Policies surrounding xenotransplantation,

and many other emerging high-technology

interventions, must balance opportunity

and risk. Whereas traditional stakeholders,

such as the researcher community,

government agencies and the commercial

sector, readily contribute to the debates

that influence policies, the voice of the

public is seldom heard. Not only does this

raise ethical concerns but also it might

ultimately prove to be shortsighted.

Before any country settles unilaterally on

comprehensive policies governing the

practice of xenotransplantation,

well-informed public opinions need to be

taken into account.

The tension between individual and

societal rights is the basis of an age-old

philosophical debate. That debate

becomes all the more urgent and complex

with the introduction of ever more potent

modern technologies that offer potential

benefits to individuals counterbalanced

by potential risks to society. The

widening of the debate is occasioned by

the growth and increasing prominence of

a powerful and essential group: the

stakeholders. This group, which includes

but is not limited to the commercial

sector, governments, non-governmental

organizations and global organizations,

brings a variety of vested interests to the

debate, not least the huge profits to be

made developing and selling

technologies. This extended conflict

between individuals, society and the

stakeholders is exemplified by the case

of clinical xenotransplantation – the

transplantation of organs, tissues or

cells from another species (probably pigs)

to humans.

There are many tens, if not hundreds of

thousands of individuals each year who

could benefit from a transplant. Yet, given

the shortage of human organs available

for transplantation, many patients wait in

vain. The United Network for Organ

Sharing (http://www.unos.org; the US

organization that maintains the nation’s

organ transplant waiting list under

contract with the Department of Health

and Human Services) has shown that in

the USA alone, the gap between organs

available and organs needed each year

currently stands at 50 000 and is growing

at a rate of 5000–10 000 per year.

However, if pigs could be used as donors,

there would, in principle, be an unlimited

supply of organs, tissues and cells.

Leaving aside the still formidable

challenge of rejection of pig organs by

non-human primates, the pre-clinical

model, the promise of xenotransplantation

has given rise to a new ethical dilemma.

As with all mammals, pigs harbor many

viruses or ghosts of viruses, some active,

some latent and others represented only

by a partial genetic sequence embedded in

the pig genome. Although it is difficult to

assign precise numbers to the risk, many

infectious disease experts agree that it is

possible that pig-endogenous retroviruses

(PERVs) could be transmitted to a human

xenotransplant recipient. In part, this

possibility rests on a 1997 demonstration

that, under specific in vitro conditions,

PERVs can infect human cells [1], and

last year’s demonstration that PERVs

carried in xenotransplanted tissue is

transcriptionally active and infectious

across the pig–mouse species barrier [2].

Given the possibility that PERVs could be

transmitted to a human xenotransplant

recipient, it is further possible that such

an infection could be passed from a patient

to close contacts and even to the general

population. Although scientists,

physicians and others disagree (often

vehemently) on the magnitude of such a

risk [3], few dismiss the risk and many

agree that it is sufficient to require very

serious concern (see Stoye, J.P.

Xenotransplation: panacea or poisoned

chalice? http://www.nimr.mrc.ac.uk/

MillHillEssays/1997/xenotran.htm).

Unfortunately, because of the absence of

data that would allow us to estimate the

likelihood of such an event, this side of the

debate has stagnated for a few years,

awaiting definitive evidence one way or

the other. In the meantime, the dilemma

between individual patient benefit and

societal risk is a significant and difficult

issue that needs to be addressed. And

adding to this seemingly intransigent

problem are the pressures brought to

bear by the various stakeholders for

whom economic considerations are at the

forefront. The economic considerations

are considerable – in 1996, perhaps the

period of peak optimism and excitement

for the commercialization of

xenotransplantation, the investment

specialist firm Salomon Brothers

(New York, NY, USA) estimated that by

2010 xenotransplantation could be part

of a US$ 6 billion market. Although

the high-tech xeno sector has since

cooled significantly, many biotech

companies have invested heavily in

xenotransplantation and are eager to see

their investment pay off. How then

should we proceed? Who is to decide

whether xenotransplantation is desirable

given our current limited knowledge of

the risks? And, if we are to proceed,

under which conditions?

