[House Hearing, 107 Congress]
[From the U.S. Government Printing Office]



 
QUICKENING THE PACE OF RESEARCH IN PROTECTING AGAINST ANTHRAX AND OTHER 
       BIOLOGICAL TERRORIST AGENTS: A LOOK AT TOXIN INTERFERENCE
=======================================================================


                                HEARING

                               before the

                              COMMITTEE ON
                           GOVERNMENT REFORM

                        HOUSE OF REPRESENTATIVES

                      ONE HUNDRED SEVENTH CONGRESS

                             SECOND SESSION

                               __________

                           FEBRUARY 28, 2002
                               __________

                           Serial No. 107-64
                               __________

       Printed for the use of the Committee on Government Reform







  Available via the World Wide Web: http://www.gpo.gov/congress/house
                      http://www.house.gov/reform


                    U.S. GOVERNMENT PRINTING OFFICE
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                     COMMITTEE ON GOVERNMENT REFORM

                     DAN BURTON, Indiana, Chairman
BENJAMIN A. GILMAN, New York         HENRY A. WAXMAN, California
CONSTANCE A. MORELLA, Maryland       TOM LANTOS, California
CHRISTOPHER SHAYS, Connecticut       MAJOR R. OWENS, New York
ILEANA ROS-LEHTINEN, Florida         EDOLPHUS TOWNS, New York
JOHN M. McHUGH, New York             PAUL E. KANJORSKI, Pennsylvania
STEPHEN HORN, California             PATSY T. MINK, Hawaii
JOHN L. MICA, Florida                CAROLYN B. MALONEY, New York
THOMAS M. DAVIS, Virginia            ELEANOR HOLMES NORTON, Washington, 
MARK E. SOUDER, Indiana                  DC
STEVEN C. LaTOURETTE, Ohio           ELIJAH E. CUMMINGS, Maryland
BOB BARR, Georgia                    DENNIS J. KUCINICH, Ohio
DAN MILLER, Florida                  ROD R. BLAGOJEVICH, Illinois
DOUG OSE, California                 DANNY K. DAVIS, Illinois
RON LEWIS, Kentucky                  JOHN F. TIERNEY, Massachusetts
JO ANN DAVIS, Virginia               JIM TURNER, Texas
TODD RUSSELL PLATTS, Pennsylvania    THOMAS H. ALLEN, Maine
DAVE WELDON, Florida                 JANICE D. SCHAKOWSKY, Illinois
CHRIS CANNON, Utah                   WM. LACY CLAY, Missouri
ADAM H. PUTNAM, Florida              DIANE E. WATSON, California
C.L. ``BUTCH'' OTTER, Idaho          STEPHEN F. LYNCH, Massachusetts
EDWARD L. SCHROCK, Virginia                      ------
JOHN J. DUNCAN, Jr., Tennessee       BERNARD SANDERS, Vermont 
------ ------                            (Independent)


                      Kevin Binger, Staff Director
                 Daniel R. Moll, Deputy Staff Director
                     James C. Wilson, Chief Counsel
                     Robert A. Briggs, Chief Clerk
                 Phil Schiliro, Minority Staff Director









                            C O N T E N T S

                              ----------                              
                                                                   Page
Hearing held on February 28, 2002................................     1
Statement of:
    Balhorn, Rodney, research director, Lawrence Livermore 
      Laboratories, Department of Energy, Livermore, CA; Stephen 
      Leppla, senior investigator for the National Institute of 
      Dental and Cranial Facial Research, National Institute of 
      Health, Bethesda, MD; and Arthur Friedlander, senior 
      scientist, U.S. Army Medical Research Institute of 
      Infectious Diseases, Fort Detrick, Frederick, MD...........    94
    Smith, Robert, founder and research director, Enzyme Systems 
      Product, Livermore, CA; Gary Thomas, senior scientist at 
      Vollum Institute, Portland, OR; John Collier, professor of 
      microbiology and molecular genetics at Harvard Medical 
      School, Boston, MA; and John A.T. Young, professor in 
      cancer research, McArdle Laboratory for Cancer Research, 
      University of Wisconsin, Madison, WI.......................    28
Letters, statements, etc., submitted for the record by:
    Balhorn, Rodney, research director, Lawrence Livermore 
      Laboratories, Department of Energy, Livermore, CA, prepared 
      statement of...............................................    97
    Burton, Hon. Dan, a Representative in Congress from the State 
      of Indiana, prepared statement of..........................     5
    Clay, Hon. Wm. Lacy, a Representative in Congress from the 
      State of Missouri, prepared statement of...................   143
    Collier, John, professor of microbiology and molecular 
      genetics at Harvard Medical School, Boston, MA, prepared 
      statement of...............................................    64
    Friedlander, Arthur, senior scientist, U.S. Army Medical 
      Research Institute of Infectious Diseases, Fort Detrick, 
      Frederick, MD, prepared statement of.......................   125
    Leppla, Stephen, senior investigator for the National 
      Institute of Dental and Cranial Facial Research, National 
      Institute of Health, Bethesda, MD, prepared statement of...   115
    Maloney, Hon. Carolyn B., a Representative in Congress from 
      the State of New York, prepared statement of...............    18
    Shays, Hon. Christopher, a Representative in Congress from 
      the State of Connecticut, prepared statement of............    16
    Smith, Robert, founder and research director, Enzyme Systems 
      Product, Livermore, CA, prepared statement of..............    32
    Thomas, Gary, senior scientist at Vollum Institute, Portland, 
      OR, prepared statement of..................................    53
    Tierney, Hon. John F., a Representative in Congress from the 
      State of Massachusetts, prepared statement of..............    21
    Waxman, Hon. Henry A., a Representative in Congress from the 
      State of California, prepared statement of.................    14
    Young, John A.T., professor in cancer research, McArdle 
      Laboratory for Cancer Research, University of Wisconsin, 
      Madison, WI, prepared statement of.........................    80









QUICKENING THE PACE OF RESEARCH IN PROTECTING AGAINST ANTHRAX AND OTHER 
       BIOLOGICAL TERRORIST AGENTS: A LOOK AT TOXIN INTERFERENCE

                              ----------                              


                      THURSDAY, FEBRUARY 28, 2002

                          House of Representatives,
                            Committee on Government Reform,
                                                    Washington, DC.
    The committee met, pursuant to notice, at 10:10 a.m., in 
room 2154, Rayburn House Office Building, Hon. Dan Burton 
(chairman of the committee) presiding.
    Present: Representatives Burton, Morella, Shays, Horn, 
Weldon, Waxman, Maloney, Norton, Cummings, Kucinich, Tierney, 
and Schakowsky.
    Staff present: Kevin Binger, staff director; Mark Corallo, 
director of communications; S. Elizabeth Clay, professional 
staff member; Robert A. Briggs, chief clerk; Robin Butler, 
office manager; Elizabeth Crane and Michael Layman, legislative 
assistants; Elizabeth Frigola, deputy communications director; 
Joshua E. Gillespie, deputy chief clerk; Corinne Zaccagnini, 
systems administrator; Sarah Despres and David Rapallo, 
minority counsels; Ellen Rayner, minority chief clerk; and Jean 
Gosa, minority assistant clerk.
    Mr. Burton. A quorum being present, the Committee on 
Government Reform will come to order.
    We have other Members who will be coming shortly. Mr. 
Waxman, the ranking minority member, is on his way, and Dr. 
Weldon I think is on his way as well.
    I ask unanimous consent that all Members' and witnesses' 
opening statements be included in the record. Without 
objection, so ordered.
    I ask unanimous consent that all articles, exhibits, and 
extraneous or tabular material referred to be included in the 
record. Without objection, so ordered.
    In today's hearing we're continuing to look at how we can 
protect Americans against biological terrorism, primarily how 
to protect people from anthrax. Last fall, on the heels of the 
tragedy of September 11th and the loss of thousands of innocent 
lives, America was once again thrown into turmoil and fear. Our 
postal system was used to send anthrax spores through the mail. 
As a result, a small child contracted anthrax after attending a 
birthday party. Through this cowardly act, five innocent lives 
were lost.
    We were caught totally unprepared. Government officials 
were forced to admit that there were serious holes in our 
treatment approach. They were forced to admit that our 
knowledge about how to treat anthrax is very limited. Right now 
we have two approaches. The first is the anthrax vaccine. The 
second is with antibiotics, and neither one is totally 
satisfactory.
    We've spent a long time looking at the problems with the 
anthrax vaccine at the Defense Department. There's been a high 
rate of adverse events. The Department has never wanted to 
admit this. We have had military members in top physical 
condition come before the committee who became very ill shortly 
after receiving the vaccine. Pilots and other members of flight 
crews became so ill that they were grounded as a result of 
being forced to take the vaccine. Many of those who became ill 
were told it was not related to the vaccine, and they sometimes 
had to fight to receive adequate medical attention. Compounding 
that problem, it isn't clear at all that the vaccine will 
protect those that we have talked about against the known 
strains of anthrax.
    I was a little disturbed earlier this year when postal 
employees and congressional staff were being offered the 
anthrax vaccine. Our health officials were really downplaying 
the problems with adverse events to those shots. I think they 
were either misinformed or they weren't being as candid as they 
should have been with the Congress. The postal workers and the 
congressional staff definitely weren't being given the facts 
about the problems at the Defense Department, and I don't think 
that's acceptable.
    The antibiotics appear to be effective, but they are pretty 
strong, and they have to be taken for several months. 
Antibiotics can have some unpleasant side effects that make it 
difficult for some people to take this for an extended period.
    So it's clear that we need to keep doing more research to 
better develop treatments that will deal with this problem. One 
of the most promising new treatments being developed is known 
as an ``anti-toxin'' treatment. That's what we're going to hear 
about today from our illustrious panel.
    Anti-toxin treatments would stop anthrax spores from 
injecting toxins into human cells. According to many medical 
experts, this type of treatment holds tremendous promise. One 
of the things I want to do is to make sure we're directing 
enough research funding into this area.
    Finding better treatments like anti-toxins is vital. 
Colonel Arthur Friedlander, a witness on today's second panel, 
is a senior scientist at the U.S. Army Medical Research 
Institute of Infectious Diseases at Fort Detrick. He has been 
part of the Army's anthrax biological defense program for a 
long time. In an article published in the journal Nature last 
year, Dr. Friedlander outlined a three-pronged approach to 
tackling the anthrax disease.
    First, vaccination to prevent bacterial infection in the 
first place; second, antibiotics to attack infection if it 
occurs, and, third, anti-toxin treatments for the bacterium's 
toxic effects.
    In order to develop effective anti-toxin treatments, it is 
important for scientists to understand how anthrax kills cells. 
Anthrax toxin, which is the dominant virulence factor of the 
anthrax bacteria, consists of three proteins. These three 
proteins--protective antigen, edema factor, and lethal factor--
are all essential elements in what takes place when anthrax 
attacks cells.
    I hope I pronounced that correctly--a senior investigator 
from the National Institute of Dental and Cranial Facial 
Research of the National Institutes of Health, is also 
testifying today. Dr. Leppla is part of a research team that 
identified how the lethal factor produced by anthrax spores 
kills cells.
    Research, while competitive in nature, is often a team 
effort. This is especially important as we look at developing 
anti-toxin treatments. Research teams led by Dr. John Young of 
the University of Wisconsin and Dr. John Collier from Harvard 
Medical School began collaboration several years ago on the 
anthrax toxin research. They are both here today to explain 
their research and the role it may play in developing an 
anthrax anti-toxin.
    I am pleased that Dr. Robert Smith could be with us today. 
He is the holder of 37 United States and foreign patents. Dr. 
Smith has made significant contributions to science. He is a 
professor emeritus of the University of California and a former 
section leader and senior biologist with the Lawrence Livermore 
National Laboratory.
    Dr. Smith has given his career to improving our 
understanding of enzyme systems and monoclonal antibodies. In 
1977, Dr. Smith founded Enzyme System Products in Livermore, CA 
to provide synthetic substrates and inhibitors to the 
scientific community. Dr. Smith will outline a proposal to 
protect against inhalation anthrax by inhibiting the furin 
enzyme on the surface of cells in the lung.
    In addition to these attributes that Dr. Smith has, he's 
also the father of my son-in-law, who is with us today, and 
that makes him even more important. Don't you think that's 
interesting? Yes, I thought that was very interesting.
    Dr. Gary Thomas, a senior scientist at Vollum Institute of 
Portland, OR, is a leading expert on human furin enzyme systems 
and has coauthored several papers with Dr. Leppla. He will 
explain how their research is contributing to our search for an 
anthrax anti-toxin.
    As we move forward in looking at new treatments for 
biological terrorism agents, the role of advanced computer 
technology becomes increasingly important. Dr. Rodney Balhorn 
of the Lawrence Livermore National Laboratories will detail the 
role of our National Laboratories in developing treatments for 
anthrax.
    We've brought together a prestigious group of experts. 
Today we will hear how this research is progressing. We will 
hear how we might achieve our goal of developing safe and 
effective treatments for our military population, first 
responders, and all Americans. The President's fiscal year 2003 
budget calls for $5.9 billion to defend against biological 
terrorism, $2.4 billion of which is for scientific research.
    This hearing will highlight one area in which, if we 
quicken the pace of the research, we may have products 
developed that can protect the public in a few years rather 
than the 12 to 15 years it is typically going to take. We don't 
have 12 to 15 years to wait. If we use just a small portion of 
the $2.4 billion this year on looking at toxin interference, we 
will be a lot closer to having a safe, effective,
and scientifically validated treatment approach available.
    I want to thank all of our witnesses for being here today. 
The hearing record will remain open until March 15 to allow for 
written submissions to the record.
    [The prepared statement of Hon. Dan Burton follows:]
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    Mr. Burton. Mr. Waxman, welcome.
    Mr. Waxman. Thank you very much, Mr. Chairman. Thanks for 
holding this hearing.
    In the aftermath of September 11th, there has been 
increasing attention paid to the country's preparedness to deal 
with the bioterror attack. In October of last year, the 
situation became even more urgent when a terrorist began 
mailing letters that contained finely milled and extremely 
dangerous anthrax, threatening the lives of postal workers and 
anyone else who could have come into contact with these 
potentially lethal spores.
    This experience underscored the need for the country to 
increase its preparedness for a terror attack. One important 
response is to search for new potential treatments and methods 
of prevention. I am pleased that we will hear today from 
scientists who are looking at new ways to protect people from 
anthrax, and I look forward to hearing about how their research 
could impact on protection from and treatment of other diseases 
as well.
    While having better protection from anthrax is an important 
component of bioterrorism preparedness, we must also recognize 
that anthrax is just one of many bioterrorism threats. We must 
commit ourselves to developing a comprehensive safety net that 
protects Americans from all threats to the maximum extent 
possible. This is an ambitious undertaking for our Nation's 
public health system.
    Hearings like this are an important part of the process, 
but we will also need strong leadership from the 
administration. With Dr. Jeffrey Koplan's recent announcement 
that he will be stepping down as the Director of the Centers 
for Disease Control and Prevention, there are four critical 
public health jobs that are unfilled. These jobs include the 
Director of the CDC, Commissioner of the Food and Drug 
Administration, Director of the National Institutes of Health, 
and the Surgeon General. Together, these positions are the 
backbone of our national leadership for health emergencies. 
They need to be filled by leaders in public health. I hope that 
the President will see to that as soon as possible.
    I thank the witnesses for coming today. I look forward to 
their testimony.
    Thank you, Mr. Chairman.
    [The prepared statement of Hon. Henry A. Waxman follows:]
    [GRAPHIC] [TIFF OMITTED] T9590.076
    
