The small scientist

Almost by accident, 25 years ago Alec Jeffreys discovered DNA fingerprinting and revolutionised criminal profiling. He tells Zoë Corbyn that 'the unexpected is what science should deliver'

September 3, 2009

Alec Jeffreys smiles as he recalls how he was characterised by a US Nobel laureate shortly after his groundbreaking discovery of DNA fingerprinting. He had given a presentation to an academic audience at Johns Hopkins University School of Medicine in Baltimore, and the summing-up fell to biologist Daniel Nathans.

"He described me as a 'small scientist'," Sir Alec says, noting that the audience winced at what they interpreted as an insult. "But I knew exactly what he meant and it was a compliment. It is someone who can deliver without an army, with modest resources and whose work is based purely upon curiosity. And he captured me very nicely. I am just a small scientist and it was one of the nicest things that has ever been said about me."

While Sir Alec may not yet have a Nobel prize for his work, the image of a "small scientist" is hard to reconcile with the worldwide impact of the discovery with which his name is synonymous.

On 10 September 1984 - exactly 25 years ago next week - the professor of genetics at the University of Leicester discovered a technique that has subsequently had an incalculable effect on society, helping to solve criminal cases, resolve immigration arguments and clarify questions of paternity, not to mention creating one of the biggest civil liberties issues of our times.

"I look back in awe at how far this field has come," Sir Alec says of his discovery, which for the first time provided a simplified but unique representation of an individual's genetic make-up.

"There has been discussion about whether this was a paradigm shift (in science) or not, but the overall impact - that is much bigger than me as an individual - has been nothing short of miraculous."

No one has kept count of how many people have been DNA profiled worldwide, but Sir Alec, who was knighted in 1994 "for services to science and technology", estimates it is "well into the tens of millions".

"And every single one of those tests - whether it is someone trying to figure out whether little Jim is his kid, an exoneration of someone on death row, a serial criminal being captured or an immigrant family being reunited - is a human drama."

Yet as well as a rich story of how science can transform lives - that elusive impact that today's researchers feel such pressure to deliver - it is also a story of the power of unfettered blue-skies research and its unexpected results.

Working in the laboratory, Sir Alec recalls, he and his technician were simply following their noses. They had "absolutely no idea" of the applications that would result from the discovery they stumbled upon.

"I have never approached an experiment with a desire to solve a practical problem," he observes, pinning down his moment of discovery to precisely 9.05am on Monday 10 September 1984. "My forensic thoughts at 8.55 on that morning were precisely zero; they simply were not there. The technology comes first and then suggests the applications, not the other way around, and you see this over and over again."

But just as he has spoken out about the ethical and moral issues concerning the use of the technology he made possible, Sir Alec is a staunch defender of Britain's curiosity-driven research. And the 25th anniversary of his discovery is, he believes, the right time to be discussing its future.

"As scientists, we have to be accountable to the public purse for the money we are spending, but if you take it too far - and in my view it has gone far too far now - it actually stifles the creativity of the very thing you are trying to promote."

His warning is simple: applied science can be managed from the top down, but we apply the same approach to pure science "at our peril".

"It is blue-skies research that is the ultimate driver - delivering the new techniques, concepts and tools that we need to progress," he says.

The history of Sir Alec's career and his discovery has been well documented. He was born in Oxford in 1950 and raised in Luton; his interest in science stemmed from the age of eight, when his father presented him with a chemistry set and a microscope (the latter will be on display at the Wellcome Trust later this year as part of an exhibition commemorating the anniversary of Sir Alec's discovery).

He took an undergraduate degree in biochemistry and a doctorate in human genetics at the University of Oxford, and embarked on postdoctoral study at the University of Amsterdam. In 1977 he took up a post at the University of Leicester to begin work on detecting inherited variation in human DNA.

Previously, the only way anyone had discovered to prove that genetic variations were passed down through generations was through visible signs of variation, such as blood group or congenital disease.

As he worked on ways to detect molecular-level genetic differences, Sir Alec found that some regions of the genome consisted of short sequences of DNA that repeated, or "stuttered", over and over. Importantly, the number of repeats varied between individuals, making the regions variable in length.

This work led, almost accidentally, to the development of DNA fingerprinting. While looking at a "blot" on X-ray film revealing the differences in these lengths of stuttered DNA between three related people, Sir Alec realised that the "rather fuzzy-looking barcode-like patterns" were the genetic fingerprints of his technician, Jenny Foxon, and those of her parents, who had provided samples.

