107th Congress

Report: Quickening the Pace of Research in Protecting Against Anthrax and Other Biological Terrorist Agents—A Look at Toxin Interference—Hearing Before the House Committee on Government Reform—February 28, 2002

Members Present

Representatives Dan Burton (R-IN), Chairman; Constance Morella (R-MD); Christopher Shays (R-CT); Stephen Horn (R-CA); Dave Weldon (R-FL); Henry Waxman (D-CA), Ranking Member; Carolyn Maloney (D-NY); Dennis Kucinich (D-OH); John Tierney (D-MA); and Janice Schakowsky (D-IL).

Witnesses

Panel One:

Dr. Robert Smith, Founder and Research Director of Enzyme Systems Products (ESP), Livermore, CA; Dr. Gary Thomas, Senior Scientist, Vollum Institute, Portland, OR; Dr. John Collier, Professor of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA; Dr. John A.T. Young, Professor in Cancer Research, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison Medical School, Madison, WI

Panel Two:

Dr. Rodney Balhorn, Research Director, Lawrence Livermore Laboratories (LLNL); Dr. Stephen Leppla, Senior Investigator, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD; Dr. Arthur Friedlander, Senior Scientist, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD

Purpose of Hearing: AccORDing to the committee, there is a need for safe and effective anthrax therapies to be used as both pre- and post-exposure treatments. The current medical model calls for vaccinations to be used, when available, as a preventive measure and for antibiotics to be used post-exposure, whether or not an individual was immunized. An area of promising focuses may rely on the development of an anthrax anti-toxin, which would prevent the toxin from inhaled anthrax spores from entering human cells. The current state of anti-toxin research was the focus of the hearing.

Summary

Representative Shays opened with comments that a sharper focus on development of antitoxins is warranted because anthrax has long been acknowledged as the most likely biological weapon threat. He said the committee's oversight report from 2 years ago found that 1) the current anthrax vaccine may cause serious adverse reactions in some; 2) it is not approved for use by children, the elderly or pregnant women; and 3) prolonged administration of broad spectrum antibiotics can also cause untoward health effects in terms of the public health threat of resistant organisms.

Mr. Burton concluded the introductions of the witnesses by mentioning that Dr. Smith is also the father of his son-in-law.

The panels presented scientific testimony about furin and how it works. Furin was described as an enzyme, called a protease, which does a very simple job-it cuts a larger protein and turns it into a smaller protein. This cleavage allows furin to generate a smaller and biologically active molecule which is responsible for the damage that is inflicted by many pathogens, including anthrax. Furin was described as the key to the pathway which begins a biological cascade that leads to cell death. This is not limited to anthrax, but also a number of pathogenic viruses which require this pathway as well. These include, for example, HIV, cytomegalovirus, ebola virus, and yellow fever virus. Further, furin appears to play a role in other diseases in humans as well, such as rheumatoid arthritis and metastatic cancer. Witnesses generally agreed that understanding furin metabolism and pathways might offer mechanisms that could interrupt the release of anthrax toxins and, therefore, might serve to develop a treatment for anthrax exposure. Witnesses were, more or less, enthusiastic about the promise of furin as a key to such treatments.

Opening Statements

Panel 1: Witnesses described in detail the process of the furin pathways and the reasons why each of them felt that understanding of this might lead to the development of new treatments for anthrax exposure and other toxic agents. While Dr. Smith felt this was far enough along scientifically that one might expect a product that could be used by the population in perhaps as short a time as a year, the majority of the panel felt much more research was needed before something might be available. Panelists also pointed out their individual support by NIH for this research over the years, noting NIAID, NIDDK, and NCI specifically.

Panel 2: Dr. Leppla was accompanied by Dr. Carol Heilman, Director, Division of Microbiology and Infectious Diseases, NIAID. There were no questions posed to Dr. Heilman. Dr. Leppla discussed his research regarding anthrax toxin and the role of the protease furin in anthrax toxin action. In his work, he generated mutated cultured cells, which lacked functional furin, and he demonstrated that these cells were highly resistant to anthrax toxin and other toxins. This has led to the concept of the possible use of furin inhibitors to block anthrax toxin action and the potential this holds for treatment of anthrax infections. He stated that scientists have identified at least eight stages in which the toxin must pass through in order to achieve its ultimate killing action on cells. Studies in cell culture models have demonstrated, in principle, that each of these stages can be blocked. Witnesses, including Drs. Collier, Young and Friedlander, provided much of the data showing that each of these separate stages represents a valid target to which scientists could point therapeutic interventions. He also mentioned a number of NIH intramural researchers who have also made important contributions in regard to furin research from NCI and NICHD. Dr. Leppla cautioned that furin has received less attention as a target for drug development, in part because the expectation has been that inhibition of this enzyme, which plays an essential role in many normal processes, might cause significant physiological damage to normal tissue, an issue which must be explored. However, he said that he anticipates that the furin inhibitors, as well as others, will be evaluated for anthrax toxin inhibition in appropriate cell culture models in the near future. If they are successful, they will be carried forward for clinical evaluation. Dr. Friedlander discussed approaches to managing anthrax bioterrorist attacks.