    Mr. Burton. Thank you, Mr. Waxman. Mr. Shays.
    Mr. Shays. Thank you, Mr. Chairman. Thank you for holding 
this hearing, and I welcome our panelists and our guests.
    The global war against biological terrorism is also being 
waged at cellular and molecular levels. Research into the 
chemical and mechanical processes of anthrax infection, 
research tragically aided by the recent mail-borne attacks, 
points the way to a better vaccine, better antibiotic regimes, 
and new treatments to block the deadly toxins produced by the 
blooming bacteria.
    A sharper focus on development of anti-toxins is warranted, 
some might say overdue, because anthrax has long been 
acknowledged as the most likely biological weapon threat. As 
this committee found in our oversight report 2 years ago, the 
current anthrax vaccine may cause serious adverse reactions in 
some, and it is not approved for use by children, the elderly, 
or pregnant women. Prolonged administration of broad-spectrum 
antibiotics can also cause untoward health effects, both in 
individuals and in terms of the public health threat of 
resistant organisms.
    So effective treatments to shortcircuit the biochemical 
roots of anthrax toxicity are a missing element in our medical 
counterterrorism arsenal. Today's testimony will help us 
understand the status and potential of research into anthrax 
anti-toxins and the role new treatments might play in national 
preparedness against biological attacks.
    So thank you again for having this hearing.
    [The prepared statement of Hon. Christopher Shays follows:]
    [GRAPHIC] [TIFF OMITTED] T9590.077
    
    Mrs. Maloney. Good morning, Mr. Chairman, and thank you so 
much for holding this----
    Mr. Burton. Mrs. Maloney is recognized for an opening 
statement.
    Mrs. Maloney. Thank you very much, and thank you for having 
this very important hearing.
    The tragic deaths of five persons from inhalation anthrax, 
including Kathy Nguyen, who worked in my district at the 
Manhattan Eye, Ear and Throat Hospital, highlighted for the 
Nation our vulnerability to biological terrorism. These anthrax 
attacks not only scared the American people, but placed a 
severe strain on the public health system. As public servants 
and policymakers, we must do all we can to prevent 
bioterrorism. Additionally, it is imperative that we learn from 
the past, so that our citizens and our government can 
effectively respond to these crises in the future.
    The men and women of our national security community have 
been battling terrorism for many years. As we will learn today, 
the Nation's scientists are critical to this fight. Our leading 
researchers are developing new approaches to preventing and 
treating many infectious agents, including anthrax infections.
    In New York State our great institutions of higher learning 
are on the case. For instance, at Columbia University 
researchers at the College of Physicians and Surgeons and 
Mailman School of Public Health are studying the genetic 
composition of various infectious agents and providing training 
and assistance to Federal and State and local governments. 
Columbia is the home of one of the CDC's funded Centers for 
Public Health Preparedness. The Columbia Center is working 
closely with the New York City Department of Health to 
strengthen the connection between our academic medical centers 
and people on the front lines of public health. In August of 
last year, the Center trained over 700 public health nurses on 
what to do in the event of a major disaster, training which, 
unfortunately, came in all very handy during our crisis on 
September 11th.
    At the Weill Medical College of Cornell University 
researchers are examining the human genes that are responsible 
for resistance to tuberculosis, to determine how these genes 
may protect an individual if exposed to anthrax infection. One 
additional example, at New York University's Medical Center, 
scientists have begun studies to examine interactions among the 
cells of the organism that causes anthrax to seek ways to 
inhibit their ability to infect people.
    In addition, New York University researchers are using 
types of recombinant DNA technology to develop improved 
vaccines.
    Although the tasks are daunting, with our country's 
scientists working to find better preventions and treatments, 
America can sleep better at night.
    I look forward to the testimony today of the distinguished 
guests. Thank you.
    [The prepared statement of Hon. Carolyn B. Maloney 
follows:]
[GRAPHIC] [TIFF OMITTED] T9590.009

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    Mr. Burton. Mr. Tierney, do you have an opening statement?
    Mr. Tierney. I will place it in the record, Mr. Chairman.
    [The prepared statement of Hon. John F. Tierney follows:]
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    Mr. Burton. Let me say, before I swear in the witnesses, 
that this is a very, very important hearing because we have 
just the two approaches that we talked about in dealing with 
the anthrax scare. This committee oversees the Postal Service, 
which has been severely threatened and impaired with the 
anthrax attacks that took place after September 11th. So we're 
very anxious to hear about your theories and alternatives to 
the conventional approaches to dealing with the anthrax threat.
    I hope that you will do me a big favor. Knowing that most 
of us up here are not scientists or doctors, if you could speak 
in laymen's terms as much as possible, we would really 
appreciate it. When we get to the question-and-answer period, I 
think your answers probably will be more easily understood by 
us, but when you make your opening statements, which we're 
going to go to immediately, I hope that you'll try to remember 
that we want to understand as much as possible, and also the 
record, which will be reviewed by all the members of the 
committee, we want to make sure they understand it as well. So 
that if there is something that we should be doing in advising 
the administration on how to spend our scientific research 
dollars, we can do that with a little more knowledge than we 
have today.
    So, with that, would you please stand so you can be sworn 
in.
    [Witnesses sworn.]
    Mr. Burton. Be seated.
    We normally have 5-minute opening statements, but I 
understand, because of the technical aspects of your testimony, 
it's going to take a little bit longer. So we'll be a little 
more lenient with our opening statements and give you the time 
that you require.
    We will start with you, Dr. Smith.

  STATEMENTS OF ROBERT SMITH, FOUNDER AND RESEARCH DIRECTOR, 
  ENZYME SYSTEMS PRODUCT, LIVERMORE, CA; GARY THOMAS, SENIOR 
  SCIENTIST AT VOLLUM INSTITUTE, PORTLAND, OR; JOHN COLLIER, 
  PROFESSOR OF MICROBIOLOGY AND MOLECULAR GENETICS AT HARVARD 
 MEDICAL SCHOOL, BOSTON, MA; AND JOHN A.T. YOUNG, PROFESSOR IN 
   CANCER RESEARCH, MCARDLE LABORATORY FOR CANCER RESEARCH, 
              UNIVERSITY OF WISCONSIN, MADISON, WI