The answer is, in part, clear. In most

societies there are elected or otherwise

designated bodies charged with such

decisions. In the USA, for example, the

government’s Food and Drug

Administration (FDA) plays a crucial role.

But should the FDA or any equivalent

national authority be given almost

complete authority in such decisions?

When dealing with the threat of infectious

agents it is wise to remember that viruses

and other agents do not respect national

borders. In this respect the decisions of

one country might impact others.

The concept of informed consent for

individual patients has become a central

tenet of Western medicine. When faced

with medical decisions, the patient is

informed of the various options and the

relative risks and advantages of each.

This information is provided in a balanced

and authoritative manner. Although

physicians offer guidance and support,

the decision on how to proceed belongs to

the patient. With information in-hand, the

patient consents to a chosen course. But

crucially, the ‘informed’precedes the

‘consent’. For the medical profession, to do

otherwise would be unethical.

Why then should we not apply the

principle of informed consent to entire

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129Forum

Science & Society

A shrewd and ethical approach to xenotransplantation

Fritz H. Bach and Adrian J. Ivinson

communities when it is the community

as a whole that is being exposed to the

risk? At the very least, informed

representatives of the public should be

given an opportunity to participate

actively and meaningfully in the decision

about whether and under what conditions

society is exposed to the risk. If it is

unethical to foist a particular medical risk

on a patient, is it not equally unethical to

expose the public to a risk without first

considering their opinion? Although we

have focused on the potential biological

risk to the public, there are other threats

to be considered. Some are deeply offended

by the thought of putting human genes

into pigs (as in the development of

transgenic pigs the organs of which are

less likely to be rejected by a primate)

whereas others do not want to see pig

organs in people. (Both groups might

worry about compromising the species

barrier.) For some, xenotransplantation

is yet another high-cost medical

procedure that widens the gulf between

the ‘haves’and ‘have nots’and threatens to

consume precious healthcare resources

that would otherwise have been directed

to many more people in need of less

expensive interventions.

We have previously argued that the

public is the most neglected participant in

the discussion about xenotransplantation

[4]. Whereas the recognized stakeholders

have well-developed mechanisms through

which they can be heard and patients

have advocacy groups promoting their

equally legitimate needs, the public has

no ready entrée to the discussion and as a

result is seldom heard. Of course some

governmental bodies do host ‘public’

meetings that anyone can attend. But

this is a far cry from a well-organized

mechanism through which opinion is

actively sought from members of an

informed public.

Critics may counter that there are no

appropriate tools for meaningful public

consultation – to which there are two

rejoinders. First, if indeed there are no

such facilities, then we must develop

them. Just as we would not accept the

defense that a physician failed to inform

his or her patient of all the medical

options and associated risks available to

them because of the lack of a nearby

consultation room, neither can we accept

that public consultation is impossible.

Second, a great deal of progress has in fact

been made towards effective consultation

of an informed public. Methods such as

Citizen’s Juries (see http://www.jefferson-

center.org/citizens_jury.htm), Consensus

Conferences (see http://www.cefic.be/

position/St/pp_st01.htm) and Citizen

Foresight (see http://www.ids.ac.uk/

ids/env/democbio.html) were developed for

just this purpose and have been used

widely by many groups including the

government (see http://www.parliament.

the-stationary-office.co.uk./pa/cm199900/

cmselect.cmsctech/465/465m52.htm),

national research institutes

(see http://www.odp.od.nih.gov/consensus.

about/about.htm), physician groups

(see http://www.rcpe.ac.uk/esd/consensus/

statements.html) and non-governmental

organizations (see http://www.actionaid.org/

pdf/jury.pdf). Indeed the question of

xenotransplantation has been considered

by a Citizen’s Jury assembled by the

University of Calgary (see http://www.fp.

ucalgary.ca/unicomm/Gazette/Jan8-

01/jury.htm). Less formal approaches are

also valuable, including town hall

meetings, and most recently the Internet

is opening up the possibility of virtual

meetings involving people of diverse

backgrounds.

