Proceedings for CAAT 20^th Anniversary Symposium

Success of Alternatives

Alan M. Goldberg
Johns Hopkins University

In the last 20 years, a growing number of organizations have revolutionized how scientists think about, and approach, the use of laboratory animals in product safety testing, biomedical research, and education. Three questions will be considered: What successes have been achieved in the alternatives field? What constitutes the alternatives "field" today? What lies ahead for CAAT? A new addition to the CAAT grants program, a new research program, and an innovative new policy focus of the center will be discussed in light of challenges facing the alternatives field today.

"I believe that more and more people are becoming aware that to use animals to thoughtlessly, without any anguish or making an effort to find another way diminishes us as human beings."

Jane Goodall, 2001

Where will the alternatives field be 20 years from now?

During this symposium we have attempted to answer this question by examining science that is embryonic today, but will, I believe, lead to more humane approaches in the years to come.

In looking back, it has been clear that science has driven our progress. CAAT played a major role in that progress, as our speakers have demonstrated, and clearly, CAAT has an important role to play in the future.

Today, I want to focus on the alternatives field as a whole, and briefly share my view of the successes that everyone working in this endeavor can claim. I also want to present my vision for CAAT. I hope to do this by answering 3 questions:

What successes have been achieved in the alternatives field?
What constitutes the alternatives "field" today?
What lies ahead for CAAT?

What successes have been achieved in the last 20 years?

The list of successes in the alternatives field is substantial, and there is no reasonable way I could cover them all, but I will highlight just a few:

Most companies in the personal care and household goods industry have stopped using laboratory animals for safety testing. Not surprisingly, almost all of these companies have served on the CAAT Advisory Board. Many of them have developed in-house research programs dedicated to alternative methods; others helped us launch the targeted team approach to research at CAAT. We call these efforts "program projects," and they have been remarkable, leading to new in vitro methods for allergic contact dermatitis testing and, recently, corneal wound healing (as we heard from Dan Sauder and Leon Bruner).
Fifteen years ago, the National Cancer Institute changed its approach to screening potential drugs from in vivo to in vitro methods. The NCI wasn't thinking about alternatives, or even about animals, when it made the switch; the in vitro methods are quicker, cheaper and better. However, the in vitro approach unquestionably was an alternative method and considerably more humane. Why did it occur? Without advances in science, all of our efforts would have led to very little. In the last 20 years, molecular biology drew the best and brightest young minds to the laboratory, and their efforts led quite naturally to the development, and use, of new cell lines and in vitro technologies -- thus, alternative methods.
An entire field -- in vitro toxicology -- was born and nurtured by cutting-edge science. More than 80 percent of the abstracts from major scientific meetings -- Aspet, Society of Toxicology, Neuroscience -- present findings derived from in vitro approaches.
Almost every Nobel Prize winner in physiology and medicine for two decades has used in vitro and other alternative approaches. The most humane science also has been the very best.
Animal welfare legislation has been important and successful. From the 1985 rewrite of the Animal Welfare Act, the founding of AWIC, the establishment of institutional animal care and use committees (IACUCs), to the formation of ICCVAM in the United States, we have seen steady support for issues of animal welfare and the use of alternatives. However, no amount of legislation can make humane science happen. For some time now, I have thought we need less legislation and more education, and I think a recent study of IACUCs proves my point. (I'll come back to this when I discuss the future.)
Next year Andrew Rowan will host the 4th World Congress in New Orleans. In 1990, I asked Bert van Zutphen to join me in establishing a world congress, every three years -- the first to be in Baltimore, the 2nd to be hosted by Bert in the Netherlands, and the 3rd to be hosted by whoever was appointed to head ECVAM. Today, there is a 501c3 world congress foundation. With the 5th World Congress to take place in 2005 in Berlin, and the 6th (2008) in planning. What is incredible is that the alternatives field has expanded to include so many different people and kinds of expertise that we need to organize a world congress regularly just to enable everyone to keep up with all that's happening.
We have a global clearinghouse for alternatives information on the web: Altweb. And Altweb, I believe, has already served to connect people to each other in a way that speeds progress. Malcolm Gladwell, a writer for the New Yorker magazine and author of "The Tipping Point," identifies in his book how and why events occur. Gladwell describes one critical component as the need for a connector -- a person or thing that connects people to an issue. For example, we all know Paul Revere -- he rode north and alerted the countryside that the British were coming. Who rode south and why don't we know him? As Gladwell points out , William Dawes was not a connector.
Altweb and its project team are connectors — in a unique way, Altweb brings together the people of our field with everyone else who needs information about alternatives -- scientists, regulators, teachers, students of all ages, animal advocates, and the public. As you heard from Frank Baker -- more than 30,000 unique individuals visit Altweb each and every month from more than 70 countries.

Altweb can make progress happen faster. For example, by 1997, many European countries had banned the use of animals for the production of monoclonal antibodies. We at CAAT decided to organize a workshop on the status of alternative methods. At the workshop, it became clear that there are a variety of in vitro methods that are cheap, effective, and far more humane than the ascites method. If we had simply published our findings in a printed report, months would have passed before the proceedings would have been ready — and the publication would have been circulated to, at best, a few hundred people.