    Mr. Smith. In the 1960's scientists struggled with the 
understanding of how the pancreatic islet cell hormone insulin 
was actually assembled into a two chain molecule with two 
connecting bridges. In 1967, Dr. Donald F. Steiner at the 
University of Washington published his findings that insulin 
was actually manufactured within the islet beta cells as a 
single chain protein, folded into a reverse position. This 
permits the formation of two disulfide-linking bridges. Only 
then is the connecting peptide proteolytically removed to yield 
biologically active insulin. The cleavage points are always the 
same, recognizing only a specific set of amino acids, and 
processed by a special enzyme called furin or converting 
enzymes, with the capability of converting an inactive proform-
hormone into an active entity.
    In 1972, as an employee of Eli Lilly and Co., I designed 
the first synthetic substrates to isolate the converting 
enzyme, and then to use that enzyme to obtain active insulin. 
My method of design was based on the active site modeling 
concept of two prominent researchers, Dr. Schecter and Dr. 
Berger of Israel. From this concept, I was successful in 
isolating a converting enzyme from human parathyroid tissue and 
converting proparathyroid bovine hormone into a functional 
hormone. The two completely distinct physiological events could 
be activated by a single pro forma mechanism suggesting the 
definition of a basic physiological axiom or principle.
    Throughout the 1980's the scientific community believed 
that most protein hormones and enzymes are naturally 
synthesized in a proactive form. In the 1990's it was 
established that many cellular processes, including gene 
expression, cell cycle, programmed cell death or apoptosis, and 
intracellular protein targeting of bacteria and viruses are 
regulated by limited proteolysis of precursor proteins.
    All of these functions are carried out by the proteolytic 
enzyme family of furins and convertases that are strategically 
localized within cells or on the cell surface. Furins within T 
lymphocytes are extremely important enzymes in the study 
because they play a major role in the processing of the 
glycoprotein of the HIV virus and the infectious strains of the 
Ebola virus. The presence of an activated furin enzyme on the 
cell surface of macrophages is necessary for a cell entry and a 
processing of bacterial toxins; most notable is anthrax.
    Bacillus anthracis secretes three proteins to form toxic 
complexes at the surface of mammalian cells. The protective 
antigen is the principal component that is proteolytically 
activated from 83kDa-activated form to a 63kDa-activated 
entity, and the edema factor and the lethal factor, to form the 
toxic complex.
    With this scientific background laid, researchers now have 
the understanding and the capability to design compounds that 
will function as protease inhibitor candidates that target 
specific enzymes, such as furins. Major pharmaceutical 
companies currently market protease inhibitor drugs that 
clinically stop, if only for a limited period of time, the 
progression of HIV infection and significantly reduce viral 
replication, except HIV protease inhibitors are generally 
directed to an enzyme endogenous to the genome of the virus and 
not to an enzyme of the candidate infectant cell. Consequently, 
the virus enzyme protein will inevitably mutate; thus, limiting 
the clinical effectiveness of the inhibitor drug.
    When a person is exposed to Bacillus anthrax, the approach 
of treatment I propose is to inhibit the furin enzyme on the 
cell surface of the macrophages and the monocytes within the 
lung. Anthrax uses this furin enzyme to activate its protective 
antigen, enabling it to initiate a toxic state. Activation of 
the protective antigen by bacteria of anthrax is integral to 
the mechanisms of anthrax toxicity.
    To be able to prevent the reduction in size of the PA 83kDa 
form to the 63kDa form would essentially enable the bacteria 
from entering the host designated cell and, most importantly, 
as a consequence, toxication could not occur. Theoretically, 
this can be accomplished with a sensitive, non-toxic, and 
specific protease inhibitor. The synthesis of such an inhibitor 
would prevent the protective antigen furin enzyme from 
functioning; thus, shutting down the enzyme before the toxic 
events could take place.
    Is there a precedent that this furin inhibition mechanism 
would work as a first order of treatment? Yes, selective serine 
protease inhibitors to furins have been synthesized and used in 
cell cultures demonstrating the inability of the PA to be 
activated with the inhibitor present. The only commercially 
available furin inhibitors are Chloromethylketone derivatives 
that are strong alkalating agents, thus unacceptable. Because 
of their toxicity, they are useful only in establishing proof 
of principle and cannot be used as potential drug candidates.
    I propose a new family of small molecular weight protease 
compounds: irreversible inhibitors, modeled around the furin 
activation cleavage site of the protective antigen with 
significant changes at the N-terminal and C-terminal ends. As a 
bioavailable agent, second-generation furin protease inhibitors 
are expected to meet the necessary criteria of low toxicity and 
high potency. There are strong scientific and financial 
arguments in defense of a protease inhibitor therapy over other 
types of therapeutic intervention for anthrax and certain 
viruses.
    Time and the economics to develop these inhibitors are 
significantly less. Inhibitors could be extremely effective 
when following exposure to large masses of the population with 
very few side effects, adding to their desirability. Protease 
inhibitors can be manufactured economically and can be 
synthesized where different sequences are appropriate to 
various strains of toxins.
    The mechanism of how HIV infects CD4 lymphocytes is 
dependent upon the furin processing of the gp160 viral protein 
at the REKR cleavage site, as shown on figure 6, to a gp120 
protein and a 40 amino acid cutoff peptide. Inhibition of the 
gp160 processing has been reported to block syncytial formation 
and results in non-infective HIV virus particles. If it doesn't 
split, it won't infect, to paraphrase Johnny Cochran.
    The findings published in science and medical journals 
indicate that furin inhibition is a feasible approach to 
preventing anthrax infection and demands rigorous exploration. 
Nevertheless, for the exploration to be practical, it will 
require the synthesis of new small molecular weight inhibitors 
that do not generate any residual cellular toxicity.
    Until October of last year, my interests had been focused 
on a group of enzymes referred to as caspases. These enzymes 
have a propinquity to furins in a group designation, and one 
enzyme of the caspase family has significant control in the 
progression of cellular inflammation which parallels anthrax 
infection, identified as caspase 1.
    In 1996, I designed an irreversible inhibitor referred to 
as Z-VAD-FMK for the study of Apoptosis, and to date over 800 
publications utilizing this compound have appeared in leading 
scientific journals, from the references that you can see on 
the side panels, in the use of the possibility for treating of 
stroke, Parkinson's disease, Huntington's disease, spinal cord 
injury, and amyotrophic lateral sclerosis.
    This same approach can bring success as an effective 
deterrent against bioterrorism through the design and synthesis 
of irreversible protease inhibitors that qualify as potential 
drug candidates.
    Dr. Anthony Fauci stated January 14th at the National Press 
Club luncheon, ``Most people don't really think about research 
as an important component of the counter-bioterrorism issue, 
because in fact researchers are not first responders to the 
act. Yet research is a very important part of a comprehensive 
public health approach. I think that bioterrorism is in reality 
within the spectrum of what we are calling emerging and 
reemerging diseases where bioterrorism microbes are 
deliberately controlled for emerging and reemerging disease 
states.''
    In conclusion, quickening the pace of research to lower the 
risk of death by bioterrorist attempts can be accomplished 
timely and economically through the design and synthesis of new 
and dynamic protease inhibitors, the vanguard of non-toxic and 
very specific compounds that target anthrax and the Ebola 
organisms.
    Thank you very much.
    [The prepared statement of Mr. Smith follows:]
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    Mr. Burton. Thank you, Dr. Smith. When we get to the 
questions, I'll ask you some questions in laymen's terms that 
perhaps you can--because you were over my head a little bit 
there from time to time; in fact, most of the time. But I think 
I got the gist of what you were saying.
    Our next panelist is Dr. Gary Thomas. He's a senior 
scientist at Vollum Institute in Portland, OR. Is that correct?
    Mr. Thomas. That's correct.
    Mr. Burton. You're recognized.
    Mr. Thomas. Well, Mr. Burton and other members of the 
committee, it's certainly an honor to be here today to 
summarize for you and explain----
    Mr. Burton. Can you pull your mic a little closer, sir? 
Thank you very much.
    Mr. Thomas [continuing]. To explain for you the role of 
furin in pathogen virulence and human disease. I have an 
overhead presentation that I'm not quite sure will work, but 
we'll give this a try, because it's slightly out of context 
from my written testimony, but we'll give it a try. If it 
doesn't work, we'll go back to my written testimony.
    But, to begin with, the reprehensible bioterrorism plot 
following the September 11th World Trade Center tragedy 
intended to inflict countless deaths by disseminating the 
Bacillus anthracis spores throughout the U.S. mail. Eleven 
victims contracted the deadly lethal form of inhalation 
anthrax, leaving five of these victims to die within days 
following infection.
    If I can have the next overhead, and one more. Now anthrax 
is a frightening pathogen, and the recent anthrax scare is 
eerily reminiscent of the near influenza pandemic that erupted 
in Hong Kong just 5 years ago, where a renegade pathogenic 
avian influenza virus jumped directly from birds to humans. 
Similar to the death rate that we experienced with the anthrax 
toxicity, 6 of the 18 persons clinically diagnosed with this 
bird flu were dead within 1 week.
    Besides illustrating our vulnerability to the deadly 
microbes, is there a link between the anthrax and the ``bird 
flu'' outbreaks? Yes, clearly one link is the enzyme furin. So 
what is furin and how does it work?
    Well, furin is an enzyme, and it's the type of enzyme 
called the protease, which does a very simple job. It cuts a 
larger protein and turns it into a smaller protein, but furin 
doesn't just cut any protein. It cuts a select group of 
proteins that contain within them a furin site.
    If I can show the next overhead, please. Now this cleavage 
that occurs allows furin to generate from an inactive precursor 
protein, a smaller and biologically active molecule, and it's 
this active protein product, that is, the smaller, biologically 
active molecule, that is responsible for the damage that's 
inflicted by many pathogens.
    Now, interestingly, the identification of the furin site 
was identified in collaboration with Dr. Steve Leppla, who is 
here as well, when we characterized the ability of furin to 
cleave the protective antigen component of the anthrax toxin 10 
years ago.
    Next slide, please. Now furin is a cellular enzyme, but 
it's probably over the last 10 to 12 years of research by my 
lab and other labs it's become recognized, I think, as really 
the Dr. Jekyll and Mr. Hyde of the South. There's certainly an 
important role that furin plays in embryogenesis, but in the 
adult there's a decidedly dark side of furin as well, and this 
is what I would like to share with you today.
    Furin is certainly involved and is necessary for the 
activation not only of anthrax, but of many bacterial toxins, 
including pseudomonas toxins, shiga toxin, gangrene-forming 
toxins as well. Specifically with anthrax, we've heard about 
this already, and I'll summarize it quickly on the next slide, 
furin at the cell surface is responsible for the activation of 
the protective antigen component of anthrax, and that's a 
cleavage that turns protective antigen from an inactive 
molecule to an active molecule.
    By activating the protective antigen component, protective 
antigen is able to deliver into the cell one of the two toxic 
factors, either the edema or lethal factor that you've 
explained, and you'll hear more about by the other panelists. 
That's what goes on to kill the cell. So, in fact, furin is the 
key to this pathway. We look at it as beginning this entire 
cascade that leads to cell death.
    Next slide, please. Now furin is not only involved in the 
activation of many bacterial toxins, but it turns out a number 
of pathogenic viruses require this pathway as well. These 
include, for example, HIV, cytomegalovirus virus, respiratory 
syncytial virus, Ebola virus, yellow fever virus. There's a 
number of viruses that have envelope glycoproteins on their 
cell surface that must be cleaved to produce infectious 
progeny.
    Not only is furin involved in pathogen activation, but 
furin plays a role in very detrimental diseases in humans as 
well. On the next two panels, it plays a role in rheumatoid 
arthritis and metastatic cancer. Now rheumatoid arthritis is 
activated--if I can also show the next slide, please--by 
furin's activation of a protease cascade that leads to the 
breakdown of cartilage in joints.
    Now metastatic tumors--if you could go back one slide; I 
don't know if we can do that or not--in the bottom righthand 
panel of that slide is actually a biopsy section from a tumor. 
Furin turns out to play a prominent role in tumor metastasis, 
where furin is upregulated in many metastatic tumors. Shown in 
that panel in the bottom righthand corner of the slide, of the 
projection, is a biopsy from a patient, and that biopsy was 
stained for furin. You can see that the staining of that tumor 
is, in fact, increased for furin, and in fact furin levels 
correlate with the invasiveness of many metastatic tumors.
    Well, because of furin's role in both pathogen activation 
and human disease, is it a target, a strategic target, for both 
bioterrorism and human disease. We think it is, and we think it 
is for several reasons. I think one of the prominent reasons is 
because Mother Nature tells us it's an excellent target.
    Please, on the next slide. That is that we find that many 
pathogens that learn to exploit the furin pathway simply become 
more deadly. I think one of the classic examples that's been 
used is the Ebola virus itself. There are various islets of 
Ebola virus. One of them is called Reston. Now Reston is 
basically non-pathogenic in humans, and it's non-pathogenic in 
part because it doesn't know how to use the furin pathway, but 
there's other islets of Ebola virus that are much more deadly, 
like Ebola Zaire, on the next panel, please.
    Ebola Zaire has mutated its glycoprotein to now use the 
furin pathway. Because it can use the furin pathway, it causes 
90 percent fulminant disease and death in humans very rapidly.
    Now is Ebola virus the only virus that has learned to use 
the furin pathway that causes such havoc on humans? No. In 
fact, on the next panel--in fact, why don't you stop there for 
just a second? That Hong Kong bird flu that jumped from birds 
directly to humans, one of the reasons it was capable of 
infecting and killing humans is because it learned how to use 
the furin pathway, this protease that we talked about earlier.
    So can we develop furin inhibitors and can we block furin 
to use to our benefit? I think that we can. We have done this 
in an approach where we have generated a protein-based 
inhibitor, and this is shown on this slide here. It's an 
inhibitor that we call Alpha-1-PDX. Basically, Alpha-1-PDX, we 
pirated a scapold of a protein that's in all of our circulation 
called Alpha-1 antitrypsin, but we've simply put into this 
protein the furin site, so that furin will try to now recognize 
this inhibitor. This inhibitor, for lack of a better term, 
functions as a molecular mousetrap.
    If you could show the next panel, please. In the next 
panel, furin will try to cleave this inhibitor--keep going; 
right there and stop--but instead of releasing from the enzyme, 
this inhibitor basically folds over the enzyme and traps it and 
it activates the enzyme. So, in fact, using this inhibitor, 
we've shown that we can simply control the levels of furin in 
cells, and that works to our advantage quite greatly for the 
ability to protect against a number of pathogens.
    There's some key advantages to using this technology. 
Please, on the next slide. One is, in fact, that it is very 
potent. Second is that it is highly selective, and the third is 
in the acute toxicity studies that we have done so far, we see 
no toxicity.
    So, actually, can this inhibitor block the furin pathway 
and protect against pathogens? Is this a novel approach to a 
broad-based therapeutic? We think it is.
    On the next slide, some examples that will show you are, 
for example, HIV. As you know, HIV infects cells, and it needs 
to do this by using a protrusion on the envelope of the virus, 
which attaches to the cell and allows the virus to fuse with 
the cell. Now the protein that needs to be processed by furin, 
so that it becomes active and fusogenic requires the furin 
pathway. This is an envelope protein called gp160. Our 
inhibitor will block this processing, and by blocking this 
processing, block the production of infectious virus.
    If you can show the next panel, what I'll show you are some 
cell culture studies that we've done just simply showing how 
this inhibitor will block the virus.
    Well, for sake of time, we can skip ahead. I think just 
stay right there. I think we're fine.
    Basically, we can block HIV because HIV uses the furin 
pathway. Now is this going to only work on HIV? No. It turns 
out that this inhibitor will block a number of viruses that 
require the furin pathway, including cytomegalovirus and 
measles virus, and we think by extension any number of other 
pathogen human viruses that simply require the furin pathway 
for their virulence.
    Is it restricted to viruses? No. In fact, we can use this 
same type of technology to actually protect cells against 
bacterial toxins. An example that we use is pseudomonas toxin. 
We think because the anthrax toxin also requires the furin 
pathway in studies that we collaborated on with Dr. Leppla, we 
think that this type of technology leads us to a path that we 
could also protect against anthrax and other deadly toxins as 
well that require this pathway.
    Now what about human disease? In fact, as I told you 
earlier a few minutes ago, in fact, furin is involved in tumor 
metastasis and plays a very ugly role in this process. How does 
it do this? Furin activates an enzyme cascade that leads to 
tumor metastasis.
    If you could just keep going through these slides, this 
activation--part of this is not going to come up--but, 
basically, this activation leads to the ability of tumor cells 
to leave a localized place and spread throughout the body 
