Three views of genetics: the enthusiast, the visionary, and the sceptic

Making genetics everyone's business

The government's plan to boost genetics is welcome news to John Burn, director of the Northern Genetics Service, Newcastle upon Tyne

The government's portrayal last week of the United Kingdom as “genetics valley” is a shot in the arm for its geneticists. Here was the ailing NHS being described by the health secretary as “uniquely placed to maximise the health benefits of the genetics advances.” And along with the rhetoric came a pledge of £30m ($42m) to double the number of specialist geneticists and extend their services (see p 1018).

No wonder Professor Burn, director of the Northern Genetics Service, at Newcastle University, is positive. After 27 years in the field, he shares the view that the NHS offers unique opportunities to conduct clinical research and develop comprehensive services. He also welcomes what he describes as “the endorsement of clinical geneticists as the leaders in the move to bring genetics out of specialised centres into everyday practice.”

Behind closed doors in genetic circles, there has been an unproductive and at times acrimonious dispute about professional boundaries. The genetics revolution has seen molecular geneticists, public health physicians, primary care doctors, physicians, and surgeons rapidly moving into erstwhile specialist geneticist “territory.”

While some have railed, Professor Burn has adopted what he calls the Dodge City principle. “If you have a rifle and a horse, you get a badge to join the posse.” Whatever his methods—and I suspect drive, charm, and guile are there somewhere—he has clearly been successful in capturing the enthusiasm and skills of different specialists to build up his multidisciplinary genetics unit.

While discussions continue about who takes the whip hand, it is evident that concerted action is needed. As genetic testing for rare inherited diseases is extended—and there is a prospect of DNA profiling before drug treatment and susceptibility testing for some common diseases—it becomes everyone's business.

Professor Burn sees the time lag of “a few years” between moving from testing a few families for rare disorders to wider diagnostic, carrier, and susceptibility testing as an advantage. It allows geneticists to develop their outreach services and spearhead educational initiatives.

As director of the Imperial Cancer Research Fund's clinical cancer genetics network he aims to demonstrate, with his colleagues, best practice in relation to breast, ovarian, and colon cancer. “About 5% (1 in 20) of patients have a single gene defect underlying their cancer but we can only find them after there have been multiple cancers in the family. As mutation scanning becomes faster and cheaper we will be able to offer this testing to all 60000 patients each year.

“By focusing on finding the 1 in 20 whose families are at greatest risk and where prevention is possible—for example by regular removal of bowel polyps in those who are predisposed to bowel cancer—we will demonstrate the benefits of genetic testing and reassure the sceptical.”

John Burn: the enthusiast

Genomic medicine as preventive medicine

A positive view of the post-genomic age is provided by Gordon Duff, professor of molecular medicine at the University of Sheffield

Genomic medicine is not a luxury for the rich West, but a necessity that will deliver cost effective health care. This is the view of Professor Gordon Duff, director of the division of genomic medicine and research dean at the University of Sheffield.

“We cannot afford not to embrace genomic medicine” he argues. “Health budgets cannot go on rising as they did in the second half of the 20th century. Preventive medicine is an economic necessity, and genomic medicine represents the best route we have to preventive medicine.”

It will be as important for poor countries as it is for rich ones. The development of effective low cost vaccines, based on DNA or related genomic research, will offer considerable help to poor countries, which carry huge burdens of infectious disease, he believes.

Although Professor Duff sees genomics taking more than 25 years to “change the way we do medicine,” he predicts that pharmacogenomics will become part of routine therapeutics in some fields within three to five years. Soon after that we will begin to feel the results of investment by the food industry in nutritional genomics.

He describes a project that his colleagues are working on defining the optimum daily dose of vitamin A. “It is particularly important to optimise intake during pregnancy, and their research shows that the daily requirement is defined genetically.”

Although he sees susceptibility testing for common diseases taking longer to reach clinical practice, he thinks voluntary gene testing will be available within five years in some countries. He does not agree that testing necessarily raises insuperable social issues. He points out that “many of the tests that are routinely done in clinical practice—measuring C reactive protein, for example—are proxy gene sequences.” And in many cases it may be cheaper and more informative to test for the latter than to carry out existing tests.

The ability to screen for genetic susceptibility, he emphasises, brings with it the possibility of modifying risk by chemoprevention, dietary manipulation, choice of work environment, and lifestyle adjustments. Ultimately, he sees it helping people to manage their own health.

