DDT Vol. 6, No. 1 January 2001 updatefeatures

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How do you see the sequencing of thehuman genome impacting on drugdiscovery in the future?I think the human genome sequence willhave an enormous impact on drugdiscovery in various ways, and will enable amuch more rational approach to drugdevelopment. The information willundoubtedly lead to the discovery of manynew targets for which a variety of newdrugs will be developed. However, wemust not expect instant discoveries. In thelong-term, we can use the genomeinformation to understand the biology ofeach system properly, which will lead us toall the other components in a particularbiochemical pathway, perhaps enabling usto find the optimal target for intervention.

Personalizing medicines is also a veryimportant area, starting with existing drugsthat are already on the market. To do thiseffectively requires the entire genome ofthe representative individual, and theability to investigate the variations betweenindividuals and how such variations affectan individual’s response to drugs andenvironmental agents. My hope is that wecan tailor existing drugs to bring somevery significant improvements inhealthcare, and this avenue could deliverresults faster than new drug discovery.Much of the groundwork has already beendone, and this approach could yield veryearly returns.

How do you think we should best tackle the problem of discovering the function ofmany of these genes?There is no easy answer to this, but it is anenormous help that through the entire

genome sequence we will have theprimary sequence of every protein, whichitself will provide much information aboutpossible function. If the sequence alreadymatches, or is homologous to, anotherprotein that we know the function of, wecan classify proteins into families withspecific functions. Of course, every proteinhas a unique function and so there is morework to be done beyond looking at thesequence.

The most important question to ask, inmy view, is what a protein interacts with,and what it binds to, because this is whatis specific to that protein and this can bemodulated by intervention with a drug. Itis also important to know where theprotein is because, while some proteins arepresent on the cell surface and are readilyaccessible to drugs, other proteins areinside the cell, inevitably creating theadditional problem of how to enable adrug to access its target. Such informationon protein binding and protein–proteininteractions can be found for exampleusing large-scale array approaches. We cannarrow the field by selecting the specifictargets that are known to be involved; forexample concentrating on those that arepresent on the cell surface.

Where do you see the main bottlenecks inthe discovery of new drugs from thisinformation and how do you think wemight best overcome them?From a biologist’s point of view, a majorbottleneck is finding the right target. Oneapproach is to use genetics to detectparticular genes involved in a polygenic(i.e. multifactorial) condition, and separatethe effects of the genes on each other fromthe effects of the environment. This is anarea that holds great promise and is wheremuch of the effort is now being directedthrough SNPs.

Another bottleneck is unravelling acomplete biochemical pathway that isassociated with a particular disease, andfinding the right target within that pathway.

How do you think company strategies inR&D, development and registration should change to accommodate thepharmacogenomics era?We have to decide how effective and howsafe a drug is for every individual in thepopulation. Currently this is done by alengthy and carefully regulated process,but does not account for possibledifferences in the genetic background ofthe individual. Genetic information on theindividual can be used to improve theprescription of drugs by tailoring dosage tosuit the individual more precisely. It mightalso be possible to introduce new drugswith the added benefit that theappropriate genetic background for theiradministration can now be monitored,where this was previously not possible.There is a potential risk in taking thisapproach, where a drug might appear onthe market which is well suited to oneperson, but could be a health hazard foranother – a distinction that would only berevealed by genetic testing. A furtherimplication of this situation is that the drugin question would only be of benefit forpart of the population. However, giventhat we are aware of the risks, personalizedmedicine has a great future.

Do you think the Human Genome Projectwill have as significant an impact on drugdiscovery as was anticipated at thebeginning of the project?I am sure it will be extremely significant.Although there is a lot of work to do indeveloping drugs and targets using thegenome sequence, we have a good idea of how to proceed. Already, many of thequestions posed about the value of theHuman Genome Project inpharmacogenetics have been answered,and there is great promise in the newavenues of research that are opening uptoday.

David Bentley discusseslife after the HumanGenome Project

Interviewed by Rebecca Lawrence

David Bentley, Head of Human Genetics, The Sanger Centre

We must not expect instantdiscoveries.

My personal view is that most,or all, of human geneticinformation should not bepatented.