because they're able to secrete some proteases that allow them 
to degrade cell barriers.
    What we find is that entire cascade starts with furin. What 
we found, in collaboration with Dr. Andres Klein-Szanto at the 
Fox Chase Cancer Center in Philadelphia, was that if we blocked 
that pathway, we can block cancer metastasis in a simple animal 
model. That's shown in the bottom lefthand corner of the slide 
here. It might be a little difficult to see, but, basically, he 
took an aggressive tumor cell and placed it in an animal. When 
he does this, that tumor cell will grow and will metastasize 
through the animal. If he treats that tumor cell with PDX, this 
inhibitor that we have, this first-generation inhibitor, in 
fact, it blocks tumor metastasis, and it's still encapsulated, 
which is shown in the middle bottom part of this panel.
    Next slide, please. So is furin a novel target both against 
bioterrorism and disease? We think that it is. We think that 
its role in bacterial toxin activation, in the activation of 
millions of many pathogenic viruses, and also in human disease, 
I think strongly suggests that furin is an excellent target for 
the generation of broad-based therapeutics.
    I think that together with the expertise of others at this 
hearing, we may, indeed, develop an exciting new strategy to 
protect against biological terrorist pathogens as well as 
debilitating human diseases. Thank you, sir.
    [The prepared statement of Mr. Thomas follows:]
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    Mr. Burton. Thank you, Doctor.
    Those buzzers you heard going off in the middle of your 
testimony indicate there's a vote on the floor of the House. So 
we will recess and come back here in about 10 minutes, and then 
we'll go to Dr. Collier and Dr. Young. Then we'll get to 
questions. So please bear with us. We'll be back in about 10 
minutes.
    [Recess.]
    Mr. Burton. If we can get everybody back to the witness 
table, we'll restart the hearing and there will be Members 
wandering back in.
    Dr. Young, I understand it's your birthday today. Do you 
want me to sing to you ``Happy birthday''? [Laughter.]
    It's your 29th, is it? [Laughter.]
    Well, you look very young, anyhow. Happy birthday to you.
    Our next panelist is Dr. Collier. Dr. Collier is a 
professor of microbiology and molecular genetics at Harvard 
Medical School. Harvard, I've heard of that school. That's part 
of the Ivy League, isn't it?
    You're recognized, Dr. Collier.
    Mr. Collier. It's an honor to be here to testify today.
    My career has largely been devoted to research on bacterial 
toxins, focusing on their structures of and how they damage 
cells of the body. For the past 15 years we have devoted 
considerable effort to understanding the structure and action 
of anthrax toxin. Our work, together with that of many others, 
including Steve Leppla, Art Friedlander, John Young, Bob 
Littington, and others, has given an increasingly detailed 
understanding of this toxin and how it acts. This, in turn, has 
revealed new ways to inhibit the action; that is, new types of 
anti-toxins, new approaches to making anti-toxins.
    I'll just briefly describe in just a few minutes two new 
ways, two new types of anti-toxins that have emerged directly 
from our understanding of the structure and action of this 
toxin. Then I'll make brief comments about our experiences in 
trying to identify a path to develop these new anti-toxins into 
therapeutic reagents.
    These anti-toxins, a third one that was developed in 
collaboration with John Young, and that Dr. Young will 
describe, are described in an article coauthored by the two of 
us in the March issue of Scientific American. Hopefully, you 
received copies of this.
    So, as you have heard, the anthrax toxin consists of three 
proteins that the anthrax bacterium releases into its 
environment. None of these three proteins alone is toxic, but 
they act together to cause damage to our cells. Two of the 
proteins, called lethal factor and edema factor, are enzymes 
that act inside our cells to alter certain aspects of 
metabolism. Alone these factors are unable to penetrate the 
protective membrane barrier that surrounds our cells. 
Therefore, they cannot enter. Therefore, they're not toxic by 
themselves.
    This is where the third protein comes into play. This is 
the protein called protective antigen [PA]. This protein 
assembles on the surface of our cells into what can be thought 
of as a molecular syringe that is able to inject the other two 
proteins into the cell, figuratively speaking. Once inside the 
cell, the edema factor and lethal factor have access then to 
their molecular targets. They modify these, and that disrupts 
metabolism in ways that ultimately lead to death of the human.
    So figure 1 illustrates the steps by which the syringe 
assembles and acts. I've only shown here the bare essentials of 
this process to keep it simple. If you'll refer to the 
Scientific American article later, you'll see that there's some 
complexities that I've left out.
    But, as shown, the first step is on the left here, the PA 
molecular released by the bacterium binds to its receptor, ATR, 
that Dr. Young will describe in greater detail. There are about 
10,000 or more copies of the receptor for PA on an average 
cell. Thus, you can get up to about that many copies of PA 
bound to a cell.
    Once they're bound, they are activated by a member of the 
furin class of proteases that have been described, and then 
they come together in clusters of seven. We've distributed for 
you these little molecular models of the molecular syringe, as 
it were, the group of seven of these heptamers. These were 
generated by Dr. Timothy Herman at the Milwaukee School of 
Engineering and provided to us today for this hearing.
    So, once the syringe is generated by aggregation of these 
single molecules of activated PA, it's then loaded with its 
cargo, EF and LF. That's shown, I think, as the next-to-the-
last step there, where we've only shown LF, the red molecule 
there on the screen coming down and binding to the surface of 
the heptamer. The syringe is now loaded. The final step then is 
for the syringe to inject the EF and LF into the cytosol. There 
it acts to generate the effects that will ultimately lead to 
death.
    So let me now, with that background then, proceed to 
describe the two new concepts about anti-toxins. Figure 2 shows 
the first one. This is the concept of a dominant negative 
inhibitor [DNI]. The DNI consists of a mutated form of the PA 
molecule. So PA molecule consists of a long string of amino 
acids, some 700 or so amino acids.
    We have found certain places in that long string of amino 
acids where we can change just one or two amino acids, totally 
change the properties of this molecule. The dominant negative 
inhibitor will still--it will combine with the normal PA that's 
produced by the bacteria in the body, but generate a mixed 
heptamer. This is illustrated here on the model. So the white 
one is meant to be a dominant negative inhibitor.
    If you now have one copy of the dominant negative 
inhibitor--we think one copy is enough--one copy incorporated 
into the heptamer, the syringe won't plunge. It will still bind 
the EF and LF, and so you will get a complex, but the complex 
is totally inactive.
    So this is one potential way--this has been shown to work 
in animals as well as in cell culture--to block toxin action. 
So this is one way, then, that we think needs to be explored as 
a possible route to a new type of anti-toxin, the dominant 
negative inhibitor.
    The next slide shows the second approach that I wanted to 
illustrate and that I wanted to tell you about and is figure 3. 
This is a type of anti-toxin that was developed, it's a 
synthetic anti-toxin developed through organic chemistry, 
developed in collaboration with George Whitesides, a professor 
in the Chemistry Department at Harvard. It's a synthetic so-
called polyvalent inhibitor that blocks loading of the syringe 
with its cargo.
    So we first isolated a peptide that's at the upper right 
here that would weakly block the interaction of the EF and LF 
with the syringe, and, thus, block those binding sites. Then we 
grafted many copies of that peptide inhibitor onto a flexible 
backbone, giving you then a polyvalental inhibitor that can sit 
down now on this seven-membered syringe, and you have many 
interaction points then. You can block essentially all seven 
sites with the polyvalent inhibitor. So this is another 
approach that's been explored. As I said, Dr. Young will 
describe the third one that we've been involved with.
    I want to emphasize at this point that all of the research 
that I've described that I've performed actually in my career, 
almost all the research has been done under grants from the 
National Institute of Allergy and Infectious Disease. The 
system of peer-reviewed grants that the NIH uses is, in my 
view, an outstanding system that's served the Nation well as a 
vehicle for building high-quality knowledge base that's needed 
to develop new treatments for diseases of mankind. It 
accomplishes this with a minimum of bureaucracy.
    This brings us to the question, then, of how to accelerate 
research and development of new therapeutics against anthrax. 
When we first discovered the strong anti-toxin activity of the 
dominant negative inhibitors, now over a year ago and long 
before the anthrax attacks of last fall, we began exploring 
ways to do the translational research needed to develop them 
into clinically useful drugs. These agents were ready to be 
developed in a corporate setting. The university setting is not 
appropriate for this type of research, and the research would 
be expensive because of the containment conditions required, 
among other things, the large number of animal experiments 
required. If the product proved efficacious, there would be 
only one customer, the Federal Government.
    It was clear, then, from the outset that the developmental 
research would need to be done under some form of government/
corporate partnership. Possible scenarios were discussed with 
various agencies, but a rapid path has been illusive until 
recently, when DARPA became interested in the project. It 
appears likely now that funds and the managerial partnership 
necessary to conduct this research on a fast track will now be 
forthcoming from DARPA.
    USAMRIID has been helpful also and will be contributing, we 
expect, funds to the project as well. So we hope to learn 
through research on animal models of infectious anthrax, 
conducted within the shortest possible time, whether or not the 
dominant negative inhibitors and the polyvalent inhibitors will 
be truly efficacious in treating anthrax in an infected animal 
model because experiments have not been done yet.
    From our experience to date, it appears that the DARPA 
model may be worth considering by other agencies that are 
seeking to support the developmental phase of studies to 
generate countermeasures against biological agents of 
terrorism.
    Apart from this, another major barrier to development of 
such countermeasures is the dearth of high-level containment 
facilities
for testing new therapeutic agents in animal infection models, 
a major problem. Rectifying this serious and widely recognized 
impediment would greatly accelerate progress in this area.
    Thank you.
    [The prepared statement of Mr. Collier follows:]
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    Mr. Burton. Thank you, Dr. Collier.
    Our next witness is Dr. John Young. He's a professor in 
cancer research at the McArdle Laboratory for Cancer Research 
at the University of Wisconsin, Madison, WI.
    Once again, this is your birthday. So you're recognized.
    Mr. Young. Thank you, Chairman Burton. It's been a pleasure 
to be here today, a tremendous honor for me.
    Let me begin by saying that I actually got into the field 
of anthrax just under 3 years ago. I'm actually a virologist by 
training. I trained with Harold Varmus, when I was a post-doc 
at UCSF. Most of my lab still works on a family of viruses, 
retroviruses that cause cancer and AIDS.
    My lab got involved in the study of anthrax in part because 
of my longstanding friendship with John Collier, but also over 
curiosity about how agents that exist outside of the cell get 
delivered into the interior of the cell. We were curious about 
the anthrax toxin receptor and how it would deliver anthrax 
toxin to its place of action.
    So a collaborative effort was initiated between Kenneth 
Bradley, a graduate student in my lab, and two post-doctoral 
fellows in John Collier's lab, Michael Moufez and Jeremy 
Mogridge. They set out to clone, identify the receptor for 
anthrax toxin, and this work was supported by the National 
Institutes of Allergies and Infectious Diseases.
    Now if I could have the first figure--I'm going to actually 
just use one figure for this presentation and take advantage of 
John Collier's figure 1. So, as Dr. Collier told you, the first 
step in anthrax intoxication is the binding of protective 
antigen to the cell surface, and it binds, a bit of antigen 
binds very specifically to this protein we've identified and 
called anthrax toxin receptor [ATR]. This is the docking 
structure for PA.
    As soon as we identified this protein, this, of course, 
suggested to us a new, direct approach to development of 
another anti-toxin that was based upon this receptor, because 
if you can produce in large amounts the part of the receptor 
that normally is the docking site for PA, then that could 
perhaps act as an effective decoy to stop PA from sticking to 
the cell surface.
    In fact, we've shown that that does work at least in cell 
culture systems. We can take cells that are growing in plastic 
dishes, expose them to toxin in the presence or absence of the 
decoy, and the decoy can protect those cells. So, at least in a 
culture system, in the culture conditions, this works as an 
anti-toxin.
    We also have initiated at my lab, John Collier's lab, and 
with groups at Millennium Pharmaceuticals and at Biogen, have 
initiated a collaboration to try to produce large amounts and 
different types of decoy molecules to see what would be the 
most effective, and those studies are currently underway. Some 
potential decoys are being tested.
    We're also in the business of trying to understand exactly 
how it is that PA touches down on the ATR receptor. We're going 
to understand the exact mechanism of recognition between these 
two proteins. In large part, this interest is driven out of 
curiosity on our part, but also it will provide in the future, 
we're sure, new types of therapeutic opportunities to interfere 
with those very specific types of interactions that these two 
proteins must engage in. So that work also is ongoing in the 
lab, and we've recently obtained new information on how these 
two proteins get together.
    Now, in addition to studying the interaction between the 
receptor and the toxin, we're also very curious about the 
normal function and properties of this receptor. It turns out 
that we actually don't know what the normal function of this 
receptor is. It's been hijacked. It's been exploited by anthrax 
toxin as a means for attachment to the cell surface, but we 
have no idea yet what the function of this protein is.
    What we do know is that the gene that encodes this protein 
is often upregulated in human tumors. So you'll find the gene 
is overexpressed in blood vessels that supply human tumors. So 
perhaps there's a role there for the protein in some aspect of 
tumor blood supply development, but we simply don't know what 
the normal function is at this point.
    What we do know is that there is not just one form of this 
protein ATR. There are multiple forms of the protein, so that 
we show one model up there, one protein that spans the membrane 
once, but we've identified several different, what we call, 
isoforms or different forms of the protein. We would like to 
understand what they do. Do they interact with anthrax toxin? 
And if they do, do they also lead to subsequent intoxication of 
the cell?
    So understanding the protein in more detail, the different 
forms of the protein, understanding some of the steps that are 
outlined in figure 1 by arrows here, what's shown here is a 
sequential step of events that must occur for intoxication to 
take place. We would like to understand what the role of the 
receptor is in getting this seven-membered ring with its cargo 
loaded onto it to the right place in the cell for that toxin to 
be delivered very effectively into the cell, so it can begin 
its toxic actions. This is essentially what we can in 
scientific terms call uptake and trafficking of these 
complexities to the site of action.
    So there is a lot of basic science in my lab aimed at 
trying to understand exactly how that process is controlled. 
Again, our goal is to understand the biology of this system in 
greater detail, but, undoubtedly, if we can do that, then, of 
course, that's going to offer new types of therapeutic 
approaches in the future, we believe, aimed at stopping those 
other aspects of the toxin entry pathway.
    So I'd actually just like to sum up at this point. When 
thinking about quickening the pace in anthrax toxin research, I 
think we have to think about this from two different 
perspectives. I think what we have to do is we have to look at 
the exciting new approaches that are available now, antibodies 
against protective antigen, these decoy types of proteins, 
these types of inhibitors that Dr. Collier mentioned, the 
polyvalent inhibitor, dominant negative inhibitor. These are 
agents that are available now and can be tested in animal model 
systems if these animal model systems become easily available 
to test them in.
    But I think we have to really think more broadly about how 
we're going to approach not just anthrax toxin, but any type of 
bioweapon agent that might be delivered, using similar 
mechanisms to those shown on this slide. I think for that we 
really have to rely upon the entire scientific community to 
better understand some of these very basic properties in the 
cell, these early steps that allow cargo to be taken up from 
the outside and delivered to the inside.
    We've made some remarkable progress, again because of the 
insight and support of NIH. The community has made tremendous 
progress understanding these processes, but we need to 
understand them in much greater detail if we are going to 
figure out very smart ways that we can stop pathogenic 
organisms from exploiting those pathways that the cell needs 
for its normal functions. So I really think that we have to 
think very, very broadly about how we go about doing this.
    With respect to that, too, it should be clear from what I 
said previously that with the anthrax toxin receptor, here's a 
gene that's upregulated in tumor blood supply. On the one hand, 
you wouldn't equate the two areas of scientific discipline. You 
wouldn't say that tumor blood supply is going to give you any 
insight into a treatment for anthrax toxin, but it may, in 
fact, be that understanding what the normal function of this 
receptor is will suggest some future therapies that could be 
used against this agent and others.
    So I'll close there and thank you.
    [The prepared statement of Mr. Young follows:]
    [GRAPHIC] [TIFF OMITTED] T9590.048
    