The implications were obvious, he recalls. "They were pretty blurry and horrible but you could see immediately that you could tell all three people apart. You could see how the technician's DNA fingerprint was a composite of her mum's and her dad's, but also unique. And it immediately suggested DNA-based biological identification that could sort out family relationships, and not just for humans but just about anything you care to think of."

Within an hour of the accidental discovery, Sir Alec and another colleague, Victoria Wilson, had brainstormed a "shopping list" of things the discovery might be used for: paternity disputes, the identification of crime-scene DNA (although recovering it in those days was still a problem); identical twin testing (they have the same genetic fingerprint), and non-human applications, including conservation biology and biodiversity monitoring. "The one thing I missed was immigration disputes and that was suggested by my wife that evening," adds Sir Alec.

He was then faced with two problems, he says.

The first was the challenge of improving the technique, so he and his assistant worked "pretty quickly" to turn the blurry, smudgy patterns into "highly discriminating true DNA fingerprints".

The second, he says, was his fear that it would be difficult to get anybody to take note of his discovery.

"Would people have noticed if I had called them by their more scientific name of 'idiosyncratic southern blot mini-satellite hybridisation profiles'? The one smart thing I did in this was to call them DNA fingerprints, because that captured what they were."

The discovery was patented in late 1984 in the name of the Lister Institute of Preventative Medicine (Sir Alec was one of their research fellows, although he also had a Medical Research Council grant for the work). It was published in Nature in March 1985.

He puts the cost of the whole development at about £50,000 in today's terms (based on his time for a year and that of his technician, working half-time). Sir Alec calls it "the bargain of the century. You don't have to spend an absolute fortune to get useful stuff."

From there on, the technique's potential applications snowballed. A London lawyer spotted a newspaper report on Sir Alec's work, and contacted him to ask whether DNA fingerprinting could be useful for an immigration case she had been handling. This led to the very first practical application of genetic fingerprinting just eight months from its discovery - an extraordinarily short time frame, given that most science takes years, if not decades, to deliver benefits.

The immigration case, in which a young Ghanaian boy was subsequently saved from deportation, convinced Sir Alec of the significance of the discovery.

"I was there at the immigration tribunal when his mother was told that the case against the boy had been dropped because of the DNA evidence. And the look in that woman's eyes... that was my magic moment. That was when I suddenly realised that it was not just science any more."

Soon immigrant families were showing up at his Leicester laboratory seeking help. In the summer of 1985, he and his assistant tackled their first paternity dispute, leading to yet more demand.

By this point it was clear, Sir Alec says, that the technique "had to go commercial". The company Cellmark Diagnostics was granted a licence to exploit the technology (with royalties split three ways between Sir Alec, Leicester and the Lister Institute), and it opened two branches in the UK and the US in 1987. "Not much of it came back to me as an individual," he says. "I've never done this for money."

Simultaneously, the technology was transferred to the Forensic Science Service under crown privilege, which allows the Government to acquire a technology, regardless of intellectual property rights, if it is felt that it is in the national interest to do so.

Sir Alec recalls it took "about a nanosecond" to work out he wanted a third party to take on the commercialisation, rather than being involved himself. Not only did he lack the experience, but he knew it wasn't what he would be good at.

Indeed, throughout the casework, Sir Alec never stopped his basic scientific work. He developed a further tweak to the technique, making it faster to use and able to accommodate smaller samples, which proved particularly useful for forensic analysis. It was known as DNA profiling and focused not on multiple regions of stuttered DNA as fingerprinting had done, but on testing just one stuttered region at a time. Soon the police were knocking on his laboratory door, seeking help to investigate the rape and murder of two Leicester schoolgirls.

"It was the first use of DNA profiling in criminology," explains Sir Alec. "We showed that a prime suspect who had confessed to one of the two murders in fact was innocent, which then led the police to initiate the first DNA-based manhunt for the true perpetrator, who is now serving two life sentences."

Sir Alec's involvement in further noteworthy cases followed, ranging from the positive identification of the remains of Nazi war criminal Josef Mengele to proving, in 1995, that Dolly the sheep was indeed a clone. The latter was the last case he was directly involved in solving.

"I do take some pride in having the perseverance to actually move out the technology to real casework," he says. "We were prepared to go that extra hundred miles... despite the fact that it was a colossal effort and a major stress on everybody involved. It would have been very easy for us to say 'we can do these DNA fingerprints but we are not getting involved', but this was something that could really impact on people's lives and to walk away from the applications of that would have been wholly wrong."