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Do you feel it is ethical to patent humangenetic information? My personal view is that most, or all, ofhuman genetic information should not bepatented. However, it is not entirely thepatenting process itself that is the problem;it is the way in which patent protectioncan be used for selectivity. While patentingis a form of publication and provides freeaccess to information, the protectionoffered can give a selective advantage tosome groups, and make it less viable forothers to use the same geneticinformation. I would be happy for everygene to be patented if it was for thebenefit of making it freely available, butnot if it is for exclusive licences and forprofit based on knowledge of the genesequence itself. Conversely, there isdefensive patenting in which genesequences can be made freely available toall, without restriction, thus levelling theplaying field.

I entirely support the idea of protectingproprietary information resulting fromnovel research using the knowledge gainedfrom discovery of genes and theirfunctions. It is vital that large investmentsare made in the development of effectivediagnostics and drugs. Patents filed onthese discoveries are then for theprotection of the truly inventive work thatgoes into using the genomic information.

What is your biggest concern about thecurrent/future research?I have two fears. One is misuse of geneticinformation – technology is highlyaccessible, it can easily be established andis applicable to all genes. There is a dangerthat use of the technology and informationcan be motivated by personal gain, leadingto incorrect use of the information.

My second fear is that communicationto the public of both the benefits and thedangers of genetic knowledge might beeither inadequate or misleading. I wouldlike to see the knowledge of geneticsbrought to the public in a realistic andinformative way so that the full potential ofthe human genome can be realized.

How do you think that scientists cancommunicate what effect the HGP willreally have on therapeutic advances anddoes the Sanger Centre have any plans tocontribute to educating the public on suchmatters?We have explored many areas ofcommunication with the public, since the

founding of the Sanger Centre. Forexample, we develop teaching materialsand run educational seminars involving awide range of people from 9 year-olds tofamily groups, to various professional andacademic gatherings. We have also beeninvolved in refresher courses for teachers,and a basic course for sixth-formers, whichextends beyond their curriculum.

There are some excellent examples inother institutions such as the DNALearning Center at Cold Spring Harbor.The Wellcome Trust runs practical coursesat a senior level, provides a comprehensiverange of publications aimed at scienceteachers, and is engaged in an initiative,which tours schools, to present sciencethrough drama. We would like to build onwhat we have learnt, possibly with a moreformal programme, and to work moreclosely with the media and the Internet.

What do you think to the future predictionthat in 20 years or more, we will be able to change people’s lifetimes and theirintelligence, and that this will create asuper-race for those that can afford thistype of treatment?Anything is possible and one cannotpredict the future. We are talking aboutthings that are of fundamental interest topeople. My personal view is that work thattouches on creating a super race would bea major abuse of this knowledge andtechnology. Also, ‘for those who couldafford it’ exemplifies the profiteering use ofsuch technology as opposed to thebeneficial use. I very much hope that, givenfreedom of information and good education,it is a possibility that will be averted.

What lies on the horizon for genomicresearch over the next five years? There will be very exciting progress inbeing able to use the knowledge of thegenome and what it contains – it willcertainly herald revolutions in medicine,although not all of it in five years. We willalways need to be patient, but we will nolonger be scratching around in the dark inmany areas of research.

We should also not forget that in thenext five years, there will be a muchgreater understanding of many othergenomes and how they compare, and thiscan be used to provide more informationon the human genome as well asinformation on biology in their own right.So far, every genome has been anenormous effort, expensive and slow, andtherefore future genomes in the short-termwill be drawn from different points in theevolutionary tree to make the most ofexamining the differences and thesimilarities. However, genome sequencingis getting easier, not only because thetechnology is improving, but also becausewe can now use some genomes as askeletal framework for building maps ofothers. In five years, we will definitely seemany more genomes, and we will learn atremendous amount from being able tocompare them. We will also ultimately beable to sequence multiple copies of thesame genome from different individuals.The possibilities are therefore unlimited,but they have to be affordable and have tobe a realistic investment.

What would you like to have achieved bythe end of your career?I think the promotion of good scientificpractice and progress in others is veryimportant. I am concerned with educationand with passing on skills and informationto others. I would be happy if I had helpedthe continual learning process ofunderstanding our genome, and how thatknowledge interacts with healthcare, theenvironment and society.

The Sanger CentreWellcome Trust Genome Campus

HinxtonCambridge, UK CB10 1SA

tel: +44 1223 834244fax: +44 1223 494919

e-mail: drb@sanger.ac.uk

I would like to see theknowledge of genetics broughtto the public in a realistic andinformative way

The possibilities for the futureare unlimited, but they have tobe affordable and have to be arealistic investment.

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