    Mr. Burton. Thank you very much, Dr. Young. Are you from 
Ireland, Scotland, or Australia?
    Mr. Young. Actually, I'm from Scotland, but I have been in 
this country for almost 15 years now.
    Mr. Burton. I thought Scotland. My son and I were over 
there playing golf not long ago, and you sounded like one of 
those people that we talked to over there, very nice people. 
[Laughter.]
    I don't like haggis though.
    Let me start off the questioning by asking, first of all, 
and Dr. Smith and I had a chance to talk before we had the 
hearing today, and I think you indicated, Dr. Smith, that at 
some point you think it's possible that people who are exposed 
to inhalation anthrax might be able to use some kind of a spray 
that would immediately inhibit that from becoming toxic to the 
human body.
    I think the first question for all of you, and I'll start 
with you, Dr. Smith, is: How long will it take, roughly, if the 
funds are adequate for research, how long will it take before 
we have some kind of a solution to this problem that the 
American people, the mass of American people, could count on? I 
mean, we're talking about the possibility of a massive attack 
in an urban area down the road from these terrorist groups that 
are around the world. So can you give us a timeframe and what 
type of spray or vaccination could we come up with that would 
be effective, not only against anthrax but against Ebola and 
other types of toxic substances?
    Mr. Smith. Thank you, Mr. Chairman. Through the History 
Channel, I'd like to make a comparison. I didn't realize that 
the Pentagon as a building was built in 1 year, but that was 
during a time at the very beginning of World War II. It will 
take far more time than that to get it back in shape after one 
plane hitting it.
    It's the speed at which we want to see something done; it 
is directed by the speed which we put behind it. I think from 
the protease inhibitor approach, as I said in my presentation, 
the Chloromethylketone, which is in the literature as a means 
of stopping infection, that has been done, but that compound 
cannot be used as a drug candidate. It would take from 90 to 
120 days, by the judgment of the synthesis chemists in enzyme 
systems products, to synthesize a first-generation inhibitor 
that could be handed, for example, to Dr. Thomas to run through 
tissue culture work and the elegant work that he has done in 
the past, to evaluate that to see if it then could be carried 
on to the other very competent gentlemen here to run in animal 
models.
    The whole thing could be done, in my opinion, in less than 
a year's time, if there was the funding behind it. It's no more 
funding to do that than to delay it, because the amount of 
funding to make these compounds is not great.
    I had the privilege to talk to Beth yesterday and said that 
it actually would be the cost of about one penny to every 
American citizen to fund that type of research. I think that 
answers itself.
    Mr. Burton. And we'll go down the panel with that question. 
So you think that within a year, if the resources were 
available and everybody got to work on this, that we could come 
up with not only some kind of approach for dealing with the 
anthrax threat, but also with these other threats as well?
    Mr. Smith. Possibly with--now anthrax could be used, 
anthrax inhibitor is seen of a molecule that is less than a 
thousand molecular weight. That means it's extremely small. It 
would be about the size of a golf ball compared to the anthrax 
bacteria itself, which would be more like the size of a 
basketball. So your drug in this particular case is much 
smaller than the organism.
    The antibody approach, or even the elegant mutated or 
designed natural molecules, are about a hundred times larger, 
in the 30,000 to 40,000 molecular weight range. I believe, 
preempting Dr. Balhorn, that he has some work that will 
ultimately show the difference and what that could mean in how 
fast we approach something.
    Mr. Burton. Dr. Thomas.
    Mr. Thomas. Well, thank you. It certainly would seem to me 
to develop novel strategies for anthrax that would be optical 
to people certainly would take some time. I would think that 
part of this would depend certainly on funding, but another is 
bringing together a team of talented scientists with different 
expertise from peptide or small molecule design, for example, 
to sub-biology-type assays, to animal studies, that I think can 
run through a number of assays that I think are probably fairly 
well established in labs around the country--at NIH, for 
example--to begin testing these.
    How long that takes is always tough, I think, to answer 
because you do go into animal models and you do go into 
unknowns. It's the mystery of science as to how long this can 
go on for, but I would imagine, certainly from the panel's 
discussion that I've listened to this afternoon, this is 
something that I think is compelling, and I think it's 
imminent, that in fact progress can be made to alternative 
strategies probably within just a short few years' time. 
Certainly the collaboration between scientists and corporations 
I think is of great benefit to some of these approaches, and so 
I think that certainly parts of this are well on the way to 
seeing some success. That's for anthrax.
    Then for the broader development, for example, other 
targets, whether we use a protease inhibitor of the kind that I 
described or new-generation protease inhibitors, I think really 
depends upon the team and the talent that we can recruit into 
this area. Certainly the talent is available around the country 
to do this. It's a matter of assembling that talent in an 
organized way in a mission such that we do attain that goal, 
and I think in just a few short years.
    Mr. Burton. Let me interrupt and just say this.
    Mr. Young. Yes, sir.
    Mr. Burton. I'm sure that NIH knows how to get this done.
    Mr. Young. Yes.
    Mr. Burton. Those of us on this panel are neophytes as far 
as this kind of information goes and how to deal with it, but 
what I would like for you to do as panelists, and you don't 
have to do this today, but I'd like for you to give me your 
best advice on the length of time that you think this would 
take, No. 1, a rough idea, and I'm sure it's going to vary; the 
amount of money that you think it might cost, and I know again 
that's probably going to be something you're going to have to 
pull out of the air, but you've dealt with this before so you 
have some idea of what research costs, and then what kind of a 
team we'd have to put together. If I could get that information 
from you and the other panelists who are going to be here 
today--do we have anybody here from NIH today? Would you raise 
your hand?
    I'm sure that we could convey that to them, and I'm sure 
they're very receptive to that kind of information, and we 
could get on with this as quickly as possible. I'm not sure, 
and I don't think anybody knows, how long we have before the 
next terrorist attack, if one does occur. But the one thing 
that I'm pretty confident of, if we have one, it's going to be 
probably as bad or worse than what we saw before. If it's a 
bioterrorist attack, it could end up killing tens of thousands 
or hundreds of thousands or more. So time is of the essence.
    So if you have information or judgments that you could give 
to us that we could convey to our friends at NIH who are here 
today, maybe we could cut through some of this paperwork and 
some of this bureaucracy that we deal with here in the 
Congress, to get to the heart of the matter as quickly as 
possible. No. 1, get you the money you need. No. 2, help you to 
assemble the technicians and the scientists that are necessary 
to come up with a solution, maybe cut through the time that's 
required for the lab tests with the animals, and so forth, so 
that we could get this thing prepared and ready for the 
population on a massive scale before we have that kind of 
terrorist attack.
    So I just hope that you'll give this committee that 
information, and at the same time it will be going to NIH, and 
then we can kind of maybe work together to make sure we get the 
funding and everything else that's necessary.
    Dr. Collier.
    Mr. Collier. I have very little to add to what Dr. Thomas 
and Dr. Smith said. It's very difficult to estimate with any 
accuracy how long it will take to develop any given drug. We 
have a number of candidates already on the table. There are 
companies and laboratories now screening libraries of compounds 
for inhibitory activity to block toxin agent.
    From what I showed on the slide, you can see that there are 
many, many steps in the action of this toxin. Potentially any 
one of those can be interfered with. We can go after the 
inhibitors either by a rational approach or by screening 
enormous numbers of compounds that might inhibit one or another 
step, and both of those need to be done and are being done.
    I think Dr. Smith didn't--the focus has been on the furin, 
inhibiting furin as a step in proteolytic activation of PA. I 
don't think he has mentioned also that the lethal factor is 
also a protease, metalla-protease. So this is another step or 
another target of the action of seeking inhibitors.
    I know at least one major drug company that's now doing 
very high throughput screening of their large battery of 
compounds for ability to inhibit the lethal factor action. I 
think I'll stop there and turn the floor over to Dr. Young.
    Mr. Burton. Dr. Young.
    Mr. Young. I actually have nothing really more to add in 
terms of timeframe. I think it's almost impossible to estimate 
with any reasonably certainty when there will be an effective 
anti-toxin on the table.
    I think that one thing that's quite clear, though, in the 
last 5 months, having gone to various institutions across the 
country and given seminars, that many scientists who, like me, 
were not involved in this area of research want to get 
involved. They really want to get involved. They want to do 
something. In order for them to do something, they have to have 
resources. I have no idea how to put a dollar figure on what 
kind of activity that would take, but it's quite clear that 
very creative people, chemists, biologists, from many different 
types of disciplines with very different skills--we think about 
problems in different types of ways--want to make a difference 
here.
    So my only suggestion then would be to make sure that they 
could do so without any barrier whatsoever, financial or a 
resource. I think that if there's a barrier in place, it's 
going to hold people back from really jumping in and trying 
something that's new, which I think might, in fact, be the 
difference.
    Anti-toxins that are on the table today may not look like 
the anti-toxins of the future. I think the sooner we get to 
that stage of having the most effective drugs and products on 
the table, the better position we'll be in to deal with any 
bioterrorist threat. So that's the only thing I would say about 
that.
    Mr. Burton. Let me say, before I yield to my colleagues, 
whatever it takes, we'll be glad to help you with to cut 
through the red tape necessary to get answers as quickly as 
possible, because I don't think anybody in the Congress doubts 
that we have to do this as expeditiously as we possibly can, 
get it done. We just don't want to see Indianapolis or Chicago 
or Los Angeles or New York suffer 100,000 casualties because we 
didn't get on this as quickly as possible.
    Connie, do you have a comment?
    Mrs. Morella. Thanks, Mr. Chairman. Since Mr. Shays yielded 
to me, he had no question, and Mr. Weldon will be back in the 
room.
    Thank you for calling this hearing. I'm glad I'm not being 
given a test on explaining exactly your material. [Laughter.]
    But in terms of the general policy provisions, this is what 
we are here for. Last year the FDA approved the antibiotic 
Cipro, a previously licensed product for the new indication of 
treating inhalation anthrax based on animal studies. Cipro had 
been tested in humans for other indications, and it was shown 
to be safe and effective.
    Developing new drugs that will protect against anthrax and 
other biological terrorism agents really presents some specific 
testing challenges, and that's what I will be asking because, 
how will we develop these drugs and test them adequately, since 
it's not ethical to intentionally expose human beings to 
inhalation anthrax to see if the treatment works? Do you think, 
therefore, following up on that, as you respond, do you think 
that there should be a different level of evidence that would 
be needed to approve these products, such as that proposed 
animal rule which would allow the FDA to approve a new drug 
that is effective against inhalation anthrax based only on 
animal data? I address it to anybody, anybody who wants to----
    Mr. Smith. May I be the first to respond then? In the case 
of the small molecular weight inhibitors, which obviously I 
champion--I champion them on the basis that, as I said, they 
have proven successful in the treatment of HIV infection, and 
there are in pre-clinical trials of these inhibitors at some of 
the major universities for the enzymes called caspase in the 
treatment of the disease states that I talked to, such as 
Parkinson's disease, ALS, Huntington's, and stroke, the furin 
inhibitors aren't too far removed from them. They're small 
molecules, and they require--just simply the first line of 
testing is to test in cell cultures the elegant systems which 
Dr. Thomas' laboratory has established.
    Dr. Thomas and I have discussed this in some detail by 
ourselves and in the presence of Beth Clay as well, as to how 
we would pursue this by doing this where no animals are 
involved, no humans are involved. If it doesn't pass muster 
there, then the technology is no good. If it does, you move on 
sequentially.
    Of course, the more positives you have, the faster you can 
buildup your data base, because of your condition to move 
quicker. I still think that the very original development of 
the chemistry--wet chemistry, as we refer to it--can be done 
within a year period of time. I'm not agating the amount of 
time that it would take would be longer to go through the 
cellular work and into the animal work; that's a given, and 
there are certain requirements and specific things that have to 
be met in accordance to the Food and Drug Administration and 
the NIH to do those type of investigations, but I think it's 
plausible.
    Mrs. Morella. Would any of the rest of our distinguished 
panelists, like to comment on that? I think that was a 
recommendation, an animal rule recommendation, that I think had 
not been followed through. Maybe this is something I should be 
asking the next panel, but I would like to get your comments on 
the testing problem.
    Mr. Thomas. I think this is where I also become a layperson 
in some of these areas, but what the committee is doing is 
really pushing scientists very hard for taking cutting-edge 
science in biological research that I think you've heard here 
today and translating that into new drug therapies. That's why 
I think you're picking up some caution on the committee, 
because we are talking about research, basic science research, 
that, in fact, we are compelled, like you, to see how we could 
translate some of our basic new findings of how cells function, 
how pathogens function, into new drugs.
    It's slightly different, for example, than coming up with a 
new sleeping pill at a major pharmaceutical company, where you 
have ideas on how to escape patent issues with competition 
somewhere else, but this is something different. This is where, 
in fact, it does always hold additional research that we need 
to do as we come into these areas. This is why I think you're 
picking up caution, and appropriately so, from the committee 
members, that in fact you do have to take this in steps and go 
through cell work, go through animal work.
    This is why it's tough to give you an exact time on when 
something is due, because what you're asking for is some 
translation of just new findings in cell function and how that 
can translate into a therapy and how fast we could do that. 
Those are tough because we really are pushing the envelope of 
what we're finding for new discoveries on how those functions.
    Mrs. Morella. Since I think I have a little more time left, 
then I'm going to avail myself of asking maybe our other two 
panelists, what specific recommendations would you make to the 
DOD and NIH today? Being on the first panel, you don't have a 
chance to interact with the second panel. So this might be your 
opportunity to offer whatever you would like.
    Mr. Collier. I guess I would simply reiterate two of the 
points that I made in my initial presentation: that, No. 1, 
there's a major need to find new models or models that will 
really work in accelerating the development through government/
corporate partnerships rapidly. As I said, it appears to me 
that DARPA has a viable model for doing that, with allowing an 
appropriate amount of money to be directed to a project, 
overseeing the project with a manager that will have 
flexibility and ability to keep close tabs on the project, be 
sure it's moving very rapidly.
    I'm a layperson as well in trying to think about these 
things, but I have not seen other models in the government 
institutions that we've spoken with that are perhaps as close 
to this as one might like. So that would be, I think, the major 
point that I would make.
    Mrs. Morella. OK. Dr. Young, do you want to add anything?
    Mr. Collier. Pardon?
    Mrs. Morella. No, thank you, Dr. Collier.
    Mr. Collier. Yes, sorry.
    Mrs. Morella. I was going to then recognize Dr. Young.
    Mr. Young. Well, if Dr. Collier feels like a layperson in 
this area, I feel like a level below that in this area. I think 
that----
    Mrs. Morella. You're making me all feel pretty good. 
[Laughter.]
    Mr. Young. It's quite clear, though, that even with 
existing anti-toxins on the table, that there are some major 
roadblocks, and have been major roadblocks, to having those 
products produced in large amounts and tested in appropriate 
model systems.
    I think that one of the big lessons for me in the last 6 
months or so has been learning not how much we know about 
anthrax and the pathogenesis of the disease, but how little we 
know about this. Despite remarkable progress that's been made 
by a number of investigators in this field, we actually know 
remarkably little about biology of the spore, for example. We 
know remarkably little about how it is that people end up dying 
from this disease.
    I think that when thinking about model systems, animal 
model systems, and advising the DOD or NIH about model systems, 
which model system is going to most closely mimic that of a 
human? You have to find something that is most closely related 
to the human condition, but we don't know much about what it is 
that we're looking for in that model system, because we don't 
understand the disease in humans well enough to really know 
that.
    So I think that really, again, my advice in this area is to 
think broadly. A number of systems may have to be tried, 
tested. They might not work. Test them as quickly as you 
possibly can, get the information, and move on. Don't sit on 
your hands, scientists sit on their hands, not the people on 
the panel there--scientists don't sit on their hands. Get 
things done; get information, and then get our heads together 
and figure out exactly how it is that we can create the best 
model system for this disease. Then ensure that people who have 
novel and creative approaches are allowed to develop them and 
have them tested in short order to see if they can then be 
translated into a product that can be used in humans.
    Mrs. Morella. Thank you. I want to thank the panel.
    Dr. Young, have you ever met Dr. Frank Young, who 
previously was an FDA Director? I know my NIH people are kind 
of smiling affirmatively. Have you ever met him?
    Mr. Young. No.
    Mrs. Morella. No?
    He had testified before a Science Committee I'm on on 
bioterrorism and the testing situation. With the same name, I 
just thought that you might have, and in similar fields. Thank 
you.
    Thank you, Mr. Chairman.
    Mr. Burton. Thank you, Mrs. Morella. Mr. Shays. Mr. Horn.
    Mr. Horn. Thank you very much, Mr. Chairman. I came in from 
other activities, and I didn't hear the first part, but I 
notice this little box here of the anthrax protective antigen. 
I thought that since my colleagues have it, that maybe we'll 
have a seniority change on this panel. [Laughter.]
    What will activate, if anything, the anthrax protective 
antigen, can you inject it in some human or is it a spray that 
you can do it? Give me some layman's response on that.