He draws a picture of tomorrow's consumer dropping into their local retail pharmacy for genome profiling. He or she will obtain advice and then download more information from the internet about how to modify the risk of developing a disease to which they are especially susceptible.

Gordon Duff: the visionary

The cautious view

Contemplating the post-genomic future, Neil Holtzman, director of genetics and public policy at Johns Hopkins University, advises against being seduced by “genohype”

The publication of the draft human genome sequence generated tremendous excitement. “I've seen a lot of exciting biology emerge over the past 40 years” commented David Baltimore in Nature (2001;409:814-5). “But chills still ran down my spine when I first read the paper that describes the outline of our genome.”

Neil Holtzman, the director of genetics and public policy at Johns Hopkins University in Baltimore, Maryland, puts it differently. “To me the project continues a pathway we embarked on 50 years ago after the discovery by Pauling of the genetic basis of sickle cell anaemia.” Not that he decries the advances in understanding the genetic basis of disease; quite the reverse. He acknowledges that the identification of (now over 1000) single gene disorders that affect 1-4% of the population may lead to reliable predictive tests and improved therapy. He also sees great potential in somatic cell genetics to enhance understanding of common diseases.

“Exaggerating the importance of genetic factors stops people thinking about the need to clean up the environment and tackle socioeconomic inequity”

His quarrel is with those who exaggerate the clinical benefits that will accrue from the human genome project. He describes claims such as those made in the editorial in Nature's genome issue that “the application of knowledge from the project will, in time, materially benefit almost everyone in the world” as ludicrous.

The claims are based on the assumption that it will be possible to unravel the polygenic forms of common diseases where clinical outcome is determined by complex gene, environmental, and behavioural interaction. In his view, however, “it will be difficult, if not impossible, to find the genes involved or develop useful and reliable predictive tests for them.”

It is because of this that Professor Holtzman believes it is unethical for the United States to be spending millions of dollars of public money searching for genes associated with common disorders such as asthma, heart disease, and hypertension. “These pursuits are better left to the private sector.” He is concerned that gene chasing projects and the publicity that surrounds them perpetuates the DNA mystique—the notion that “it is all in our genes.”

“Exaggerating the importance of genetic factors as determinants of health stops people thinking about the need to clean up the environment and tackle socioeconomic inequity,” he said.

But what about pharmacogenetics? Isn't the industry predicated on the assumption that exploration of individual genotypes will allow doctors to prescribe tailor made therapy and avoid adverse drug reactions? “It is, and it won't” is Holtzman's succinct reply.

“Sure, there are few cases where testing patients for certain enzymes involved in drug metabolism may help but it's ridiculous to suggest that drug sensitivity and resistance are wholly determined by inherited genetic profiles. Other factors, such as diet and smoking, are as important. The science is a lot more complex than the scientists would have us believe.”

Holtzman's critical views are based on experience. After taking degrees in history, medicine, and epidemiology, he spent two years of his paediatric training studying children with phenylketonuria. He came away acutely aware of “knowledge gaps, laboratory variability, and deficiencies in scientific method”—insight that doubtless explains why a colleague describes him as the “most informed sceptic I know.”

A few weeks ago he participated in one of the meetings of the multidisciplinary group set up to look at the ethical, legal, and social issues raised by the human genome project. There was much speculative debate about behavioural genetics and the possibility of genetic enhancement.

“The idea that we will be able to select genes we like and weed out those we don't to produce customised children is absurd”

“It may keep the ethicists and philosophers in business,” said Holtzman, “but I think the term ‘ethereal debates’ describes them best, for they are built on a house of cards. The idea that we will be able to select genes we like and weed out those we don't to produce customised children is absurd.”

He is similarly fired up about commercial firms such as Myriad Genetics and Athena Diagnostics marketing tests directly to the public, without having to prove their validity and utility. After steady lobbying, he and others have now persuaded the US's Food and Drug Administration to regulate the use of genetic tests.

It is hard not to be won over by Holtzman's arguments. His concern that society should be rational, honest, and prudent in funding post-genomic research —and not overblow its potential—is palpable. His reference to shaky stockmarkets and venture capitalists losing money in genome industries seems well informed.

Journalism, not medicine, was Holtzman's first choice of career, and he likens some of his work and his publications to investigative reporting. He is tempted to return to his first love. With the Economist (2001; 14 May:21-4) deploring politicians' ignorance of genetics and suggesting that human cloning will precipitate the United States's next ethical war, now might be a good time.

Neil Holtzman: the sceptic