Regardless of the particular approach

taken, if public engagement of this sort is

to be effective, it is crucial that

participants are well informed by

balanced and authoritative data. All sides

of the issue must be presented without

any attempt by the moderators to elicit a

given response or steer the discussion.

The public participants must arrive at

their own conclusions.

The practice of public engagement

does not mean that the few public

representatives set policy. The

responsibility for final decisions and

ensuing polices should not be ceded to the

few tens, hundreds or even thousands of

individuals consulted. Such groups cannot

be representative of the whole population

and were not elected to represent the

population. For that, in many countries

there are political representatives to

whom we delegate such decisions.

Instead, the value of public engagement

is in providing those with ultimate

authority a further angle from which to

view their decisions. In this way, the

public’s voice is added to those of the

traditional stakeholders.

In some countries, such as Denmark,

public involvement in national and local

policy decisions is routine and public

participation has become a civic duty.

In many others, including the USA,

although the principle and desirability of

public participation has been recognized,

it has not been acted upon. Thus,

whereas meetings of the FDA are open to

the public, it is expecting a lot for all but

the most committed members of the

public to find out where and when such

meetings are to be held and then to make

(and fund) their own way to Washington

DC to participate in a meeting often

front-loaded with stakeholder agendas.

Equally important, there is no effort

made to assure that the participants in

these meetings are well informed and

have access to the people and other

resources needed to answer their

questions. (This is a criticism that

applies equally to the well-meaning

attempts by some to gauge public

opinion on complex science by way of

questionnaires or opinion polls.)

Although the future of public

engagement on issues of science and

technology is by no means assured, there

are promising signs. Some researchers,

governmental and non-governmental

organizations and advocacy groups are

turning more of their attention to the

issue. Perhaps most welcome are the

early signs that the commercial sector is

also recognizing the need to involve the

public as evidenced by the recent

experience with genetically modified

(GM) foods. GM foods are a classic case of

potential risk and potential opportunity.

Whereas some argue that GM technology

can revolutionize our ability to grow more

and better food in places that need it the

most, others are concerned with

individual safety, environmental safety

and the dominance of multinational

companies. For better or for worse, the

marketing of GM foods has met strong

opposition. The commercial sector

recognized a potentially powerful

technology and dived headlong into

development and commercialization,

fully expecting to be applauded for their

efforts. Yet in many parts of the world

there was outright rejection of GM

technology. Whereas scholars have

argued long and hard about why GM was

rejected by so many, it soon emerged that

public opinions had formed in a relative

vacuum of objective information. (In a

1999 ‘Eurobarometer’survey on

biotechnology, 35% of respondents agreed

to the statement ‘Ordinary tomatoes do not

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130 Forum

contain genes while genetically modified

tomatoes do’ and 30% answered that they

‘did not know’. See http://europa.eu.int/

comm/research/quality-of-life/

eurobarometer.html) Ignorance of the

true risks and opportunities gave way to

anger and fear.

Could public involvement in the

development of GM technology have

helped? The answer is almost certainly

yes, as suggested by Hendrik Verfaille,

the President of Monsanto (St Louis, MD,

USA), perhaps the biggest commercial

player: ‘We thought we were doing some

great things. A lot of other people thought

we were making some mistakes. We were

blinded by our own enthusiasm. We

missed the fact that this technology raises

major issues for people – issues of ethics,

of choice, of trust, even of democracy and

globalization. As we tried to understand

what had happened, we realized that we

needed to hear directly from people about

what they thought, what their concerns

were and what they thought we ought to

do. If we are to close the gap between

those who believe in the benefits and

those who have concerns, then something

has to change.’

The experience of Monsanto

demonstrates that not only is public

consultation the ethical approach but it

also makes sound business sense.