    Mr. Smith. Well, if that's in reference to anthrax that 
would be inhaled, that there is a possibility with low-
molecular weight inhibitors that they could, subsequently, 
within a matter of the most convenient and most expeditious 
time period, with an inhaling mechanism inhaled the potential 
protective antigen inhibitor because it is such a small 
molecule. In other disease states, where the furin enzyme plays 
a very important role, I think it would probably have to 
ultimately be injected in some form, especially if you were 
trying to ward off an Ebola attack.
    Mr. Horn. Any other comments on this? Dr. Collier.
    Mr. Collier. Yes. With regard to the inhibitors described, 
these are large molecules. Our thinking is that they probably 
would have to be injected. Possibly a spray delivery system 
might be developed or possibly even enteric pill that you could 
swallow, but at this point our thinking is that it's likely 
that they would have to be injected, yes.
    Mr. Horn. Dr. Young, do you have any thoughts on this?
    Mr. Young. I have nothing to add other than what Dr. 
Collier has already said.
    Mr. Horn. Does the drug development research have to be 
conducted in a B-4 level laboratory? That's the highest level, 
is it not, in handling this, or this very difficult to spread 
it out? How many laboratories do you think could do this and 
work with this? We know Harvard can. We know Wisconsin can. We 
know NIH can. What is going on in Europe on this? What do we 
know as scientists? Are you all waiting for the Nobel Prize? 
[Laughter.]
    You're not playing any cards.
    Mr. Collier. Probably Dr. Friedlander on the next panel 
might be best equipped to answer this, but there are only two 
or three places, Art, in the country that can handle 
inhalational anthrax that are equipped to do those types of 
experiments. What we badly need is possibly a single center in 
the country with much greater capacity. Capacity to do the 
appropriate experiments needed to test these compounds, there's 
a major roadblock there that needs to be overcome. I know that 
NIH is thinking about this; CDC is thinking about this, and I'm 
sure the Army. But this is something that really needs to be 
considered.
    Mr. Horn. Now is this a vaccine that we're headed for more 
than that? Let's say you have--I'm going to Nashville tomorrow, 
and we're going to have data on chemical attacks, biological 
attacks, nuclear, etc. We're doing that in a number of cities 
across America, just to alert people that what are the things 
one can do. So I would be curious what would be things that 
people can do, the local sheriff, the local public health 
authorities, the hospitals in the area. What would you suggest 
the kind of questions we ought to pry to see if something 
happens and the people in Nashville, say, have something in the 
water system?
    Mr. Collier. Well, I think you should tell them that we're 
working avidly on all of these approaches. The panel today is 
concentrating mostly on therapeutic approach to anthrax. We 
have heard a number of candidates put forward, and a number of 
others are being thought about.
    Vaccine, new types of vaccines are being developed and 
being considered. In fact, the NIH has an initiative now to do 
a very fast-track development of a new vaccine. Beyond that, I 
don't know how to recommend what you should say to the folks in 
Nashville.
    Mr. Horn. Nashville, Milwaukee, we're looking at the 
medium-sized cities. The big cities, New York and Dallas and 
all of the 1 million or more, they usually have fairly good 
emergency management and public health, but we want to see what 
else is happening. Because when you add all the others up, 
you're talking about millions of people.
    Dr. Young.
    Mr. Young. Yes, I think the message should really be that 
the existing vaccine, while effective, obviously, has 
complications. There are new types of vaccines already in the 
pipeline, at least one that's being pushed hard at the moment 
to be tested.
    But, undoubtedly, as more and more people get involved in 
this type of research, then the whole area of vaccine 
development will also be one that will go through some form of 
evolution. It will change from perhaps its current state into a 
new one that might be more effective.
    So I think the message to the people of Nashville should be 
that scientists are working very hard on trying to come up with 
ways to develop an effective vaccine with minimum side effects.
    Mr. Horn. Dr. Smith, how long does it take to develop the 
products necessary to test for toxin interference?
    Mr. Smith. The small molecular type inhibitors are done, as 
I've tried to articulate, by what is laboratory simple 
chemistry, where you use flasks and beakers and reagents of 
that nature in an organic synthesis type of setting. There are 
many major pharmaceutical companies that do this. There are 
several pharmaceutical companies that presently are making HIV 
protease inhibitors and marketing them, as I'm sure you know. 
This is a continuation of that concept, and if we can take that 
same approach, only not attacking the organism, the HIV or the 
anthrax, but attacking the part of the cell--and if it won't 
split the protective antigen, it cannot infect. We try to avoid 
that split. If we can do that, we have made it. If we can't, we 
have failed. It's a simple yes-or-no answer.
    Mr. Horn. 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?
    Mr. Smith. Because it's the first cellular organelle entry, 
etc., that the anthrax organism sees. To be sure, as Dr. 
Collier said, there is another enzyme within the cell which is 
known as the lethal factor. It is a protease as well, but it 
involves a different type of protease called a metalla-
protease, and those proteases are down the line. It's not the 
first line of defense. It would have to be defined as the 
second line of defense.
    Mr. Horn. Do you think the other stages should be explored 
simultaneously?
    Mr. Smith. Well, certainly. I wouldn't leave out vaccines 
although I'm not a devotee of vaccines.
    Mr. Horn. What about other medical conditions that are 
likely to benefit from the research conducted on the anthrax 
anti-toxin?
    Mr. Smith. I think Dr. Thomas stated it very eloquently: 
the various forms of cancer, the various other types of 
infectious disease from measles to cytomegalovirus to 
mononucleosis. There are different types of kissing cousins, so 
to speak: the Marbur virus to the Ebola viruses. All of these 
could in one form or another cause minimal concern by causing 
havoc by just diphtheria or measles epidemic.
    Mr. Horn. What other biological agents act similarly to 
anthrax that we might develop treatments in a similar fashion?
    Mr. Smith. Well, the interesting thing about these 
inhibitors is that they are extremely specific. By changing 
just single amino acids within a protein to accommodate a 
particular organism, one gets a degree of specificity, and we 
don't know today how extensive that specificity can be.
    Mr. Horn. Now we've got currently an outbreak of Ebola in 
the Congo. 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?
    Mr. Smith. With the appropriate synthetic protease 
inhibitor, I think there is a good possibility. I certainly 
couldn't give you a guarantee, but I think it's route of 
treatment would not be inhalation or topical as would be in the 
case of anthrax, but would have to be intravenous injection 
since the Ebola virus works in a very different way in its 
killing process, by destroying the liver and blood vessels.
    Mr. Burton. Mr. Horn, can we catch you on the next round?
    Mr. Horn. All right, this last question is----
    Mr. Burton. OK, sir.
    Mr. Horn [continuing]. Are we working on this in the United 
States or in Europe?
    Mr. Smith. We've done some limited work and have theorized 
on paper what these inhibitors should look like chemistry-wise, 
but I don't know of anyone personally anywhere else in the 
whole world who has done it yet, besides ourselves.
    Mr. Horn. Well, I thank you for your judgments on this. 
It's very important.
    Mr. Burton. Thank you, Mr. Horn.
    Mr. Thomas, you indicated while Dr. Smith was talking that 
you might have something that you wanted to add real quickly. 
Did you have something you'd like to----
    Mr. Thomas. It was just a followup, but I think Dr. Smith 
handled it very well: that why to go after furin is it really 
represents, I think, the tip of an iceberg for the activation 
of a number of bacterial and viral pathogens, as well as a 
number of human diseases. We went through a couple of examples, 
including rheumatoid arthritis and metastatic cancer. It's, in 
fact, those reasons why I think that targeting furin could have 
potentially broad application for a broad-based therapeutic. 
But I think it was answered eloquently enough by Dr. Smith.
    Mr. Burton. Thank you.
    Dr. Weldon.
    Dr. Weldon. I want to thank the chairman. My occupation 
before coming here was I practiced medicine. I still see 
patients once a month, internal medicine, and I actually did 
infectious disease for about 7 years. My undergraduate degree 
is in biochemistry.
    This is fascinating, Mr. Chairman, bringing these people in 
here and to hear this kind of research. It's fascinating to see 
how sophisticated our knowledge and understanding has emerged 
at least over the last 20 years since I was a college student.
    Let me just understand correctly this model, Dr. Collier. 
You arranged to have this provided to us, correct? Is that 
right? And it was made by Dr. Herman in Milwaukee, is that 
correct?
    Mr. Collier. Yes, yes.
    Dr. Weldon. This is a model of the protective antigen 
with--and it's normally heptamer-7----
    Mr. Collier. Yes.
    Dr. Weldon [continuing]. Protective antigens that are 
linked together and then put in this one; the white one is the 
one that has some amino acids altered.
    Mr. Collier. Yes.
    Dr. Weldon. And this is one of the concepts that you have 
for a drug treatment, correct?
    Mr. Collier. That's correct.
    Dr. Weldon. Why is it called protective antigen? That is 
very confusing. I don't know who picked that name, but I would 
highly suggest you change the name. [Laughter.]
    Because it's protecting edema factor and lethal factor, is 
that why they gave it that kind of a name?
    Mr. Collier. No, this is a name that emerged way back in 
the 1950's, I guess.
    Dr. Weldon. In the 1950's?
    Mr. Collier. Yes, when the protein was first discovered. 
It's the part of the toxin that induces protective antibodies 
in the body, the most effective one.
    Dr. Weldon. So that's how it was given that name?
    Mr. Collier. That's how it got its name, yes. We might name 
it a little bit differently now----
    Dr. Weldon. This is nasty stuff, correct? I mean, this is--
--
    Mr. Collier. In actual fact, the protein itself by itself, 
as far as one can tell, is not toxic at all, unless it has the 
other two.
    Dr. Weldon. It needs the other two?
    Mr. Collier. Yes.
    Dr. Weldon. Now the patient comes in, is diagnosed with 
inhaled anthrax, is given antibiotics, but ends up dying anyway 
because in some cases the bacterial load in the bloodstream is 
so high that they're going to die of shock, no matter what. But 
in some of them it's because the body burden of lethal factor 
and edema factor and this injection mechanism is so high that, 
even though you've killed and eradicated all the active 
bacteria in their body with antibiotics, with high-dose 
antibiotics, this stuff is going to kill them anyway, correct?
    Mr. Collier. That's the current thinking.
    Dr. Weldon. OK. And your thinking is, by introducing, 
either through injection or through a tablet form you 
mentioned, something like the white one here, it would just 
interfere with the whole pathophysiologic mechanism that's 
involved in the terminal phase of the disease?
    Mr. Collier. That's the hope, and at what stage, obviously, 
at some point in the stage the patient can't be rescued; no 
question. So how late in the course of the disease something 
like this inhibitor could be administered and still save the 
patient is right now anybody's guess.
    Dr. Weldon. OK. And, Dr. Young, you said, I think, in your 
presentation the other idea, other than having a genetically 
engineered variant of the protective antigen, is to approach it 
several other ways to block the mechanism of injection with 
smaller molecules, correct? And you've mentioned the peptide, I 
think?
    Mr. Young. Yes. Actually, it could be done with either 
antibodies that we bind to protective antigen and stop it from 
binding to cell surfaces or it can be done with a decoy type of 
protein I described.
    Dr. Weldon. Right.
    Mr. Young. Small molecules that would disrupt that 
interaction have not been discovered yet, but, obviously, that 
would be a goal for future research, to find something like 
that.
    I think that an important thing to bring up is that the 
lesson from HIV has been you must use a cocktail of inhibitors 
if you want to really, as effectively as you can, stop----
    Dr. Weldon. Shut it off?
    Mr. Young [continuing]. Shut off the process. So it may be, 
in fact, that one anti-toxin isn't going to be sufficient. You 
may have to target the eight steps that Dr. Leppla has 
outlined, eight different steps of this process, to get really 
effective blockage of toxin action.
    Dr. Weldon. Right.
    Mr. Young. But the strategies that target the steps on the 
outside of the cell are just much more accessible----
    Dr. Weldon. Sure.
    Mr. Young [continuing]. Than those inside the cell. So 
that's why they're attractive as a first step in this process.
    Dr. Weldon. Now, Dr. Thomas, if I understand you correctly, 
the furin enzyme is necessary for the formation of these 
proteins, is that correct?
    Mr. Thomas. Yes, so the furin pathway, the furin enzyme is 
necessary for activating the larger form of protective antigen. 
When the bacterium releases protective antigen, it releases it 
as a larger inactive protein, and it has to be cut by furin to 
generate the smaller active form that can form as heptamer. So 
the idea would be for furin inhibitors is, if you block furin, 
then you block the ability of this protective antigen to form 
this heptamer that can produce a syringe-like quality.
    Dr. Weldon. So the anthrax has released all of this protein 
in the bloodstream that has protective antigen in it, and the 
furin on the cell surface is actually cleaving that protein to 
produce the active form of this? So your theory is, if you can 
block the cell surface furin, that's another potential way to 
block the toxic cascade essentially?
    Mr. Thomas. Exactly.
    Dr. Weldon. OK. Are you getting enough research funding, 
all of you? We talked a little bit about this. Most of you, I 
would assume, are funded by NIH or one of its affiliated 
agencies. With more funding, you could accelerate your work? Is 
that what you're telling us here today? I know every scientist 
says that, but----
    Mr. Thomas. I think it would be----
    Dr. Weldon. Pardon me?
    Mr. Thomas. I'm sorry, I didn't mean to interrupt. I was 
just going to mention I think it would be rare to find a 
scientist who says he's adequately funded nowadays.
    Dr. Weldon. Right.
    Mr. Thomas. But in the context of our work, we are funded 
by NIDDK. We were funded originally by NIDDK, that led to the 
funding or led to the invention of the furin inhibitor that I 
did describe this morning. That actually translated into 
research that was subsequently funded by NIAID on basic 
questions on cytomegalovirus assembly.
    But, specifically, on the PDX inhibitor that I've described 
for you and the various uses of it, in fact, we're not funded 
on it currently, but it's something that we're preparing for in 
the laboratory, for doing.
    Dr. Weldon. So you plan to apply for grants to help 
something like this?
    Mr. Thomas. Sure, certainly.
    Dr. Weldon. Did you say that you've done some toxicology 
studies on the PDX inhibitor that----
    Mr. Thomas. Yes, there has been some short-term toxicity 
studies done in rats by a couple of groups, taking the PDX, and 
through injection, and they found no short-term acute toxicity 
with this reagent.
    The reagent right now is made in bacteria. So it has a 
fairly short half-life in the animal. So we think that to 
increase its bioavailability would mean that we would change 
the ways in which we would make PDX. We would make new 
generations of this inhibitor.
    But one potential use of this, particularly thinking in 
terms of anthrax, is that we did build this inhibitor based on 
a scaffold of a protein that's well characterized called Alpha-
1 Antitrypsin, certainly with its roles in emphysema, for 
example. A lot of the pharmacokinetics of Alpha-1 Antitrypsin 
are fairly well-established, and it's known, coincidentally, to 
concentrate in the lung.
    Dr. Weldon. Right.
    Mr. Thomas. So maybe there's a possibility that, by a 
second-generation-type inhibitor that we're developing, that we 
could maybe have one that's more bioavailable, longer-lasting 
that would target the lung, and maybe we would see some success 
in this area. But this is something that just hasn't been done 
yet. So we don't know.
    Dr. Weldon. Now if I understand you correctly, and I think 
the next witnesses are going to elaborate on this more, 
vaccination of the whole population would be very difficult. We 
could probably vaccinate first-responders, but if we were not 
to vaccinate the whole population, we would need other drugs to 
help us in the setting of a mass outbreak because, clearly, 
antibiotics given late don't always work; you can still lose 
people. That's where these products could find an application.
    If I understand you correctly, you feel very strongly that 
they could have applications in the management of cancer as 
well, correct?
    Mr. Thomas. Yes, we think so. We see certainly some 
preliminary data and some very simple animal models that, in 
fact, we can block metastasis by blocking this particular 
pathway. The cascade that furin initiates that leads to tumor 
metastasis I think is fairly well understood because it 
activates actually multiple protease systems that themselves 
have been allowed tumors to metastasize and invade other 
tissues.
    In fact, with colleagues at the Fox-Chase Cancer Center, 
they have been able to show that, if they use this particular 
reagent that we've developed, that in a very simple animal 
model, mind you, they still can block the metastatic potential 
of these tumor cells. So it's a proof of concept, in fact, 
that----
    Dr. Weldon. Yes, I found it very interesting, actually, 
when you presented that to us. Have you presented that 
information at any of the cancer meetings?
    Mr. Thomas. I think that my colleague, Dr. Andres Klein-
Szanto at the Fox-Chase Cancer Center has presented this at 
several meetings this last year, and it was recently published 
in the National Academy of Sciences this past fall.
    Dr. Weldon. Great. Thank you very much, Mr. Chairman.
    Mr. Burton. Unless there's further questions, we'll thank 
this panel very much for your expertise and your testimony. 
Before you leave, let me just, once again, ask you to, if you 
have some suggestions on funding or research or team research, 
or things that we've talked about here today, I wish you would 
not only convey those to NIH, but also to Beth on our 
committee, so that we can do what we can to help do whatever it 
is possible to get additional funding for the research that's 
necessary.
    In particular, this area of metastatic cancer you're 
talking about, I have a personal experience with my family with 
that right now. I want to tell you, there's so many people in 
this country that have been just devastated by the 
metastasizing of cancer, that it's not funny. Boy, I'll tell 
you, I wish you all the success in the world in getting that 
research done as quickly as possible, in addition to the 
research on these other things.
    So thank you very much. I want to thank all the panel.
    We'll now bring our next panel forward. Our next panel 
consists of: Dr. Rodney Balhorn, he's research director at 
Lawrence Livermore Laboratories; Dr. Stephen Leppla, he's the 
senior investigator for the National Institute of Dental and 
Cranial Facial Research of the National Institute of Health in 
Bethesda; Dr. Arthur Friedlander, he's a senior scientist in 
the U.S. Army Medical Research Institute of Infectious Diseases 
at Fort Detrick, MD.
    Would you please stand, so we can swear you in? This is a 
common practice we do here. I don't think it needs to be done 
today, but we'll follow that common practice.
    [Witnesses sworn.]
    Mr. Burton. Be seated.
    I think we'll go right down the list here. Dr. Balhorn, 
would you like to make an opening statement, sir?