Instead, via Altweb, we published conclusions and recommendations a week after the workshop. Shortly afterwards, the NIH issued a "Dear Colleague" letter that indicated ascites could only be used if nothing else worked. The entire process took only a few weeks. Although many institutions have yet to stop using the ascites method, many others have made the switch to more humane methods.
Lastly, a growing number of alternative methods have been validated for regulatory use, companies have been established that provide new alternatives, and contract research organizations (CROs) dedicated to in vitro technologies exist.

A pretty impressive beginning — and we have just begun.

What constitutes the alternatives "field" today?

A field is more than ideas; it is the translation of those ideas into specific programs, areas of specialization, and organizations. As CAAT grew, so did the alternatives field. Almost every country has an alternatives center — FRAME led the way, but there is also ZEBET in Germany, the NCA in the Netherlands, ANZCCART in Australia, and the CCAC in Canada, among others. In the United States, CAAT has been joined by the UCCAA and IIVS. All of these centers have somewhat different approaches and missions, but all have humane science at their core.

A field is also its people. Many of these organizations began with one or two individuals, but today beside the in vitro toxicologists you will find statisticians looking at experimental design, veterinarians focused on anesthesia or humane endpoints, animal behaviorists considering environmental enrichment, information specialists building web sites, conducting literature searches, or building databases.

The U.S. regulatory community has begun to focus on alternatives as well, and with the permanent establishment of ICCVAM, federal agencies now have a formal structure for collaboration and progress.

The animal welfare community has played an important role in shaping and supporting the growth of the alternatives field. Organizations such as HSUS, MSPCA, ASPCA, ARDF, among others, devote long hours and increasing amounts of money to promoting the development or use of alternative methods. The HSUS is leading an effort to focus attention on the third R, refinement, in its "pain & distress" campaign. The ARDF focused U.S. attention on the monoclonal issue.

The alternatives field has a thriving commercial base today -- instrument companies like Molecular Devices (responsible for the microphysiometer), cell and tissue culture companies like Clonetics, companies like Xenogen that use bioluminescence to allow us to study disease less invasively... it's not well known that either I, a CAAT grantee, or a CAAT board member worked with each and every one of these companies to get its product to market.

What lies ahead for CAAT?

All of CAAT's current activities will continue -- our grants, outreach, and information and education programs. We will continue to support new science, sponsor workshops and symposia through efforts such as TestSmart, and disseminate information through Altweb and our other websites and publications. CAAT will continue to advocate the best, most humane science for the benefit of both people and animals. As I told Henry Spira 20 years ago, we'll provide the science -- you use this information to support your activism.

So now I will focus on four new directions for CAAT: emphasizing refinement, building the CAAT faculty, creating a new "omics" program, and developing an approach to education that we believe holds the key to increasing the use of the 3Rs.

Emphasizing Refinement

When Bill Russell and Rex Burch described the 3Rs in their book, Principles Of Humane Experimental Technique, they presented the use of anesthesia -- any anesthesia -- in surgery as a refinement method, noting that using a restraint or paralysis alone was inadequate. Yes, 40 years ago not all animals were anesthetized before surgery.

In workshops and journals, listservs and regulatory hearings, the pain and distress of laboratory animals has become a hot topic. The HSUS hopes its campaign will end pain and distress by the year 2020, and the USDA is considering both new methods for reporting pain and distress and new definitions.

Today, it is not unusual for workshops to be entirely devoted to non-invasive technologies such as telemetry and imaging, or to pain management and humane endpoints. One common complaint at such meetings is the lack of basic research in the area of pain assessment and alleviation. To address this need, CAAT recently announced plans to establish a major research program focused on refinement issues. This program, as far as we know, is the first of its kind. The first of the research grants, which will be funded by the Helaine Heilbrunn Lerner fund, will be awarded in November.

When CAAT first was established, we focused on in vitro methods exclusively, because we believed this was where we could make progress most quickly. Today, however, we have telemetry, non-invasive imaging, outcomes from enrichment studies -- new technologies and knowledge that make it possible to truly diminish, and in many cases, eliminate, the pain and distress associated with animal protocols for which no replacement exists. Further, these techniques will allow us to ask the most fundamental questions about pain and distress itself, thus providing the possibility to truly minimize or eliminate it in experimental protocols.

The CAAT Faculty

When CAAT began, we established the grants program for both Hopkins scientists and others from around the world. During these 20 years, we have funded about 150 different projects, most of them start-up grants lasting for three years. The scientists behind these projects provided us with the scientific underpinnings of new methods (some of their work was highlighted last night). They have helped shape the alternatives field.

During the last few months, a different group of experts from Johns Hopkins and elsewhere -- veterinarians, toxicologists, and policy specialists -- have come together to form a CAAT faculty. By working and thinking together, these are the individuals who will help train future specialists in the alternatives field, shape the direction of CAAT symposia and workshops, and serve as leaders in the academic community (and elsewhere) for the use of alternatives methods.

