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13 May 2000

Table of Contents

Precautionary Principle (the view of the US establishment)
Gene therapy corporate connections
UK ACTION: What to do if there is a GM Test Site near you
Gene Therapy on Trial
Gene Therapy Corporate Connections

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Date: 11 May 2000 19:16:29 +0100
From: "j.e. cummins" jcummins@julian.uwo.ca

K. R. Foster is usually at the Department of Bioengineering, University of Pennsylvania, Philadelphia PA 19104, USA; he is now on sabbatical at World Health Organization (WHO), Geneva, Switzerland. P. Vecchia is at the National Institute of Health, Physics Laboratory, Istituto Superiore di Sanite, I-00161 Rome, Italy. M. H. Repacholi is at the Department of Protection of the Human Environment, WHO, Geneva, Switzerland.

*To whom correspondence should be addressed. E-mail: kfoster@seas.upenn.edu

Precautionary Principle (the view of the US establishment)

RISK MANAGEMENT: Science and the Precautionary Principle

By Kenneth R. Foster,* Paolo Vecchia, Michael H. Repacholi*
kfoster@seas.upenn.edu

Few policies for risk management have created as much controversy as the Precautionary Principle. Emerging in European environmental policies in the late 1970s (1), the principle has become enshrined in numerous international treaties and declarations. It is, by the Treaty on European Union (1992), the basis for European environmental law, and plays an increasing role in developing environmental health policies as well.

Despite its seemingly widespread political support, the Precautionary Principle has engendered endless controversy, in part because critics have interpreted "precautionary" decisions as veiled forms of trade protectionism. Recent examples are disputes resulting from "precautionary" decisions to ban American and Canadian beef (because of the use of growth hormones) and to delay approving genetically engineered crops for sale in European markets.

But its greatest problem, as a policy tool, is its extreme variability in interpretation. One legal analysis (2) identified 14 different formulations of the principle in treaties and nontreaty declarations. The Treaty on European Union merely refers to the principle, without defining it. Despite a growing body of case law, including important decisions by the (European) Court of Justice, the legal community remains divided about the meaning and applicability of the principle (3).

In its "strongest" formulations, the principle can be interpreted as calling for absolute proof of safety before allowing new technologies to be adopted. For example, the World Charter for Nature (1982) states "where potential adverse effects are not fully understood, the activities should not proceed." (4). If interpreted literally, no new technology could meet this requirement (5).

Other formulations open the door to cost-benefit analysis and discretionary judgment. For example, the Rio Declaration (1992) says that lack of "full scientific certainty shall not be used as a reason for postponing cost-effective measures to prevent environmental degradation" (6). Still other formulations call for decisions in the absence of any scientific evidence at all: A 1990 declaration on protection of the North Sea calls for action to be taken even if there is "no scientific evidence to prove a causal link between emissions [of wastes onto ocean waters] and effects" (7).

An issue of particular interest to scientists is the relation, if any, of the principle to science-based risk assessment. The principle was initially applied to environmental issues, such as ocean dumping of pollutants, that are characterized by sparse scientific data useful for making policy. Its use has now expanded to protection against environmental health risks, for which extensive toxicological and epidemiological data are often available, notwithstanding gaps and inconsistencies in the evidence. The question arises how to reconcile the principle with the weight of evidence analysis typically used by scientists and health agencies. Recent "precautionary" policies regulating human exposure to radio frequency (RF) fields, such as those produced by communications and broadcasting transmitters, show that there need not be a conflict between the two. This case history is interesting because it involves more nuanced policy options than simple bans of new technologies.

Regulating Exposure to Radio Frequency Fields The possible health effects of RF energy have been studied since World War II, and several thousand bioeffects studies and relevant engineering studies are in the literature. National and international exposure guidelines (8, 9) offer a high level of protection against established hazards of RF energy. These guidelines apply to long-term and short-term exposures of the general public and workers. They were based on a painstaking evaluation of the relevant scientific literature, but do not directly consider cost-benefit analyses or issues of risk acceptability.

These guidelines, however, are based on a literature that is unclear and controversial in many respects. A large number of biological effects of RF energy have been reported, some at low exposure levels, many of which cannot be independently confirmed. Several epidemiological studies have reported weak associations between exposure to RF fields and risk of various diseases including cancer, but these have technical flaws (principally, inadequate exposure assessment) (10). No major scientific review panel in the United States or Western Europe has concluded that low-level exposure to RF fields actually causes health problems.

Yet there has been substantial public concern about health effects from exposure to RF fields, causing widespread and often emotional opposition to the siting of cellular telephone base stations. The RF exposure levels to the public from such facilities are invariably far below international exposure guidelines (11).

In response, several countries have adopted precautionary measures to limit public exposure to RF fields. In 1998, Italy introduced "cautionary" limits that are as low as one-hundredth of international guidelines. Switzerland followed in 1999 by instituting similarly low RF exposure limits for "sensitive-use areas" (such as residential areas, schools, and hospital wards) and banning new construction in areas in which the precautionary limits are exceeded (12). Both limits are somewhat above exposure levels from most cellular base stations but are far below exposure levels from many other RF sources in the environment, including television and radio transmitters. The Swiss limits were based on the lowest levels that were deemed economically and technically feasible. They do not apply to industrial and medical equipment, or even mobile telephone handsets themselves, which are all sources of far higher exposure than cellular base stations.

New Zealand took a different precautionary approach in 1999 when it issued RF exposure standards that follow the international guidelines. The Ministries of Health and Environment considered the limits to "provide adequate protection" but recommended "...minimizing, as appropriate, RF exposure which is unnecessary or incidental to achievement of service objectives or process requirements, provided that this can be readily achieved at modest expense" and called for industry to reduce community concern through nonregulatory approaches (13).

These two approaches differ sharply; in one case, by setting mandatory exposure limits for precautionary reasons and, in the other, by supplementing international limits with precautionary policies aimed at improving the public acceptability of new RF transmitters. The latter is clearly more consistent with traditional approaches to setting exposure limits and is easier to apply in a consistent way to the diverse sources of RF energy in modern society. None of these precautionary approaches were based on any newly identified hazard from low-level exposures.

Guidelines for Use The elusive nature of the Precautionary Principle and the potentially high stakes involved (an industry press release claimed that the new Swiss limits would cost 1 billion Swiss francs) make it important to clarify its use. A recent communication by the European Commission (14) is an important and (by virtue of its official source) influential contribution intended to ward off arbitrary use of the principle (15).