   STATEMENTS OF RODNEY BALHORN, RESEARCH DIRECTOR, LAWRENCE 
 LIVERMORE LABORATORIES, DEPARTMENT OF ENERGY, LIVERMORE, CA; 
STEPHEN LEPPLA, SENIOR INVESTIGATOR FOR THE NATIONAL INSTITUTE 
 OF DENTAL AND CRANIAL FACIAL RESEARCH, NATIONAL INSTITUTE OF 
HEALTH, BETHESDA, MD; AND ARTHUR FRIEDLANDER, SENIOR SCIENTIST, 
 U.S. ARMY MEDICAL RESEARCH INSTITUTE OF INFECTIOUS DISEASES, 
                  FORT DETRICK, FREDERICK, MD

    Mr. Balhorn. Yes, I would. Thank you very much for the 
invitation, and for giving me a chance to speak.
    I think the panel that spoke before us, at least from my 
point of view, set the stage very well for what I would like to 
describe. They told you a lot about several different 
approaches that can be used to design new inhibitors to block 
anthrax toxin, and minimize its effectiveness.
    What we have been doing at Lawrence Livermore National Lab, 
in collaboration with other National Labs, as part of the 
Chemical and Biological National Security Program, is to design 
very specialized, small molecules that target and attach to 
specific sites on proteins, and this approach could be applied 
directly to inhibitor design. What we are currently doing is 
using the molecules for detection. So as part of this CBNSP 
program, we're designing new molecules that can detect anthrax, 
various other bacteria and viruses and toxins that don't have 
DNA. These same approaches are exactly applicable to what we're 
talking about today.
    So what I was going to do is briefly describe how we do 
this, so you have an understanding of how the process works, 
and then I'll give you two examples of how we can apply this to 
anthrax. The approach is one in which we use a combination of 
computers and experimental methods to identify these small 
molecules that attach to proteins. The key here is that we're 
mimicking what the body does naturally when it designs and 
produces antibodies to attack foreign molecules that come into 
the bloodstream.
    What makes an antibody unique is that it binds very 
specifically and very tightly to protein's and other molecules 
by making multiple contacts with them. If you can imagine 
trying to hold onto something, and if you hold onto something 
with one hand, you've got a certain amount of strength to hold 
the individual thing that you're attaching to, but if you have 
two hands or if you had multiple hands, you could hold even 
more tightly. That's how it works.
    We use a computer to display the structure of a protein 
molecule. What a protein is is just a long chain of amino acids 
that's folded up into a ball. Upon folding, it has a surface 
structure that has a lot of pockets or cavities distributed 
across the surface.
    Now the way that proteins function is by having some of 
these pockets interact with something else, bind to them, and 
then change it. What we do is we design molecules that bind 
into these pockets.
    So the way that you can actually go about designing a very 
specific molecule to bind to a certain site is to use a 
computer to screen the hundreds of thousands of compounds that 
might bind to certain sites and predict which ones might, sort 
of rank them. Then we can go through and, instead of spending 
our lifetime screening 300,000, we can screen maybe 50 or 100 
or 1,000 and speed up the process dramatically.
    In doing that for botulinum toxin and designing molecules 
that bind to it, we have been able to work out the methods, so 
that up to 50 to 60 percent of those predicted to bind actually 
do bind, and that speeds up the process dramatically.
    The next step, once you've identified a set of molecules 
that bind to one site, and then a set that bind to another 
site, is to link pairs of them together to give you sort of the 
effect of two hands, that when they attach to the protein, 
attach very tightly, so they don't come off, because that's 
what you want for an inhibitor, something that binds and 
doesn't leave, so it blocks the action of something else. It 
also gives you specificity, because it says, this one has to 
bind in this special site and this one has to bind in this 
special site, and they have to be a certain distance apart. 
Otherwise, they don't bind tightly.
    So if you have one molecule that binds to one site and you 
attach another one to it, now you have this bivalent inhibitor. 
The two will bind on the order of a thousand to a millionfold 
stronger than the individual one. So that gives you the added 
advantage of doing this.
    So the two previous examples, Dr. Smith described, and Dr. 
Thomas, described the production of inhibitors for furin. This 
is a protein where we don't know the structure of it yet, but 
Dr. Thomas has produced the protein and we've talked about 
crystallizing it, so that it's something that can be done in 
the near future.
    The approach there would be to take known inhibitors, small 
molecule inhibitors for that particular protease, look at the 
structure of the molecule, and define another site nearby that 
we can target a second molecule to, that we can identify by 
computer modeling, and then synthesize a series of compounds 
that link the two together.
    Now the reason we want something more specific than you 
currently have is that there are a lot of proteins like furins 
that need to function in the body. So you need to target that 
specific one as best you can to inhibit the activity, so that 
you have minimized side effects.
    Now the next two examples involve a protective antigen that 
we've talked a lot about. One of the steps that's essential for 
function of the toxin, as you have seen in the model you have, 
is for the individual protective antigen molecules to come 
together to form a heptamer. Now the structural work on this, 
the crystal structures of these proteins have already been 
done. So we know what it looks like. There's actually been a 
fair amount of work done by others showing that there are 
certain regions on the surface of the protein that function by 
attaching each other together, where they stick together.
    So one can design small molecules that target and bind 
around that site to block their coming together and forming 
protective antigen heptamers. That would be an effective set of 
drugs.
    The next slide is a second set where you have talked about 
this furin protease that clips the end off the toxin, the 
protective antigen, so it can come together and form a 
heptamer. That clippage is also required for edema factor and 
lethal factor to attach to the top. So by designing a set of 
small molecules that bind to a specific site on the top of the 
molecule, you can actually block the toxins from being loaded 
on and injected into the cell.
    Now these are methods that are currently being used. They 
have shown us that we can really speed up the process. I think 
that probably one really important thing to do would be, as you 
had asked questions before, bring together the right people, 
the right teams, to actually combine all of these techniques, 
to actually produce a series of different compounds that can be 
used as inhibitors. Because as, I think it was, Dr. Thomas 
said, what you really need is a cocktail. You don't want to 
rely on any one because in some cases the load is so great in 
these individuals by the time you've determined that they have 
the infection that any one probably won't work well enough.
    So I think that's pretty much it.
    [The prepared statement of Mr. Balhorn follows:]
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    Mr. Burton. We'll get back to you with questions.
    Dr. Leppla.
    Mr. Leppla. Mr. Chairman, members of the committee, I 
appreciate the opportunity to appear before you today to 
describe my research regarding anthrax toxin and the role of 
the protease furin in anthrax toxin action. Included in my 
remarks will be some discussion about the possible use of furin 
inhibitors to block anthrax toxin action and the potential this 
holds for treatment of anthrax infections.
    Also here today is Dr. Carole Heilman. Dr. Heilman is the 
Director of the Division of Microbiology and Infectious 
Diseases of the National Institute of Allergy and Infectious 
Diseases. As you know, the NIAID spearheads the bioterrorism 
research effort at the National Institutes of Health, and in 
fact the NIAID supported the recent studies by Drs. Collier and 
Young which we've heard described today, which has elucidated 
important aspects of the mechanism by which anthrax toxin 
destroys cells. As we've heard, the information gained from 
these NIH-supported studies is likely to hasten development of 
new drugs to treat anthrax. Dr. Heilman will be pleased to 
respond to questions you may have regarding NIAID efforts to 
counter bioterrorism.
    First, in regard to my own work, I have some comments in my 
written testimony regarding work that I have done in previous 
years on the anthrax toxin receptors. I think I'll just 
abbreviate that because you've heard the elegant work done by 
Dr. Young, which identified the anthrax toxin receptor, and 
that work was published in Nature several months ago. It showed 
that the anthrax toxin receptor is, indeed, probably this 
molecule called tumor endothelial marker 8. That protein was, 
in fact, described just 1 year ago by Dr. Ken Kinzler at Johns 
Hopkins University, and that's, of course, work supported by 
the National Cancer Institute.
    So as Drs. Young and Collier pointed out in their 
publication, as was mentioned earlier, their discovery opens 
several avenues toward development of new therapies. 
Specifically, they showed that a portion of the receptor, 
essentially a receptor decoy made in Escherichia coli, was able 
to block toxin action in cultured cells. There's good precedent 
for receptor decoys being effective therapeutic agents. There's 
a drug on the market called Enbrel, which is a tumor necrosis 
factor soluble receptor. It is a decoy, and it is quite 
effective in treating rheumatoid arthritis. So there's good 
precedent for the approach that they have described.
    Then I can also refer to some of my own work on furin. 
You've heard this protein described. Furin is a member of a 
family of similar enzymes that are required for generating the 
final active forms of hormones such as insulin. It's an 
essential enzyme, as was mentioned by Dr. Thomas. There's 
what's called the ``mouse knockout.'' That is, if you knock out 
the gene in mice, that causes the death of mice during 
embryonic development. So that does show that the enzyme furin 
is an essential enzyme.
    I began work on anthrax toxin a number of years ago. At 
that time it was clear that a number of bacterial toxins 
require proteolytic activation. That is, the toxins had to be 
cut at a specific site to be made fully active.
    During our first efforts to purify anthrax toxin protective 
antigen, we recognized that it was very easily cleaved at a 
single site by cellular proteases and by bacterial proteases. 
We identified the cleavage site to be a sequence of four amino 
acids: arginine-lysine-lysine-arginine. We then showed that 
removal of that cleavage site by changing the protein made 
anthrax toxin inactive. So this was proof that cleavage at that 
site was absolutely required for the toxin to be effective.
    We set out to identify the cellular protease that was 
required for anthrax toxin action. We did this by changing a 
small number of amino acids within the protein sequence of 
protective antigen by a mutagenesis procedure, and we replaced 
each of the amino acids in this sequence arg-lys-lys-arg, which 
we had defined as the point at which cleavage occurred.
    We found that any toxin that had arginine at both the first 
and the fourth positions was toxic to cells. It didn't matter 
what was in the second and third positions.
    At the time that we were doing this work, other 
researchers, as you have heard, had been looking for many years 
and finally had found this family of proteases, of which furin 
is a member, because these are essential enzymes required to 
process proteins like the insulin precursor. Persons working in 
that field had identified one member of that family, the 
protease we've heard a lot about, furin, and, in fact, 
suggested that the sequence that it recognized was exactly the 
same as what we had defined in the anthrax toxin protein. So we 
suggested that anthrax toxin was being cleaved by furin, and we 
began a collaboration with Gary Thomas, which you've heard 
about. He quickly proved that purified furin does, indeed, 
cleave protective antigen.
    Subsequently, we generated mutated cultured cells. This is 
a very convenient model system. We made these cells, which lack 
functional furin, and we showed that these cells were highly 
resistant to anthrax toxin and other toxins. In fact, similar 
mutant cells had been made earlier by Thomas Moehring at the 
University of Vermont, but the genetic defect in the cells 
wasn't known at that point.