The "Omics" Revolution

Genomics, proteomics, and metabomics -- have all become known as expression systems. Just as stem cell research offers huge promise for the future, expression systems offer huge promise for alternatives. Three years ago the EPA, ACC and ED established a voluntary program to provide hazard evaluation data for 3000 chemicals produced in amounts greater than 100 million pounds a year. We knew immediately that this testing program would use a lot of animals. TestSmart, a humane and efficient approach to regulatory toxicology testing, was developed. As a result, the EPA realized that estimates of animal use could be decreased by 80% while increasing the amount of information collected on the chemicals. By making humane science an equal partner with scientific quality, we found a way to obtain more information, less expensively, and with considerably fewer animals. It sounds pretty good to me. But it gets better.

TestSmart came about because Ellen Silbergeld helped us understand the issues and develop the concept. Today, the HPV program is beginning to put basic information about these chemicals into the public domain. With the "omics" revolution we believe we can use this data to develop an understanding of the functionality of this new data. Ellen will establish an expression program at Hopkins as part of CAAT, and we will apply expression science to environmental chemicals -- truly combining animal welfare, the new toxicology, and a focus on the environment.

And lastly,

A New Approach To Animal Welfare -- Education

If you have time to read the numerous newsletters and listservs that our field produces, you will know that the next great challenge for the alternatives field lies primarily in academia with basic scientists and the infrastructure that supports them.

The headlines -- do IACUCS function properly? Are rats, mice, and birds animals? Do scientists labor under an unnecessary administrative burden? -- stem from debates that occur, largely, in academia.

Consider this: if one reads the Animal Welfare Act, as Paul Locke shared with us, a role of the IACUC member is to be an advocate for the animals; we have surrogate responsibility. Yet, I would venture to guess that if IACUC members are asked what is your responsibility on the IACUC? -- few, very few would say they are there to be an advocate for the animal. Instead, they will list all the other responsibilities.

Rats, mice and birds are currently excluded from coverage by the AWA, even though the act includes all vertebrate animals. Does this sound like a contradiction? There is great fear on the part of some academic scientists, albeit I believe unwarranted, that to include rats, mice and birds will be a huge administrative burden. My own university -- alone among universities -- has chosen to fight the inclusion of rats, mice and birds. I disagree with this position and believe there is no reason, scientific or administrative, to exclude them.

These are but two examples of how a lack of understanding about the law, the responsibility of those who use animals, and how the public feels about laboratory animal welfare affects their use.

In the recent publication of Plous & Herzog in Science this summer, they demonstrated what many of us suspected -- institutional animal care & use committees are at best inconsistent. In their study, they demonstrated that two different IACUCS reviewing 150 protocols, disagree 79% of the time. The results showed that approval decisions were statistically unrelated. In most cases, proposals that were disapproved by one committee were approved by the second committee. Clearly, we have to rethink the training of IACUCS members and how to change this.

In the Netherlands, a student/scientist cannot use an animal in research until they complete a 3-week, 5-day/week, 8-hour/day, course. The text for this course has been translated into several (about 6) languages, and scientists from throughout Europe have produced similar courses. Twice yearly, a 2-week intensive version is offered in English at the University of Utrecht. This course has now been available for several years and is always sold out, yet, not one person has enrolled from the United States (I'll be the first next year).

Earlier this summer, I retook the course required of all investigators at JHU who submit animal protocols for review or order animals for use in their laboratories. The class lasted from 4-5 p.m. on July 10^th. Need I say more?

In all fairness, I must add, Hopkins is not unique. During the next few years, CAAT will begin to analyze how U.S. institutions educate their scientists and examine ways to improve upon the current approach. Are there ways to increase education about animal ethics, use, and alternative methods while decreasing the burden on scientists? Can we train IACUC members better and educate scientists so that the job of the IACUC becomes easier from the start? We believe it is possible to combine education with change (both legislative and leadership) in a way that increases humane science -- in short, to make humane research an equal partner with quality science in advancing our knowledge.

CAAT's history has been based on trying to find common ground and a win-win situation for all parties. We still want to achieve this goal -- with a combination of education for scientists, improved accountability for animal use, and reasonable oversight.

As Jane Goodall says, not just for the animals, not just for the science, but for all of us, as human beings.

I'd like to close with a quote from Thomas Kuhn, in his book, The Structure of Scientific Revolutions:

"Each of them (refering to scientific revolutions) necessitated the community's rejection of one time-honored scientific theory in favor of another incompatible with it. Each produced a consequent shift in the problems available for scientific scrutiny and in the standards by which the profession determined what should count as an admissible problem or as a legitimate problem-solution. And each transformed the scientific imagination in ways that we shall ultimately need to describe as a transformation of the world within which scientific work was done. Such changes, together with the controversies that almost always accompany them, are the defining characteristics of scientific revolutions."

I believe we are in the middle of a scientific revolution.

CAAT 20th Anniversary Symposium

Proceedings for CAAT 20th Anniversary Symposium