From the point of view of science-based risk assessment, the document is conventional and reassuring, relying for much of its intellectual framework on the famous 1983 "red book" of risk assessment (16). The communication stresses the need for "reliable scientific data and logical reasoning." Before "triggering" the use of the principle, it requires identification of a potentially hazardous effect, with "all effort" being made to "evaluate the available scientific information," "leading to a conclusion which expresses the possibility of occurrence and the severity of a hazard's impact on the environment, or health...." The analysis must also include an assessment of the uncertainties in the scientific data. It stresses the wide range of actions that may be taken under the principle, including no action at all. Perhaps more importantly, the communication provides five guidelines for using the principle in a politically "transparent" manner (see the table below).

Guidelines for Application of the Precautionary Principle* Proportionality
"Measures...must not be disproportionate to the desired level of protection and must not aim at zero risk" Nondiscrimination
"comparable situations should not be treated differently and... different situations should not be treated in the same way, unless there are objective grounds for doing so." Consistency
"measures...should be comparable in nature and scope with measures already taken in equivalent areas in which all the scientific data are available." Examination of the benefits and costs of action or lack of action "This examination should include an economic cost/benefit analysis when this is appropri ate and feasible. However, other analysis methods...may also be relevant" Examination of scientific developments
"The measures must be of a provisional nature pending the availability of more reliable scientific data"... "scientific research shall be continued with a view to obtaining more complete data."
*EC Commentary, 2 February 2000

These recommendations are explicitly aimed at risk management, and the communication stresses that decisions to act (or not) are essentially political. Viewing the Precautionary Principle as part of a process for making provisional decisions about risk management under uncertainty would reduce criticism from its more fervent critics or advocates for more extreme interpretations of it.

Clear guidelines are still lacking for the weight of evidence needed to trigger the principle, and for deciding which of the large range of precautionary measures should be applied in given circumstances. Different standards of proof seem to be needed to invoke the principle than for other regulatory actions –ut how much different are they? Can one justify using the principle to limit public exposure to RF energy to levels far below the threshold for established hazards to address public concerns on the basis of scientific data that major scientific review committees find unpersuasive of a hazard? Conversely, how much evidence of safety should proponents of a new technology be required to provide? Such issues will generate endless controversy and, indeed, may only be settled by litigation (17).

Although some standard of proof is needed, it need not be as high as scientists themselves might wish. For example, in the United States (where few if any laws cite the Precautionary Principle) courts have upheld the ability of government to base regulatory decisions on substantial evidence that is "less than a preponderance, but more than a scintilla" (18). This does not preempt the need for basing decisions on a careful analysis of the relevant scientific data –hich clearly has not occurred in some applications of the principle.

However it is applied, the Precautionary Principle is enshrined in international law, and it is destined to remain a permanent fixture in environmental and health protection. It makes sense to find ways to use it appropriately. By providing guidelines for use of the principle in a politically transparent process, while emphasizing the need for a careful review of scientific data, the EC commentary may help reduce the contentiousness of its application. The Commission certainly leaves a role for science in the process.

References and Notes

  1. However, one authority traces its use back to 1854, in the famous incident when John Snow removed the pump handle from a London well, "curing" a cholera epidemic in the neighborhood. D. Gee, Financial Times (London), U.S. ed. 2, 16 December 1999, p. 14.

  2. D. Vanderzwaag, J. Environ. Law Pract. 8, 355 (1999). See also www.ec.gc.ca/cepa/ip18/e18_00.html

  3. D. Freestone and E. Hey, Eds. Intl. Environ. Law Policy Ser. 31 (1996).

  4. World Charter for Nature, U.N. GA Resolution 37/7 (1982).

  5. One wag has suggested that the Precautionary Principle should be applied (presumably in a strong form) to the use of the Precautionary Principle, which would result in no action – good or bad thing, depending on one's point of view.

  6. Rio Declaration on Environment and Development, 13 June 1992 (U.N. Doc./CONF.151/5/Rev.1).

  7. Declaration of the Third International Conference on the Protection of the North Sea (Preamble) (1990).

  8. International Commission on Non-Ionizing Radiation Protection (ICNIRP), Health Phys. 74, 494 (1998).

  9. IEEE (Institute of Electrical and Electronics Engineers) Standard for Safety Levels with Respect to Human Exposure to Radio Frequency Electromagnetic Fields, 3 kHz to 300 GHz, IEEE Std. C95.1, 1999 Edition.

  10. J. M. Elwood, Environ. Health Perspect. 107 (Suppl. 1), 145 (1999).

  11. Maximum levels of RF exposure to the public from typical cellular base stations are about 1 _W/cm, a factor of about 500 below U.S. regulatory limits at 850 MHz (which generally follow the IEEE C95.1 standard). Cellular base stations transmit at similar power levels as police, fire, and other emergency communications systems and paging systems, and far below those of commercial radio and television broadcasting transmitters.

  12. Swiss Bundesrat, Decree Concerning Protection from Non-Ionising Radiation (NISV). See www.admin.ch/ch/d/as/2000/213.pdf [in German].

  13. For discussion see New Zealand Ministry for the Environment, Ministry of Health, "Towards national guidelines for managing the effects of radiofrequency transmitters: A discussion document," Wellington, New Zealand: Ministry for the Environment. See www.mfe.govt.nz/about/publications/rma/draft_rf_guidelines.pdf

  14. Commission of the European Communities, Communication on the Precautionary Principle, Brussels 02 February 2000. See http://europa.eu.int/comm/off/com/health_consumer/precaution.htm

  15. The commentary does not have binding status as would a regulation or a directive (which are EU "laws"), but is a general guidance as to the basis of future Commission decisions. Most countries mentioned in this Policy Forum are not part of the EU, and the commentary would have only an indirect impact on them.

  16. National Research Council, Risk Assessment in the Federal Government: Managing the Process (National Academy Press, Washington, DC, 1983.

  17. Only limited case law exists on the principle. A recent decision by the European Court of Justice upholds a ban on the export of British beef into EU countries: "[I]n view of the seriousness of the risk [of bovine spongiform encephalopathy] and the urgency of the situation, the Commission did not react in a manifestly inappropriate manner by imposing, on a temporary basis and pending the production of more detailed scientific information, a general ban on exports of bovine [products]." Case E-180/96, United Kingdom of Great Britain and Northern Ireland v. Commission of the European Communities, 5 May 1998. See http://europa.eu.int/cj/en/jurisp/index.htm

  18. Cellular Telephone Company v. Town of Oyster Bay, 166 F.3d 490, 494 (2d Cir. 1999).

Volume 288, Number 5468 Issue of 12 May 2000, pp. 979 - 981 ©2000 by The American Association for the Advancement of Science.