Yet two-and-a-half decades after that memorable morning, Sir Alec is adamant that he is not defined by this discovery. "I have always described forensic DNA as an entertaining diversion in my life. But it is not the core me."

By the early 1990s, he felt that the basic scientific questions surrounding genetic fingerprinting had largely been solved. Sir Alec then returned to the field of research he had originally set out to pursue at Leicester - inherited variation in human DNA - which remains his focus today, and where he continues to make important inroads, including pioneering alternative approaches, such as the screening of sperm, to study DNA mutation and recombination.

He feels frustrated, he says, if he does not spend at least a third of his life in the laboratory. "Fiddling around with things and actually getting your own results stimulates the imagination."

And no other institution has come close to spiriting him away.

"I am in a department rooted in intellectual curiosity and academic freedom and I took to this place like a duck to water," he says, adding that he is comfortable leading a small team.

"Offers have come in but they have always tended to be either pressure-cooker type environments or running some enormous great institution, and I am just a small scientist."

Yet while his science has moved on, he continues to keep a "very active watching brief" over developments in the use of the technology he fathered.

And, acknowledging his "privileged position as total loose cannon", he says he is not afraid to sound off.

The most memorable example so far has undoubtedly been his very vocal stance on the proliferation of the national DNA database in the UK.

"The problem at the moment is the retention of innocent people on the DNA database. At the last count, more than 800,000 entirely innocent people who just happen to have been arrested by police but not charged with anything are on it."

But his reckoning is that, on balance, DNA fingerprinting has been a good force in society.

"In the scales of righteousness, there is a pretty heavy load on the good side... but the innocent people on the database are a significant load on the bad side."

Would he wish away his invention? The answer is an unequivocal no. "Any technology will always be dual use - used for both public good and potentially for public ill. But these are issues that are nothing to do with science and all to do with policies and legislation," he says.

Sir Alec speculates on what would have happened if, rather than the discovery happening as it did, he had been given a £1 million grant to develop a viable DNA-based identification system to assist in police forensic work (a scenario for managed research that is not unlikely today).

"I would not have got anywhere because I wouldn't have touched it. I would have said: 'Forensic investigations? - well, I am looking at gene evolution, and what on earth have they got to do with each other?'"

His point is that research clearly needs to be done to help address societal problems, but it "mustn't be the be-all and end-all of science. Underneath that you have to have the curiosity-driven stuff."

Not, Sir Alec says, that he wants to get into a blame game. Research councils "do try to protect a patch" for blue-skies research, he believes, and notes that although the signals are less consistent, the right noises do emanate from Government.

The point he makes is that the gradual erosion of British scientists' ability to conduct blue-skies research is a matter of concern.

He does not dispute that taxpayers deserve a return for their money, but argues that it is a "matter of educating" the public and Government so they understand that the scientific process can't be predicted.

"There is an education gap there in having to explain why science that appears to be of no consequence whatsoever may, ten years down the line, trigger a revolution. Yes, there is going to be a lot of waste of taxpayers' money, but for every hundred projects you fund, if one comes up with something exciting and really new, that would be a more than adequate pay-off."

Provocatively, Sir Alec also speculates that had he invented DNA fingerprinting today - in a world where scientific freedom is so much more restricted - he might have run foul of his funders.

DNA fingerprinting had "absolutely nothing to do" with the work for which he had been given his Lister fellowship and his MRC grant, he observes. Not that it bothered the two organisations, who realised completely that "the unexpected was what science should deliver".

But he worries that funders may no longer take that view. "In today's climate, I might well have been criticised because it wasn't within the strict remit of the research that I had proposed."

Sir Alec also takes exception to the pressure put on young researchers, the burgeoning of large research teams, and the "quality assurance" that he believes can prevent individual scientists from following their noses.

"Back in those days, we did not have impact factors, we did not have quality assurance, we did not have research assessment exercises and instead we had something called fun. As a researcher leading a group of one - which was you - you could basically just follow your nose and do interesting stuff."

Indeed, although he acknowledges that there are many approaches to research, his preferred model is one in which both senior scientists and PhD students work at the lab bench, driven purely by their curiosity, with "no room for science managers".

In summing up his philosophy, Sir Alec advocates "minimum top-down control and maximum intellectual freedom to follow your nose, in the full realisation that a lot of this will not result in anything of any great significance - but there will be the occasional jackpot to make it all worthwhile".

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