The position of mutuality

Increasingly, patient and professional

guidelines recognize and encourage an

ethical duty to warn. In the position of

mutuality, it is the health professional’s

duty to warn in cases where the patient

refuses to do so. This discretionary duty

or permission is not without certain

parameters and continues to be seen as

a last resort.

In the situation of repeated refusal by

the patient, four conditions must be met

before it is seen as ethically permissible

for the physician to breach medical

confidentiality: (1) the condition in

question must be serious with (2) a

high probability of occurrence, (3) in an

identifiable blood relative(s) and

(4) prevention or treatment must be

available.

In this way, a serious burden on others

can be avoided. This position, however,

in no way advocates a legal duty to warn.

For now such ethical ‘permission’will at a

minimum serve as a defence in a possible

suit for breach of confidentiality [6].

Nevertheless, it seconds the position that

between the human genome at the

collective level being considered the

common heritage of humanity and at the

personal level as being unique and

belonging to the individual, the

information it contains is also familial.

The adoption of this translation of the

principle of mutuality with respect to

genetic information will reinforce what

the World Health Organizaton (WHO)

has maintained with regard to DNA

samples which it sees as subject to

familial control [7].

In short, the very nature of genetic

information, as both individual and

universal, now mandates its treatment

as familial. The future availability of

inexpensive multiplex testing might

allow routine individual knowledge of

thousands of mutations and so lessen

the need to warn at-risk relatives.

However, at present, the acceptance of

the principle of mutuality in the sharing

of information in families (and hopefully

one day in whole communities at risk),

serves to reinforce the notion that we are

literally our brothers’ keeper. Finally, the

sharing of genetic information could also

serve to ‘normalize’ it. If so, we can one

day end the stigmatization and

discrimination that is currently

associated with genetic information and

integrate it into modern medicine, as

normal medical information in more

caring and sharing families.

References

1 European Parliament (April 1990) Resolution on

the ethical and legal problems of genetic

engineering. Bull. Med. Eth. 8, article 12c

2 Council of Europe (1997) Convention for the

protection of human rights and dignity of the human

being with regard to the application of biology and

medicine: convention on human rights and

biomedicine. Int. Dig. Hlth Leg. 99, 48:1, article 10

3 United Nations Educational, Scientific and Cultural

Organization (International Bioethics Committee)

(November 1997) Universal Declaration on the

Human Genome and Human Rights, UNESCO,

Paris, France)

4 Health Council of the Netherlands (1989)

Heredity: Science and Society – On the

Possibilities and Limits of Genetic Testing and

Gene Therapy. pp. 91, The Hague

5 Group of Advisors to the European Commission

on the Ethical Implications of Biotechnology

(GAEIB) (1996) Ethical aspects of Prenatal

Diagnosis. Opinion 2.8

6 American Society of Human Genetics (1998) ASHG

Statement. Professional disclosure of familial

genetic information. Am. J. Hum. Genet. 62, 474

7 World Health Organization (1997) Proposed

International Guidelines on Ethical Issues in Medical

Genetics and Genetic Services (Table 10), guideline 2

Bartha Maria Knoppers

Canada Research Chair in Law and Medicine,Faculty of Law, CRDP, University of Montreal,CP 6128 succ. Centre-ville, Montreal, Quebec,Canada H3C 3J7.e-mail: knoppers@droit.umontreal.ca

TRENDS in Biotechnology Vol.20 No.2 February 2002

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86 Forum

Book Review

Designing

combinatorial libraries

for drug discovery

Combinatorial Library Design and

Evaluation. Principles, Software Tools,

and Applications in Drug Discovery

Edited by Arup K. Ghose and Vellarkad N. Viswanadhan. Marcel Dekker, Inc., 2001. US $195.00 (hbk)(xv + 631 pages) ISBN 0 8247 0487 8

Without doubt, combinatorial chemistry

and combinatorial library design have

become an integral part of the drug

discovery process. In only a few years,

computational approaches to library

design have matured from a novel

research topic to a mainstream tool in the

pharmaceutical industry. This book offers

a timely overview of the current state of

affairs of in silico design of combinatorial

libraries and includes theoretical

principles, available software tools and

examples of applications. Many chapters

in the book are written by recognized

experts in the field and provide

comprehensive introductions to the

various computational aspects of drug

discovery and library design.

The first chapter outlines a chemist’s

view of the library design process as well

as important synthetic considerations.

Because the final step in designing a

library is to successfully make chosen

compounds, it is important to understand

the features and limitations of common

solid-phase and solution-phase

synthesis techniques as well as pooled-

and parallel-synthesis strategies.

This chapter also introduces

classification of chemical libraries

according to their intended purpose –

‘discovery’ or ‘screening’, ‘focused’ or

‘targeted’ and ‘optimization’ being the

classification groups.

The remaining 19 chapters of the book

are organized into three parts that offer

progressively more in-depth discussions of

the computational methods and tools used

in combinatorial library design. The first

part outlines fundamental design

principles including pharmacophore

modeling, quantitative structure–activity

relationship (QSAR), structure-based

drug design and property prediction.

The second part reviews current state-of-

the-art methods and software tools for

designing combinatorial libraries that are

effective in generating prospective lead

compounds. The third part includes

several case studies to illustrate the

practical application of various

approaches to library design. Many

chapters provide extensive references of

recent publications in the field.