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Date: 11 May 2000 19:24:52 +0100
From: "j.e. cummins" jcummins@julian.uwo.ca

Corporate Connections may also be in crop GM?

Gene therapy corporate connections

BIOMEDICINE: Gene Therapy's Web of Corporate Connections

By Eliot Marshall

Mark Kay, a researcher at Stanford University who has chalked up several recent triumphs in gene therapy, says there was a time when he advised patients directly about enrolling in his studies of hemophilia B. But not any more. Because he is on the scientific board of a company backing this research – Avigen of Alameda, California – he says he keeps an arm's length from clinical work. He lets others who have no stake in the business handle patients. "I still give talks," he says, "but I always mention that I am on Avigen's board and that I get remuneration for this."

Welcome to the new world of genetic medicine. Researchers in gene therapy have become extremely sensitive about perceived conflicts between their financial and scientific portfolios, following the death last year of a volunteer in a clinical trial at the University of Pennsylvania's Institute for Human Gene Therapy (see main text). The trial used a technique for inserting genes into cells that was developed and patented by the institute's head, James Wilson. Wilson and Penn itself have a financial stake in a company Wilson founded to develop the technology.

Wilson's business connections are not unusual. Company sponsorship is pervasive in gene therapy – and for good reason, according to Ronald Crystal, another pioneer in the field, now at the New York Hospital-Cornell Medical School in New York City. Crystal, who developed early cystic fibrosis treatments, says that scientists had to turn to private investors because the clinical tools they need are "very expensive" to develop and were not likely to be funded by National Institutes of Health (NIH) grants.

Indeed, W. French Anderson, the former NIH scientist who filed one of the first applications to perform a clinical trial in gene therapy and who also holds one of the first broad patents in the field, left NIH to pursue this research. In 1987 Anderson helped launch one of the first companies in the field, Gene Therapy Inc. of Gaithersburg, Maryland. By seeking private money, researchers "flipped the whole paradigm of drug development on its head," Crystal says: It put academic clinicians in charge of developing their own medical products – not just testing products created by others. "We are playing the role of a pharmaceutical company."

Crystal holds patents on many gene therapy inventions. He, too, founded a company: GenVec of Gaithersburg, Maryland, which exploits his discoveries under license agreements. In return, GenVec helps pay for Crystal's studies at the New York Hospital. Data from Crystal's efforts to grow new blood vessels in patients with heart disease, for example, are featured in GenVec's press releases. But Crystal says that, to avoid conflicts, he does not get directly involved in patient care. Nevertheless, his dual roles as clinician and businessman recently drew press attention, because he asked the government not to disclose a report he filed on deaths that had occurred among his patients. Crystal and outside reviewers had concluded that the deaths were caused by the patients' underlying disease, not gene therapy. Crystal's request, which was not honored, did not violate federal guidelines.

It was the Penn case, however, that brought potential conflicts of interest to the fore. Like other leaders in the field, Wilson holds patents on several gene therapy delivery techniques, one jointly with Francis Collins, director of the National Human Genome Research Institute. And in 1992, Wilson founded a company – Genovo of Sharon Hill, Pennsylvania – which has R&D agreements with two larger companies, Biogen Inc. and Genzyme, both in Cambridge, Massachusetts. Genovo uses some of the revenue from these deals to help support Penn's gene therapy institute, reportedly providing about $4 million a year. The institute, which has a budget of about $25 million, also receives federal grants and other revenue. Penn's guidelines do not allow faculty members to hold an executive position in an outside business such as this. But Wilson, an unpaid consultant to Genovo, holds equity in the company, as does Penn.

News reports have spotlighted an apparent conflict between Wilson's and Penn's responsibility to give primary attention to the needs of patients and their obligation to provide data to corporate sponsors. The gene therapy trial in which the patient died was not expected to benefit the enrolled patients, but it had a good chance of developing information that could improve the prospects of Genovo. Although Wilson was involved, his connection to Genovo apparently did not violate university or NIH guidelines on conflict of interest because Wilson was not directly involved in the recruitment or care of patients in the clinical trial, nor did Genovo finance the trial. Arthur Caplan, director of Penn's Institute for Bioethics, says Wilson was just "the vector supplier," and it is "irresponsible" to suggest he was influenced by financial interest. (Wilson declined to comment through a Penn spokesperson, who also declined to respond to questions about the university's policies submitted by fax.)

The furor over this case prompted the American Society of Gene Therapy, of which Wilson was president in 1999, to issue a statement on conflicts of interest in April. It essentially echoes the NIH guidelines. It says that members who are "directly responsible for patient selection, the informed consent process and/or clinical management in a trial must not have equity, stock options or comparable arrangements in companies sponsoring the trial." Crystal supports it, saying, "we already had that in place" in his clinic. Anderson, likewise, says he has followed this rule in all 16 clinical trials he's been involved in.

The American Society of Human Genetics (ASHG) – whose membership is less directly involved in gene therapy – also issued a statement in April calling for caution in gene therapy. But it stopped short of ruling on conflicts of interest. ASHG president Ron Worton of Ottawa Hospital Research Institute says: "We debated ... a ban on recruitment of patients by physicians who have a financial interest," but board members didn't want to take that step, arguing that "this is something traditionally policed by the universities." But, as the Penn case illustrates, universities themselves may have potential conflicts to be policed.

Volume 288, Number 5468 Issue of 12 May 2000, pp. 954 - 955 ©2000 by The American Association for the Advancement of Science.


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Date: 12 May 2000 05:26:22 +0100
From: RBBAX@aol.com
From: jeanews@gn.apc.org (Jean Saunders) FoE campaigner

PLEASE CIRCULATE

Here is some helpful advice.......

UK ACTION: What to do if there is a GM Test Site near you

Sections:
Prepare yourself
Fund raising
Holding a public meeting
Ideas for events during the campaign
Types of Direct Action (DA).
Ideas for events during the campaign
Types of Direct Action (DA).
'Symbolic' crop pulling actions in the genetiX snowball style.
Crop Squats.
'Known and trusted' daytime actions.
Covert crop-pulling.

Panic, over react and then kill yourself.

OR:

Prepare yourself

Fund raising

Holding a public meeting

Ideas for events during the campaign

The ideas below often fulfil several different purposes - group bonding, awareness raising, involving more people, pressuring the farmer, creating media opportunities and 'hooks' for stories.