Questions

Panel 1:

Representative Burton:

(To Dr. Smith) Dr. Leppla's written testimony states that there are at least eight distinct phases in which the anthrax toxin may be interrupted. Why have you selected the furin interference as the stage to develop? Do you think the other stages should be explored simultaneously?

What about other medical conditions that are likely to benefit from the research conducted on the anthrax antitoxin? Could we possibly develop a treatment that would be effective both for protection against a terrorist threat and to help outbreaks of ebola in the Congo and the other African nations?

Representative Weldon:

What is the role of protective antigen, and what are the specifics of how the cascade of events ultimately may cause the death of someone exposed to the inhaled form of anthrax? Is the goal of a drug to be developed to interfere with the whole pathophysiologic mechanism?

Are you getting enough research funding? I would assume some of you are funded by NIH or one of its affiliated agencies. With more funding, could you accelerate your work?

Panel 2:

Representative Burton:

How would a vaccine prevent the proliferation of the bacterial infection antibodies against the protective antigen? Can you explain that to me? What is in the current vaccine?

Do you see cost as a hurdle for the application of some of the technologies you are developing right now for the development of these products? Would you say the level of funding has been adequate so far for the type of research that needs to be done in this arena?

Representative Shays:

Dr. Friedlander, I'm well aware of the Government's program to vaccinate. And I do have my differences with that program. I am interested to know from the three of you your reaction when you started to see that we were under attack by anthrax.

At hearings held by this committee, we were told that the whole justification for the military's program of vaccination was if you contracted anthrax through a weaponized program of inhaling it, it was uniformly fatal. Were you surprised that the country was able to deal with inhaled anthrax?

Are we talking more of a cure rather than a prophylactic? And we are not going to vaccinate all the American people, or even all of the military forces, is that correct?

Dr. Leppla, I want to know your reaction to the anthrax letters? Were you involved in the anthrax program before September 11 at all? Dr. Leppla responded that, as an intramural researcher at NIH, he had been working on very basic aspects of anthrax toxin for 20 years, initially at USAMRD and then at NIH. He pointed out that NIH is not a front-line responder to public health emergencies.

(To Dr. Leppla) What did you think of the military's program to vaccinate every person in the military whether or not they were going to be in a theater under threat? Do you not have a problem with the fact that military personnel were required to do it, even under threat of being dishonorably discharged? You're working for the Government now, is that why you're reluctant to answer the question? Dr. Leppla responded that this was a policy issue that's well beyond his area of expertise, and that he is not involved in any way in evaluating the vaccine nor did he have access to the data that the DoD has collected.

(To Dr. Leppla) When you saw letters that contained anthrax and buildings of the Government being shut down and a question mark on whether we had run out of anthrax as a vaccine, what was going through your mind? Dr. Leppla acknowledged that he had all the same concerns of any other citizen, but it was not something that was part of his job function. As a witness representing NIH, he declined to comment on his personal views.

If there is a vaccine that hasn't been tested for efficacy with humans, one has to be very cautious, correct?

Please walk me through the challenge of defensive side of biological agents. You have to make the weapon in order to know how to defend against it. Isn't that true?

After September 11, did you start to redesign your activities and your research?

Dr. Leppla, are you being asked to evaluate a lot of different private sector ideas?

What's different in your life since September 11?

Dr. Leppla said that there are many people who want to contribute, and he said that he is glad to be able to advise them or provide them with reagents.

Representative Burton:

Dr. Friedlander, we've heard that anthrax spores used in the mail attacks that we dealt with here on Capitol Hill originated at Fort Detrick. Do you have any information about that?

Prepared by Anne Houser, OD/OLPA, March 8, 2002