Returning to the example of

xenotransplantation, several countries in

Europe have maintained a moratorium,

or the equivalent thereof, on

xenotransplantation. Meanwhile, the

FDA has indicated a willingness to

entertain protocols for

xenotransplantation and has given

permission for certain trials of cellular

xenotransplantation. Although we cannot

predict the outcome of these trials, we do

not want to see the future of

xenotransplantation dictated by the

uninformed fears or enthusiasms of any

group, including the public. There is still

time to seek meaningful public

engagement on this question and in so

doing to set the precedent for how we will

tackle questions surrounding cloning,

engineering weather patterns,

nanotechnology and the myriad other

technological opportunities that are

coming our way.

References

1 Patience, C. et al. (1997) Infection of human cells

by endogenous retrovirus of pigs. Nat. Med.

3, 282–286

2 van der Laan, L.J.W. et al. (2000) Infection by

porcine endogenous retrovirus after islet

xenotransplantation in SCID mice. Nature

407, 90–94

3 Daar, A.S. et al. (1998) Xenotransplants: proceed

with caution (Correspondence). Nature 392, 11–12

4 Bach, F.H. et al. (2001) Ethical and legal issues in

technology: xenotransplantation. Am. J. Law &

Medicine 27, 283–300

Fritz H. Bach*

Harvard Medical School, Boston, MA 02115,USA.*e-mail: fritzHbach@aol.com

Adrian J. Ivinson

Harvard Center for Neurodegeneration andRepair, Harvard Medical School, 220Longwood Avenue, Boston, MA 02115, USA.e-mail: adrian_ivinson@harvard.edu

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131Forum

Book Review

Making biotech

Engineering and Manufacturing for

Biotechnology – Focus on Biotechnology.

Volume 4

Edited by Marcel Hofman and Philippe Thonart. Kluwer AcademicPublishers, 2001. £119/US$ 189. (490 pages)ISBN 0 7923 6927 0

The rapid growth in biotechnology

over the past 20 years has led to the

development of ‘Bioindustry’. The editors

of this book have chosen the latest topics

in biotechnology to be the nine categories

featured. The book covers 32 subjects

that were presented at The 9th

European Congress on Biotechnology,

which was held in Brussels, Belgium,

11–15 July 1999.

The most striking feature of this book

is that the editors did not focus on the

recent ‘star’ technologies such as, genetic

engineering, animal cell technology,

cell and tissue engineering, plant

biotechnology, bioinformatics and so on.

Instead, the editors concentrated on basic

microbial-based biotechnology, which

strongly supports the traditional

fermentation and is essential for

‘bioindustry’.

In the manufacture of products using

microbes, development of bacterial strain,

construction and development of the

culture medium, the fermentation process

itself, monitoring the technology and

control systems for cultivation and reactor

engineering to support suitable fermentors

for production, were all necessary.

Part 1 introduces the pretreatment

processes of molasses for utilization in

fermentation, lactic acid fermentation of

hemicellulose and enzymic solubilization

of proteins from fish materials. These

topics are simple but necessary for

bioindustry. In part 2 (entitled ‘process

modeling’) motivation and means of

mathematical modeling were described

and various new and effective procedures

were discussed in detail. Examples of such

methods are macroscopic modeling, the

model discrimination approach, model-

based experimental design and metabolic

flux modeling. This chapter comprised,

more than one third of the book. In part 3

(integrated process), and part 4

(monitoring and control), the integrated

process that combines ultrafiltration and

fermentation, the KLa evaluation method,

respiration quotient (RQ) estimation

method, fuzzy and neural network control

and model-based predictive control were

explained. These techniques are well

known but still important for

fermentation. Part 5 (reactor engineering)

includes one very interesting topic

entitled ‘bioreactors for space’, which

discusses how in the 21st century,

humankind should exploit space.

In contrast to part 5, the development of

immobilization and permeabilization in

traditional fermentation (brewing),

challenging topics in the traditional field,

were well described in part 6.

The editors introduced the idea that

produced materials should be purified

and manufactured as products in part 7.

In the first part of this section, the reader

is taken on a guided tour of industrial

processing and is subsequently introduced

to two good examples.

In the penultimate section, economical

benefits of biotechnology applications were

described and eight detailed case studies

were introduced. In part 9 (patents and

licenses), the patent difference between

Europe and the USA were discussed, and

the important points for translating

European biotechnology into US patents