Types of Direct Action (DA).

Types of DA will depend to a large extent on the local group dynamics and size of the site. The question 'what are we trying to achieve with this action?" needs to be asked as early as possible. Some of the methods that have already been used are highlighted below. There are a huge variety of approaches, all of which have their advantages and disadvantages. Some will appeal to certain parts of the community while others may feel alienated by them, again a difficult balance to strike.

Certainties are few and far between in the world of direct action. Coping with uncertainty can be very hard and stressful but taking direct action can be one of the most wonderful and liberating experiences. However, some people can be traumatised by the event. (See http://www.whytakeda .) The level of preparation and planning is likely to maximise the effectiveness and minimalise the 'causalities'. There are many vital tasks involved in any DA, which have virtually no chance of arrest. So if people support the DA but for whatever reason do not want to risk arrest they can still be involved. Farmers are obviously not going to take kindly to any form of DA on their land.

What we need to bear in mind is that the farmers may be scared of us. Covert or partly covert actions may make them think that their lives, families and farms are under threat, possibly eliciting a dangerously violent response. (Images of groups of masked people with scythes at night are understandably scary, even if the person behind the mask is the most peaceful person on earth.) The time to decide, if the group is taking any sort of action (apart from mass open actions) whether to employ the 'all for one and one for all' or 'every person for themselves' strategy is not when you're up to your neck in GM plants.

The legal notes at the bottom of each type of action are for guidance only and only relate to the situation in Britain. The response of the 'justice' system can vary considerably with the political climate, local attitudes, individuals involved, type of action and company response. If you're seeking the advice of lawyers avoid putting them in professionally difficult situations by letting them know of a "crime" that might be committed. By asking hypothetical questions "hypothetically speaking if someone were to pull up the site what might the charges be?" Lawyers seem to be duty bound to tell you the worst case scenario which, by it's nature, is actually highly unlikely - you may have to push hard for the most likely outcome.

Here is some more helpful advice.......

Ideas for events during the campaign

The ideas below often fulfil several different purposes - group bonding, awareness raising, involving more people, pressuring the farmer, creating media opportunities and 'hooks' for stories.

Types of Direct Action (DA).

Types of DA will depend to a large extent on the local group dynamics and size of the site. The question 'what are we trying to achieve with this action?" needs to be asked as early as possible. Some of the methods that have already been used are highlighted below. There are a huge variety of approaches, all of which have their advantages and disadvantages. Some will appeal to certain parts of the community while others may feel alienated by them, again a difficult balance to strike.

Certainties are few and far between in the world of direct action. Coping with uncertainty can be very hard and stressful but taking direct action can be one of the most wonderful and liberating experiences. However, some people can be traumatised by the event. (See www.whytakeda.) The level of preparation and planning is likely to maximise the effectiveness and minimalise the 'causalities'. There are many vital tasks involved in any DA, which have virtually no chance of arrest. So if people support the DA but for whatever reason do not want to risk arrest they can still be involved. Farmers are obviously not going to take kindly to any form of DA on their land.

What we need to bear in mind is that the farmers may be scared of us. Covert or partly covert actions may make them think that their lives, families and farms are under threat, possibly eliciting a dangerously violent response. (Images of groups of masked people with scythes at night are understandably scary, even if the person behind the mask is the most peaceful person on earth.) The time to decide, if the group is taking any sort of action (apart from mass open actions) whether to employ the 'all for one and one for all' or 'every person for themselves' strategy is not when you're up to your neck in GM plants.

The legal notes at the bottom of each type of action are for guidance only and only relate to the situation in Britain. The response of the 'justice' system can vary considerably with the political climate, local attitudes, individuals involved, type of action and company response. If you're seeking the advice of lawyers avoid putting them in professionally difficult situations by letting them know of a "crime" that might be committed. By asking hypothetical questions "hypothetically speaking if someone were to pull up the site what might the charges be?" Lawyers seem to be duty bound to tell you the worst case scenario which, by it's nature, is actually highly unlikely - you may have to push hard for the most likely outcome.

'Symbolic' crop pulling actions in the genetiX snowball style.

See http://www.gn.apc.org/pmhp/gs . A small number of plants are safely, openly and accountably pulled up. These can be very 'press friendly' actions.

This type of action is very challenging to the companies involved, breaking down the myth of 'vandals'. Legal A wide range of responses. From nothing through to being charged with aggravated trespass under the criminal justice bill '94. Furthermore injunctions have been awarded against participants of genetiX snowball actions, if you don't break the injunctions then no further action is likely. Surprisingly nobody has been charged with 'criminal damage' which would be the most likely charge. Because of the tight 'affinity group' nature of these actions the risk of "inappropriate" behaviour, i.e. being violent, by any of the people on the action is massively reduced.

Crop Squats.

There have been several successful crop squats. A very clear demonstrable action that moves from problem to solution, i.e. stop GM and grow diverse, locally consumed organic food. (Some of the authors question whether giving the impression that you can grow 'organic' food in a former GM site is a good idea. However they recognise that we need to show what the positive alternatives are.)

Crop squats can either be on sites that have not been planted (very difficult to find!) or on sites that have already been destroyed. The group needs to decide how long they intend to stay. Previous ones in Britain have ranged from one day to two weeks. Is there adequate people, energy and resources to hold the site?

Legal Nobody has been arrested at a crop squat, it is primarily a civil issue between the farmer and the squatters, although the police may have some powers under the criminal justice act to remove people.

Mass public open crop pulling actions, like the massively successful Watlington action in '99 when over 500 people openly pulled up a farm scale trial. Variations of this rally to or near the site, and then for those who want to pull up as many plants as possible, have been done over the past few years. The police response is likely to be a major factor in the level of crop pulling and potential arrests. Mass actions do have a large 'unknown and uncontrollable' element which make them exciting but stressful to organise.

Legal Again massive variation. Sometimes the police have 'picked off the organisers' at the action and left other people to 'get on with it', or at Watlington the police seemed to make a few 'symbolic arrests' just so they appeared to be doing something.

'Known and trusted' daytime actions.

Quietly publicised among 'known and trusted' people, halfway between covert and open actions. A group of people go to the site without trying to attract attention, do the job and leave. These type of actions get away from a lot of the paranoia of covert actions but can lead to serious legal ramifications so should not be entered into lightly. Legal Hopefully the action should be a straightforward. People should be prepared to be arrested and the possible serious consequences.

