

In a first sweep, we have, in the left-hand column, a long list of rare diseases. In the right-hand column, we have approximately 15 billion possible drug combinations, all proven to be safe. The object of the exercise is to find a match between the drugs and the disease. As with Viagra, it’s all about “repurposing”. “We’re not in the business of inventing new molecules,” says Brown. “Why invent new ones when there are old ones that can help right now at a fraction of the cost? We’re looking at combinations, because most diseases are going to need treatment with more than one drug.” It is these combinations that promise to help the Tranfaglias and Sireaus.

Brown and Guilliams both stress that their new methodology is not exclusively data-dependent. You still need shrewd human beings to make relevant decisions. The machine helps humans come up with ideas they wouldn’t have thought of in the first place at a faster rate with larger data-sets. But the humans, with pharmacological expertise, have to help the machine narrow down the options. The task of “data curators” is to “train” the algorithms in a process of “supervised machine learning”.

Brown offers an analogy. “You remember how Gary Kasparov was beaten by Deep Blue? Now an average grand master with a laptop can easily beat the successors to Deep Blue.” You still need grand masters, in other words. Drug hunters like Brown himself.

The “best bets” of the new/old drugs Healx has proposed are now starting clinical trials. And they won’t take years either. In the new hi-tech approach everything goes so much faster. It’s like the difference between slow-burn courtly love and speed dating. The end result is similar but elaborate courtship rituals are kept to a minimum. Both Tranfaglia and Sireau are optimistic about their new “combination” treatments. “It’s already working,” says Tranfaglia. Sireau says, “If all goes well, my boys shouldn’t develop the worst symptoms. We’re lucky. Most rare diseases have no treatment on the horizon.”

The pace of change is so fast that the new paradigm may quickly become old hat. Brown and Guilliams are already talking about a “Third Generation” approach. They are throwing up new and unexpected results, with a combination of two or three existing drugs which could have efficacy not just on rare diseases, but on better known ones, like diabetes and the child cancers that can kill kids before the age of 3 – all without chemotherapy and without side effects.

Brown doesn’t need to earn any more money, but he does have a hankering to help humanity. “If there are one in 17 with a rare disease, you’ve got to do something,” he says. Brown himself takes Viagra, but generally only to help with breathing and altitude sickness, notably when he goes to Tibet to visit an orphanage he supports. And he reckons that the unpromising and so nearly rejected drug first tested on the unemployed miners of Aberystwyth will in the future be shown to have beneficial effects on a host of other diseases, including cancer.

Brown, even though approaching 70, recently ran a half-marathon and finished the race in a time of 2 hours and 13 minutes. I probably don’t have to ask him the question, “What are you on?”

Andy Martin is the author of ‘Reacher Said Nothing: Lee Child and the Making of Make Me’ and teaches at the University of Cambridge.