Pharmacophore modeling of

ligand–receptor binding and available

software for automated discovery and

matching of essential pharmacophores is

discussed in Chapters 2 and 14. A concise

review of classical QSAR is given in

Chapter 3 and includes a table of ‘success

stories’where drugs developed with the

help of the QSAR approach have

subsequently been developed and

marketed. Both receptor- and ligand-

focused 3D QSAR approaches are

discussed in Chapter 4. Computational

algorithms for designing diverse libraries

with additional constraints from large

virtual libraries are summarized in

Chapter 10, which is complemented by

Chapter 11, which reviews structural

descriptors and similarity measures

commonly used in the diversity analysis.

Chapters 6 and 17 address de novo design

tools available for building combinatorial

libraries by connecting docked fragments

or by the progressive build-up of ligands.

Corresponding software packages

detailed include GRID, DOCK, FlexX,

GOLD, SEED, CAVEAT and LUDI.

Several contributors address

optimization aspects of library design

that include the use of stochastic

sampling techniques such as the Monte

Carlo method or genetic algorithms.

A continuous theme throughout the

book is the importance of not only the

binding affinity or structural diversity

but also pharmacologically relevant

physicochemical and biological

properties (or ‘drug likeness’) when

designing compounds. Many of the

authors agree that attention to ‘drug-

likeness’ of the designed libraries during

the earlier stages of the drug discovery

process helps decrease the percentage of

leads abandoned later on owing to

bioavailability or toxicity problems, and

hence decreases the cost of developing

new drugs. Chapter 7 describes an

integrated approach for simultaneous

optimization of pharmokinetic properties

and binding affinity through QSAR and

property prediction techniques.

Chapter 8 presents a ‘consensus’

definition of drug likeness, which can be

used for profiling combinatorial libraries

and is less broad than Lipinski’s ‘rule of

five’. Alternative use of neural networks

to evaluate a ‘drug-likeness’ score is

discussed in Chapter 9.

This book will be useful to graduate

students and synthetic chemists who want

a good introduction to the field of

combinatorial library design and who

want to learn the underlying principles

and available techniques in this area.

Computational chemists will find this

book to be a good review of various aspects

of library design and a source of references

to more detailed publications.

Victor S. Lobanov

3-Dimensional Pharmaceuticals, Inc.,665 Stockholm Drive, Suite 104, Exton,PA 19341, USA.e-mail: victor@3dp.com

Back to basics?

Basic Biotechnology (2nd edn)

Edited by Colin Ratledge and Bjorn Kristianson. Cambridge UniversityPress, 2001. £29.95 pbk (xiii + 568 pages) ISBN 0 521 77917 0

Medicine, food technology and

environmental management are just a

few of the disciplines about which our

perceptions have been changed by the

advances made in the multi-disciplinary

activities of modern molecular biology.

Recombinant DNA techniques, cloning

and genetics have helped to make

biotechnology one of the major industries

of the twenty-first century and yet for the

full benefits of the industry to be reaped,

manufacturing capability involving the

large-scale processing of biological

material is required.

Basic Biotechnology is an excellent text

that introduces a wide breadth of topics

relevant to this industry from molecular

biology and genetics to biochemical

engineering allowing the reader that is

new to the subject to gain an insight as to

how these disciplines interrelate.

The book will be most useful for

undergraduate students studying

biotechnology or bioprocess engineering

because it gives a good overview of a wide

range of subjects likely to be directly related

to their course. To label this book as solely

for undergraduates, however, would be to

do it an injustice for it contains sufficient

depth of detail on many topics to make it

of interest to post-graduates, researchers

and teachers alike. Chapters are laid out

in an easy to read manner while still

enabling the book to be used as a reference

text for specific pieces of information.

Despite contributions from a large number

of authors the book admirably achieves a

continuity of style that is both easily

understood and suitably succinct.

Each chapter is concluded with suggestions

of up-to-date texts for further reading.

Basic Biotechnology is divided into

two sections of approximately equal size.

Part One, entitled ‘Fundamentals and

Principles’, contains chapters on the

biochemistry and physiology of cell

growth and metabolism, genome

management and analysis, bioreactor

design and downstream processing.

The chapters are well ordered and

demonstrate how knowledge of molecular

biology and a familiarity with laboratory

techniques can enhance production

processes and have positive consequences

for process economics. Part Two, entitled

‘Practical Applications’, illustrates and

reinforces the ideas introduced in

Part One with a substantial number of

examples of production processes

covering a broad spectrum of products

such as amino and organic acids,

antibiotics, enzymes and high-value

recombinant proteins. Excellent chapters

are included on biotransformations and

the environmental applications of

biotechnology. The text is deliberately

biased towards established processes

with the philosophy correctly being that

future advances will build on the

application of basic knowledge. This is

not to say that the technologies

discussed are anything but up to date,

because new technology can of course be

applied to well defined processes. Yet

despite this philosophy and given the

likely significance of gene therapy and

DNA vaccines, the production of DNA for

use as a medicine is still perhaps a

notable omission.

It was refreshing to find in a text of

this sort that chapters had been included

on subjects such as the business of

biotechnology, process economics and the

public’s perceptions of biotechnology.

These are topics that have previously been

overlooked in texts of this ilk aimed at the

undergraduate reader. Hopefully this

indicates a growing trend by which students

embarking on careers within the biological

sciences are encouraged to consider more

carefully the economic implications of

research and appreciate that during the

course of their careers they are likely to

have to fulfill roles as decision-makers

within organizations. However, the

continued reluctance of editors such as

Ratledge and Kristianson to include

sections of any substance on regulatory

affairs, validation or current good

TRENDS in Biotechnology Vol.20 No.2 February 2002

http://tibtech.trends.com 0167-7799/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S0167-7799(01)01866-2

87Forum