Covert crop-pulling.

Is usually effective, exciting and empowering. Nearly 40% of commercial tests were pulled up in Britain in 1999, by people doing some 'night time gardening'. See http://www.nighttimegardeningguide . Legal Nobody has been caught yet so the legal response is unknown, but is

likely to be 'criminal damage'. The police may be keen to try and pin other similar offences on anyone so 'leave no trace' and 'no comment' ALL their questions. See http://www.don'tgetcaught/ .

Mechanical means to destroy the crop. In '99 Greenpeace used a tractor and disk cutter to chop down most of a farm- scale trial. Various other types of vehicles and rollers or cutters could be very effective at destroying the crop. What effect it would have on the public mind is difficult to predict. Legal The 'justice' system is likely to take a very dim view of such actions. Any machinery or vehicles used are likely to be impounded.

Direct action is about taking control of every aspect of our lives. The homes we build, the food we eat, the way we travel, the culture we enjoy, the games we play. It is not just about the occasional protest but about taking power away from the politicians, businesspeople and, bureaucrats, and participating immediately and directly in radical social and ecological change.


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Date: 12 May 2000 07:50:01 +0100
From: "j.e. cummins" jcummins@julian.uwo.ca

Gene Therapy on Trial

By Eliot Marshall, Science May 12 2000: 951-957.

Sections:
Design by committee
Surprising toxicity

A flurry of reports and congressional hearings, sparked by the death of a volunteer in a study at Penn, are due in the next few weeks. The Penn episode points up a central problem: The field still lacks an ideal vector

Dusty Miller, a veteran gene therapy researcher, wants to test a new idea for treating cystic fibrosis. He has engineered a strain of virus to create a new "vector" to inject useful genes into cells. He has tested it in his lab at the Fred Hutchinson Cancer Research Center in Seattle, getting "wonderful" results in mice. Although he can't guarantee that it's safe for human use, he's confident that it is. Yet he's hesitating about testing it in patients, stretching out preliminary research while using an established but, he thinks, less efficient vector in volunteers. He's being supercautious, he says, because the "climate for gene therapy" has turned cold.

The chill set in on 17 September 1999. That's when Jesse Gelsinger, a young volunteer, died in a gene therapy trial at the University of Pennsylvania in Philadelphia, triggering a blitz of media and government attention. The Food and Drug Administration (FDA) has issued Penn a warning letter and shut down all clinical trials at Penn's Institute for Human Gene Therapy while it investigates what happened. The chill intensified last week when FDA made public a warning letter to cardiac specialist Jeffrey Isner of St. Elizabeth's Medical Center in Boston, alleging infractions of FDA rules in a gene therapy trial for heart disease in which one patient's cancer could have been exacerbated by the treatment and, FDA contends, a death was not properly reported. Isner's studies are now on hold. FDA also halted several other gene therapy trials around the country last winter while investigating vector toxicity.

And the climate is likely to become even more inhospitable over the next few weeks, when a blizzard of reports and hearings are expected. The Senate Health committee is planning a public hearing, its second on the Penn case. The House Commerce subcommittee on oversight and investigations has a probe under way; Penn, according to an official, has sent the committee "truckloads" of files, many of them demanded by Representative John Dingell (D-MI), the committee's fearsome inquisitor. The National Institutes of Health (NIH) has two groups looking into what happened. Penn is conducting two inquiries of its own: one led by its provost and another by an outside panel, due this week. In addition, Penn is concerned that Gelsinger's family may sue. Meanwhile, FDA and other agencies are scrutinizing gene therapy programs around the country. Miller, for example, says FDA inspectors have paid two surprise visits to his lab this year, demanding to see colleagues' lab notes.

Public attention in this round of reports and investigations is likely to focus on who's to blame for errors, whether patients were adequately informed of the risks, and whether the tangle of relationships among companies, investigators, and institutions has created unacceptable conflicts of interest in the field (see sidebar, p. 954). Many clinicians fear that support for gene therapy will buckle under the onslaught.

At the scientific level, what happened at Penn holds two important lessons that are likely to get swamped in the publicity over the next few weeks. The first is the story of the vector James Wilson, director of Penn's gene therapy institute, and his team used: a patented version of a common respiratory tract virus – adenovirus – that had been stripped of certain genes to make it more innocuous. Researchers had once pinned their hopes on adenovirus vectors, believing they would overcome a basic problem that has dogged gene therapy since its inception: the difficulty of getting genes into target cells and, once there, getting the genes to express their proteins. Now some investigators think that, because of their inherent problems, adenovirus vectors may be limited to narrow uses. The problem is, every vector that has been investigated also has limitations (see sidebar, p. 953).

"Cannonball with spikes." The adenovirus capsid protein, which encases the genome, may trigger a powerful immune reaction at high doses, many researchers believe. It is essential for transporting genes into target cells.

ILLUSTRATION: C. CAIN

The second lesson involves the nature of clinical research itself. Although it's a shock when a patient dies in a toxicity test, says a clinician who has supervised many such trials, it is not unusual. "If you were to look in [a big company's] files for testing small-molecule drugs," he insists, "you'd find hundreds of deaths." Often, warning signs become clear only in retrospect, and many clinicians believe that's what happened in the Penn trial. Hints of toxicity had cropped up in previous experiments done by Wilson and others, but the Penn team may have been misled in one crucial respect by animal data that did not translate to humans.

But others suggest that clinicians at Penn should have been more sensitive to the risks, especially because they were injecting a potentially toxic vector into relatively healthy volunteers. "There were many places where this should have been stopped," says Huntington Willard, a molecular geneticist at Case Western Reserve University in Cleveland and a member of the American Society of Human Genetics board. Several leaders in the field have said that they knew that directly injecting the livers of volunteers with huge quantities of immunogenic viral particles (38 trillion at the highest dose) was risky. But they did not intervene, and the trial was given a green light by several local and federal agencies. Today, Willard sees "a very strong parallel" between a rush to the clinic in gene therapy and the space shuttle Challenger explosion. "It takes an event like that," he says, to let people see "just how dangerous some of this stuff really was." Willard concludes that "we need to take a much more sober view of where this field is going."

Design by committee

Regardless of what the critics think, says Arthur Caplan, director of Penn's Institute for Bioethics, people designed this gene therapy trial with the best intentions. He recalls how Mark Batshaw, a pediatrician at Penn in the early 1990s, now at Children's National Medical Center in Washington, D.C., wanted to save children born with a deadly liver problem.

The disease occurs when a gene on the X chromosome is missing or defective, producing too little of a liver enzyme, ornithine transcarbamylase (OTC), that's needed to remove ammonia from the blood. Many infants become comatose at birth and die. Some with mild deficiencies – like Jesse Gelsinger – can survive if they keep to a strict diet and take compounds that help eliminate ammonia. But there's no substitute for natural OTC. And even mild deficiencies can be deadly. Gelsinger, for example, neglected his OTC regimen and nearly died in 1998. Caplan says Batshaw "was the pivotal guy" in Penn's OTC gene research: "He was tired of burying babies."

Batshaw, Wilson, and a surgeon at Penn named Steven Raper, the principal investigator, devised a plan in 1994-95 to transfer healthy OTC genes into people who lack them. (Through a Penn spokesperson, Raper and Wilson declined to comment.) The objective, according to the protocol, was to develop "a safe recombinant adenovirus" that could infect the livers of patients and release OTC. Wilson's institute at Penn and the private company he founded had additional goals: to develop vectors for treating liver diseases and other illnesses.

The improved adenovirus vector developed at Penn seemed like a "wonder vector" back in 1995, Miller recalls. It was easy to grow, versatile, capable of infecting both dividing and nondividing cells, targeted the liver (as everyone assumed), and was quick to express genes in tissue. This vector was the right tool, Batshaw still argues: "Adenovirus is the only one that works rapidly enough, even now." He explains that whereas most other vectors take 3 to 6 weeks to begin working, adenovirus vector starts to express genes within 24 hours.

This could be crucial for treating newborns with severe cases of the disease. You need quick action, he says, "if you're trying to get kids out of hyperammonemic coma" and prevent death or mental retardation. "Our plan was to use the adenovirus to get them out of coma; that would last for a few months," then go to second-stage gene therapy with a different vector – one problem with this vector is that gene expression is of limited duration – or possibly to liver transplantation.

But the plan changed when ethicists looked at it. Caplan, who was recruited to Penn shortly after Wilson, argued that it would be preferable to begin with adult volunteers because the trial was designed only to test toxicity. Later, infants could be enrolled. The initial subjects would have no chance of benefiting, in part because adenovirus vector can be given only once. It sets up an immune response that usually causes the body to eliminate the vector if it is used again. This meant that no one who took part in this trial could hope to benefit from adenovirus gene therapy at a later time.

Even in ordinary circumstances, Caplan says, obtaining parental consent for experiments on children is "a problem." But it's especially tough "if you're trying to explain to parents in the middle of a crisis that you're only doing a safety study" that would not help a critically ill child. Caplan argued that it was "wrong to do nontherapeutic research on someone who cannot consent."

Batshaw and other OTC experts then took part in a meeting of the National Urea Cycle Disorders Foundation, run by parents of OTC children, to talk about these issues. "At the end of a 2-hour conference," Batshaw recalls, "they came to the same conclusion: It would be better to treat the adults." NIH's Recombinant DNA Advisory Committee (RAC) agreed in a 1996 discussion.

The RAC review was just one of many ethics and safety reviews the trial had to clear before it could begin. The process brought about several small changes and one double reversal. Some members of the RAC thought the plan to inject adenovirus vector directly into a hepatic artery was too risky. But the majority gave consent, provided that the vector was put in a peripheral vein. Penn agreed to this change.

In 1997, safety reviewers at the FDA argued that it would be less risky to go directly into the liver. FDA at that time was worried that gene therapy experiments might alter human germ cells and pass risky genes to future generations. FDA's experts felt that by channeling the virus vector into the hepatic artery, it would be concentrated in one lobe of the liver, limiting overall exposure. Everyone assumed that adenovirus had a strong affinity for human liver cells and would be quickly concentrated in them. The Penn team agreed to go back to its original plan of inserting the vector directly into the hepatic artery. But Wilson neglected to inform RAC that it was taking FDA's advice. Wilson apologized to the RAC in December 1999.

Routine toxicology studies in mice, rhesus monkeys, and baboons were reassuring, Penn concluded, although they indicated toxicity at high doses. For example, early versions of the adenovirus vector plus OTC gene damaged the liver of rhesus monkeys, and monkeys given the highest doses died. The improved vector to be used in the clinical trial – from which a different viral gene was removed – appeared to be less toxic, although baboons still showed liver inflammation at high doses. The Penn team proposed using a maximum dose in humans that would be about 5% of the dose that produced maximal toxicity in nonhuman primates. And they proposed climbing toward that level in five threefold increases, with each step involving three patients.

Satisfied with Penn's plan and responses to queries, FDA gave the trial a green light in 1997. The first of 18 volunteers, a woman, was given a 2-hour infusion of vector with OTC genes on 7 April 1997. Most patients experienced fever and other moderate symptoms. The 10th and 12th patients exhibited signs of liver stress, with liver enzymes in serum higher than the normal upper limit (8 and 5.3 times higher, respectively). FDA later reprimanded Wilson's team for failing to pause and consult FDA by phone at this point. The trial proceeded "like a train," says one outside clinician, until it was halted abruptly on 17 September 1999 when Gelsinger, the 18th patient, died.

Surprising toxicity

After Gelsinger's death, Wilson led scores of researchers in a months-long search for a cause. As possibilities were eliminated, the Penn clinicians were left with one conclusion: Gelsinger died from a massive immune response to the adenovirus vector itself.

The "most unexpected finding" in the postmortem, Raper said at a RAC meeting in December 1999, was that precursors for red blood cells in the boy's bone marrow had been wiped out. The Penn team concluded that this probably did not happen in the short 4-day period of gene therapy. Raper and Wilson speculated at the RAC meeting that a preexisting parvovirus infection might have done the damage. In addition, Batshaw notes, it's possible Gelsinger had inherited a mutation that caused an exaggerated response to adenovirus. But no evidence for either theory has been found. The blood cell problem remains unexplained but appears not to have been the cause of death.

Wilson and Raper also noted that Gelsinger's blood contained high and sustained levels of interleukin-6 (IL-6), a cell signaling protein (cytokine). Even now, researchers don't understand why it was so high, but they do know that IL-6 often surges after an insult to the body, contributing to inflammation. Raper called it "an immune revolt." A systemic inflammation flooded Gelsinger's lungs with fluid, causing acute respiratory failure and death.

Vector designers have long known that adenovirus triggers an immune response, but for gene therapy trials, they have taken out some of its genes in an attempt to reduce its immunogenicity. Wilson and Ronald Crystal at the New York Hospital-Cornell Medical School in New York City, among others, have patented forms of adenovirus with bits of the genome removed. For the OTC trial, Wilson used a 1996 version of the vector with two key genes deleted.

Some researchers – such as Art Beaudet of Baylor College of Medicine in Houston and Inder Verma of the Salk Institute in La Jolla, California – say there were warning signs that vectors containing any active adenovirus genes were risky and could cause inflammation. The most dramatic early sign came in a 1993 gene therapy trial conducted by Crystal. He was using an early adenovirus vector to inject healthy genes into the lungs of cystic fibrosis patients. During the experiment, a subject known as "patient number three" developed a severe inflammatory reaction, including a rapid increase in IL-6.

Crystal reported later that he saw patients' IL-6 levels rise in serum "within 2 to 4 hours after vector administration," and that the peak IL-6 "correlated well" with vector dose. Crystal felt that the inflammation had not been caused by adenovirus itself but by the large volume of fluid used to deliver it. Animal studies had not warned of this possibility, he wrote: It "was a surprise."

Some see a parallel with Gelsinger's reaction: "The patient had high IL-6 levels in plasma, the whole syndrome, including a single-lobe ARDS [adult respiratory distress syndrome]," the proximate cause of Gelsinger's death, says one clinician. The patterns, he says, are "similar." Beaudet, who saw a baboon die of adenovirus toxicity in a preclinical study, also sees a similarity.

But Crystal does not think the 1993 and 1999 cases are comparable. In a RAC meeting last December, he said the inflammation in 1993 was the only serious adverse event attributable to adenovirus in his team's "140 administrations of vector." It occurred "when we were using a larger volume to administer the vector to the bronchi" and a primitive vector containing more viral genes.

Crystal wasn't the only one, however, to report an inflammatory response. Among others, Richard Boucher of the University of North Carolina, Chapel Hill, also ran into the problem in 1994-95 while treating cystic fibrosis patients. He abruptly stopped the trial. "We had two concerns," Boucher recalls. One was that adenovirus "just didn't work," because "it didn't get in" to the targeted cells. And second, "if you pushed [the dose] you got into troubles from flat-out protein load."

The North Carolina group followed up with animal studies and concluded that adenovirus vector was stimulating nerve fibers in the epithelium and triggering an inflammatory response. Boucher concluded in 1995 that "it was a capsid protein problem" – a reaction caused by the virus's outer shell – and sent his findings to FDA and published them.

An expert who followed these results, speaking on background, says: "In retrospect, we really should have learned more" from Crystal's experience. "We knew this stuff was toxic back in 1993" for use in the lung. "Why did we think that a damaged liver would be any different?" But, although cytokine release may seem important now, this expert still doesn't think it points to a "clear answer." It only suggests that, "in some people, you get a whopping cytokine response." Robert Warren, an oncologist at the University of California, San Francisco, pointed out at the December RAC meeting that he gave 25 cancer patients adenovirus vector doses nearly as large as the one given to Gelsinger, "and we have not seen anything close to this problem." However, several patients did have other serious adverse reactions, including loss of blood pressure.

The Penn team was taken aback by the lung inflammation, but in view of that reaction, it was astonished to see little liver damage. Relying on mouse studies, they had expected to see adenovirus concentrated in the liver. Instead, as a postmortem revealed, the vector was everywhere. To figure out what happened, Wilson gave the vector intravenously to mice. Tagged adenovirus vector first appeared in macrophage or scavenger cells in the liver, called Kupffer's cells (which secrete IL-6). Later, it reached the intended target, primary liver cells (hepatocytes). This "may not be a good thing," Wilson said at the RAC meeting in December, because low doses of vector might not put enough OTC genes into hepatocytes, and high doses might saturate nontarget organs. This might explain the low gene transfer rate (less than 1%).

Animal data may have given clinicians false hope that adenovirus would work well in the human liver. A key docking site adenovirus uses to enter a cell, known as the Coxsackie adenovirus receptor (CAR), is much more abundant in mouse livers than in human livers. In fact, "rodent models might be misleading" for gene therapy, says Jeffrey Bergelson of the Children's Hospital of Philadelphia.

Again, the warning signs were there before Gelsinger entered the Penn experiment but may have become obvious only in retrospect. Bergelson published a paper in 1998, a year after the trial began, reporting that he found "barely detectable" signs of CAR in human liver, while signs of CAR were "off the wall" in mouse liver. One implication, Bergelson notes, is that clinicians relying on the mouse model may find it necessary "to give higher and higher doses" to deliver genes to the human liver.

A mortal blow for adenovirus? Expert opinion is divided on whether the tragic events at Penn should spell the end of the once-promising adenovirus vector for treating genetic diseases. The key question is whether the virus can be re-engineered to eliminate the immune response.

Researchers have been trying for more than a decade to create a tamer adenovirus. The virus is shaped like an icosohedral box studded with "penton" bases that support long fibers – described by FDA gene therapy specialist Philip Noguchi as "a cannonball with spikes." The box, or capsid, shields the genome. Modifications such as those used by Wilson and Crystal have focused on editing out key bits of DNA inside the capsid that are expressed early during infection of a cell, genes labeled E1 through E4, which trigger immune reactions. The goal is to make the vector as stealthy as possible. The fewer viral proteins the immune system "sees," the less likely it will attack. And the longer the vector survives, the better its chances of delivering therapeutic genes.

For the OTC trial, Wilson used a version with E1 and E4 genes deleted. In his cystic fibrosis trials, Crystal has used a version with E1 and E3 deleted, which he claims can even be given safely in repeat doses. Since switching to an inhaled spray containing this new vector, Crystal says, "we have had no significant serious toxicities."

Some scientists have also attempted to create fully "gutless" vectors by hollowing out all viral genes and replacing them with substitutes. They include Jeffrey Chamberlain at the University of Michigan, Ann Arbor, Beaudet and Larry Chan at Baylor, and a group at Merck in Whitehouse Station, New Jersey, under former executive Thomas Caskey. Beaudet and Caskey say researchers in their labs have observed virtually no toxicity when their gutless vector is given to mice at high doses. However, it is hard to eliminate contamination by live "helper" virus and to produce high-concentration batches.

High doses may still be required to produce a clinical benefit, and, as Boucher suggested in 1995, high doses may run into toxicity from capsid proteins. Wilson suggested as much in the December RAC meeting, and Noguchi and FDA toxicologist Anne Pilaro have raised this possibility in several meetings. So has Salk's Verma, who co-authored a 1998 study of adenovirus vector that called for a "reevaluation" of its use in long-term gene therapy.

Recently, FDA staffers heard from another scientist who concluded 5 years ago that adenovirus capsid protein toxicity was a problem: Prem Seth, senior scientist at the Human Gene Therapy Research Institute in Des Moines, Iowa. Based on studies he did in the mid-1990s, he concluded that "empty capsids appear to be immunogenic, like intact virus," and produce similar effects, like cytokine release. He never published the data, because "there wasn't much interest."

This analysis suggests that even gutless vectors may be dangerous in some circumstances, but the jury is not in. "It's still debatable," says Chamberlain. Beaudet agrees: "Based on our published mouse data," he says, "we think the capsid proteins are not a big problem." But he concedes that there are "not convincing data yet" from nonhuman primates to settle the issue.

As far as Noguchi is concerned, "the most critical issue for the field right now" is determining the risk of these new, "safe" vectors. "Are there two types of toxicity with adenovirus or just one?" he asks. Is the shell itself a problem, in addition to viral gene expression? "What is its inherent toxicity? Is this the dose-limiting thing? We need to rethink these hard questions."

For many people in the field, however, the critical question over the next few months is whether they will be able to continue gene therapy trials while everyone rethinks these questions.


Top PreviousFront Page

Date: 12 May 2000 08:12:22 +0100
From: "j.e. cummins" jcummins@julian.uwo.ca

Gene Therapy Corporate Connections

By Eliot Marshall

Mark Kay, a researcher at Stanford University who has chalked up several recent triumphs in gene therapy, says there was a time when he advised patients directly about enrolling in his studies of hemophilia B. But not any more. Because he is on the scientific board of a company backing this research – Avigen of Alameda, California – he says he keeps an arm's length from clinical work. He lets others who have no stake in the business handle patients. "I still give talks," he says, "but I always mention that I am on Avigen's board and that I get remuneration for this."

Welcome to the new world of genetic medicine. Researchers in gene therapy have become extremely sensitive about perceived conflicts between their financial and scientific portfolios, following the death last year of a volunteer in a clinical trial at the University of Pennsylvania's Institute for Human Gene Therapy (see main text). The trial used a technique for inserting genes into cells that was developed and patented by the institute's head, James Wilson. Wilson and Penn itself have a financial stake in a company Wilson founded to develop the technology.

Wilson's business connections are not unusual. Company sponsorship is pervasive in gene therapy – and for good reason, according to Ronald Crystal, another pioneer in the field, now at the New York Hospital-Cornell Medical School in New York City. Crystal, who developed early cystic fibrosis treatments, says that scientists had to turn to private investors because the clinical tools they need are "very expensive" to develop and were not likely to be funded by National Institutes of Health (NIH) grants.

Indeed, W. French Anderson, the former NIH scientist who filed one of the first applications to perform a clinical trial in gene therapy and who also holds one of the first broad patents in the field, left NIH to pursue this research. In 1987 Anderson helped launch one of the first companies in the field, Gene Therapy Inc. of Gaithersburg, Maryland. By seeking private money, researchers "flipped the whole paradigm of drug development on its head," Crystal says: It put academic clinicians in charge of developing their own medical products – not just testing products created by others. "We are playing the role of a pharmaceutical company."

Crystal holds patents on many gene therapy inventions. He, too, founded a company: GenVec of Gaithersburg, Maryland, which exploits his discoveries under license agreements. In return, GenVec helps pay for Crystal's studies at the New York Hospital. Data from Crystal's efforts to grow new blood vessels in patients with heart disease, for example, are featured in GenVec's press releases. But Crystal says that, to avoid conflicts, he does not get directly involved in patient care. Nevertheless, his dual roles as clinician and businessman recently drew press attention, because he asked the government not to disclose a report he filed on deaths that had occurred among his patients. Crystal and outside reviewers had concluded that the deaths were caused by the patients' underlying disease, not gene therapy. Crystal's request, which was not honored, did not violate federal guidelines.

It was the Penn case, however, that brought potential conflicts of interest to the fore. Like other leaders in the field, Wilson holds patents on several gene therapy delivery techniques, one jointly with Francis Collins, director of the National Human Genome Research Institute. And in 1992, Wilson founded a company – Genovo of Sharon Hill, Pennsylvania – which has R&D agreements with two larger companies, Biogen Inc. and Genzyme, both in Cambridge, Massachusetts. Genovo uses some of the revenue from these deals to help support Penn's gene therapy institute, reportedly providing about $4 million a year. The institute, which has a budget of about $25 million, also receives federal grants and other revenue. Penn's guidelines do not allow faculty members to hold an executive position in an outside business such as this. But Wilson, an unpaid consultant to Genovo, holds equity in the company, as does Penn.

News reports have spotlighted an apparent conflict between Wilson's and Penn's responsibility to give primary attention to the needs of patients and their obligation to provide data to corporate sponsors. The gene therapy trial in which the patient died was not expected to benefit the enrolled patients, but it had a good chance of developing information that could improve the prospects of Genovo.

Although Wilson was involved, his connection to Genovo apparently did not violate university or NIH guidelines on conflict of interest because Wilson was not directly involved in the recruitment or care of patients in the clinical trial, nor did Genovo finance the trial. Arthur Caplan, director of Penn's Institute for Bioethics, says Wilson was just "the vector supplier," and it is "irresponsible" to suggest he was influenced by financial interest. (Wilson declined to comment through a Penn spokesperson, who also declined to respond to questions about the university's policies submitted by fax.)

The furor over this case prompted the American Society of Gene Therapy, of which Wilson was president in 1999, to issue a statement on conflicts of interest in April. It essentially echoes the NIH guidelines. It says that members who are "directly responsible for patient selection, the informed consent process and/or clinical management in a trial must not have equity, stock options or comparable arrangements in companies sponsoring the trial." Crystal supports it, saying, "we already had that in place" in his clinic. Anderson, likewise, says he has followed this rule in all 16 clinical trials he's been involved in.

The American Society of Human Genetics (ASHG) – whose membership is less directly involved in gene therapy – also issued a statement in April calling for caution in gene therapy. But it stopped short of ruling on conflicts of interest. ASHG president Ron Worton of Ottawa Hospital Research Institute says: "We debated ... a ban on recruitment of patients by physicians who have a financial interest," but board members didn't want to take that step, arguing that "this is something traditionally policed by the universities." But, as the Penn case illustrates, universities themselves may have potential conflicts to be policed.