    We showed that the furin-deficient cells were resistant to 
several toxins. Dr. Moehring had already shown that these cells 
are also resistant to a number of viruses. It's been mentioned 
that furin is required for viral envelope protein activation.
    My lab has actually not been working actively on furin in 
the last few years, although we're beginning again to do this, 
but, as you've heard, Dr. Thomas has continued to work actively 
and productively in that field. He's provided us a full account 
of the important role of furin.
    So now I want to offer some comments regarding possible 
therapeutic opportunities for anthrax infections. As was 
mentioned, we've identified at least eight stages which the 
toxin must pass through in order to achieve its ultimate 
killing action on cells. Studies in cell structure models have 
demonstrated the principle that each of these stages can be 
blocked, and Drs. Collier, Young and Friedlander from USAMRIID 
have provided much of the data showing that each of these 
separate stages represents a valid target to which we could 
point therapeutic interventions.
    In trying to find targets for intervening in infectious 
diseases, most researchers will focus on identifying target 
molecules that are unique to the pathogen. In the case of 
anthrax, a unique target is the anthrax toxin lethal factor. 
It's been shown that Bacillus anthracis bacteria lacking lethal 
factor are greatly weakened in their ability to cause disease. 
As we've heard, there's the precedent of treating HIV with 
protease inhibitors, so I think there are many researchers who 
believe that there's a great opportunity for the treatment of 
anthrax by using and developing inhibitors of lethal factor 
protease. Pharmaceutical companies and academic researchers 
have extensive experience in developing inhibitors of 
proteases, and already some of that expertise is being 
redirected toward developing lethal factor inhibitors.
    The NIAID has for several years been supporting at least 
two research groups studying lethal factor structure and 
inhibitor development. An important advance in this area 
occurred several months ago with the publication of the crystal 
structure of the lethal factor protease. This work was done in 
the laboratory of Robert Liddington at the Burnham Institute in 
La Jolla, CA. Dr. Collier and I were collaborators in that 
work.
    The availability of the complete crystal structure of 
lethal factor has encouraged many researchers to either begin 
or intensify existing efforts to develop lethal factor 
inhibitors. My lab is providing purified lethal factor protein 
to a number of these groups to facilitate their work. I 
personally have considerable hope that this developmental 
effort will lead to a specific lethal factor inhibitor that, in 
fact, will have efficacy in treatment of anthrax.
    The other protease, of course, involved in anthrax toxin 
action is furin, which we've heard about. I can abbreviate my 
comments here. In addition to the inhibitor that Dr. Thomas has 
developed, which is to my knowledge the most potent furin 
inhibitor available, which I know by the names of the 
``Portland'' inhibitor or the PDX inhibitor, potent furin 
inhibitors have also been developed by two other NIH-funded 
researchers, Drs. Iris Lindberg, of Louisiana State University, 
and Robert Fuller, of the University of Michigan. The 
inhibitors developed by these three NIH-funded researchers, now 
including Dr. Thomas, employ three different approaches to 
inhibitor design, and together identify a number of 
opportunities for development of even more potent furin 
inhibitors.
    It should be mentioned that intramural NIH researchers have 
also made important contributions in regard to furin research. 
Drs. David FitzGerald and Ira Pastan of the National Cancer 
Institute proved that furin has an essential role in the 
activation of Pseudomonas exotoxin. Dr. Juan Bonifacino of the 
National Institute of Child Health and Human Development has 
provided important knowledge about the movement of furin 
between various compartments within a cell. Several other NIH-
funded studies include analysis of the properties and functions 
of furin as a part of larger studies of various disease 
processes. This portfolio of investigator-initiated extramural 
and intramural research provides a strong knowledge base on 
which to base therapies for those diseases in which furin plays 
a role.
    I mentioned earlier that drug developers prefer to target 
molecules that are unique to a pathogen. For this reason, I 
think furin has received less attention as a target for drug 
development. 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. 
Consistent with that prediction is the fact I mentioned before, 
that genetic inactivation of furin causes death of mouse 
embryos. Nevertheless, I do believe that inhibition of furin 
should be examined as one possible avenue toward development of 
therapies for anthrax. I'm encouraged by Dr. Thomas' remarks 
regarding the preliminary toxicity studies of his inhibitor 
that perhaps current inhibitors may not be as toxic as one 
might predict.
    Given the renewed interest in anthrax, I anticipate that 
the furin inhibitors mentioned above, as well as others, will 
be evaluated for anthrax toxin inhibition in appropriate cell 
culture models in the near future, and if they're successful, 
we hope they will be carried forward to clinical use.
    That concludes my testimony.
    [The prepared statement of Mr. Leppla follows:]
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    Mr. Burton. Thank you very much, Doctor.
    We will now hear from Dr. Friedlander.
    Dr. Friedlander. Mr. Chairman, it's a privilege to appear 
before the committee today on my very last day of active duty 
in the U.S. Army.
    [Applause.]
    Mr. Burton. We hope you are going to stay on as a 
consultant.
    Dr. Friedlander. I'm planning to.
    I welcome the opportunity to explain my published remarks 
on the approaches to managing anthrax bioterrorist attacks. I 
am here to discuss the scientific issues. Other questions 
dealing with the DOD's research portfolio, the funding, and 
policy have been forwarded to OSD, and they are preparing a 
response for the committee.
    I am a physician trained in infectious diseases and a 
scientist who has worked in research in infectious diseases, 
including anthrax, for many years. The effective management of 
human cases of anthrax is dependent upon our knowledge both of 
the bacterium that causes this disease as well as the processes 
by which the bacterium counteracts the normal host defense 
mechanisms.
    Anthrax is due to the invasion and prolific growth of the 
bacterium in host organs and the production of toxins and other 
disease-enhancing factors. Thus, anthrax is, like other 
diseases, caused by invasive bacteria such as the pneumococcus, 
the streptococcus, and those causing serious hospital-acquired 
infections. It is distinctly unlike bacteria that cause disease 
solely by their production of toxins without invading the host, 
such as diphtheria, tetanus, and botulism.
    Inhalational anthrax begins and is concentrated in the 
central portion of the chest, where it destroys the tissue 
architecture. This leads to large accumulations of fluid, often 
with blood in it, in and around the lung, and this is an 
important contributor to the cause of death.
    The toxins are thought to be harmful to the body's 
phagocytic cells that are normally responsible for destroying 
the bacteria when it comes in. The toxins may also cause the 
release of chemical mediators from host cells that, in turn, 
when they are present in excess, can contribute directly to 
death of the host.
    Now there are three general ways that we deal with 
infectious diseases such as anthrax. The first is prevention of 
the disease by vaccination. The second is destruction of the 
bacterium by antibiotics, and the third is neutralization of 
the organism's toxins or the toxin-induced chemical mediators 
that contribute to disease.
    Now prevention of disease with vaccination is the ideal 
because any invasive bacterial disease, including anthrax, has 
a high mortality. The mainstay of treatment for this disease, 
anthrax, as for other invasive bacteria infections, is 
antibiotics. Antibiotic treatment, coupled with modern clinical 
management in the current outbreak, has established that 
although the disease is not invariably fatal, nonetheless, 
mortality remains high.
    Effective treatment of anthrax has been demonstrated, 
however, only with a very limited number of antibiotics, but in 
the test tube the organism is susceptible to many antibiotics 
that have not yet been tested for their efficacy.
    Now knowledge of the toxins has developed over the last 20 
years with very significant and important advances being made 
in the last few years. The committee has heard about these in-
depth from the previous presenters, and I won't repeat these 
statements, but my comments are present in my written 
testimony.
    In theory, as has been suggested, it should be possible to 
develop rational anti-toxin treatments that target each and 
every of the at least eight steps in the intoxication process, 
from the initial binding to the damage to the cell. We've heard 
about non-toxic mutant PA molecules and small molecule 
inhibitors and the soluble toxin receptor that had been shown 
to neutralize the toxin, and it's anticipated that others 
targeting various pathways will be found.
    Other approaches, however, to anti-toxin therapy might 
focus on developing treatments that neutralize those chemical 
mediators that are released from the cell when the toxin 
damages the cell. In fact, there have been decades of research 
that has only recently led to the licensure of such a drug that 
counteracts the effects of mediators produced during other 
invasive bacterial infections. This drug is now licensed, and 
similar approaches should be taken with anthrax. It's likely, 
however, that as with other invasive bacterial infections, 
these anti-toxin treatments will be used as adjunctive therapy 
to antibiotics.
    A final therapeutic approach is based upon the use of 
antibodies against the toxin and the bacterium. Antibodies were 
used in the pre-antibiotic era to treat human cases of anthrax, 
and animal experiments suggest they are of some value. In fact, 
attempts to develop human antibodies against the toxin are 
under development as adjunctive therapies.
    In summary, then, prevention of infection remains the 
ideal, and antibiotics constitute the mainstay of treatment. 
New antibiotics, as well as adjunctive therapies to include the 
wide possibilities with anti-toxins and antibodies, all need to 
be evaluated rapidly in carefully controlled studies.
    Now because of the difficulty of performing human trials, 
the testing of new antibiotics and adjunctive therapies will 
require the development of a large-scale capability for 
carrying out such studies in the appropriate animal models.
    That's the end of my testimony.
    [The prepared statement of Dr. Friedlander follows:]
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    Dr. Weldon [assuming Chair]. Thank you very much. I enjoyed 
all of your testimony.
    Dr. Friedlander, I understand the protective antigen was 
labeled as a protective antigen because it produces protective 
antibodies in the bloodstream.
    Dr. Friedlander. That's correct.
    Dr. Weldon. It can't be the only protective antibody in the 
bloodstream. The vaccine, I'm just kind of curious how that 
would prevent the proliferation of the bacterial infection 
antibodies against the protective antigen. Can you explain that 
to me?
    Dr. Friedlander. I'll try. As Dr. Young mentioned, there's 
a lot we don't know about this infection. There's a lot we 
don't know about how the vaccine protects.
    We do know that I think most people believe that the 
predominant component that is protected, and it's been 
demonstrated with highly purified protein, is protected 
antigen.
    Dr. Weldon. But protective antigen is sort of an endotoxin 
that's released----
    Dr. Friedlander. Correct, an exotoxin.
    Dr. Weldon. Exotoxin----
    Dr. Friedlander. Right.
    Dr. Weldon [continuing]. That is released by the bacteria. 
So if I have antibodies to protective antigen, how do they 
prevent the bacteria from proliferating in my lungs and in the 
lymph nodes in my pulmonary hylum?
    Dr. Friedlander. First of all----
    Dr. Weldon. You don't know, correct?
    Dr. Friedlander. We don't know for sure. We do know a few 
things, and I'll just briefly mention them.
    First of all, there is some proliferation that occurs, even 
in a protected animal, as is the case with other vaccines. It's 
not necessarily a sterile immunity.
    Second, the antibodies that are produced do neutralize the 
toxin, but, in addition, they appear to have some effect on the 
bacterium itself. This is an area that is being actively 
pursued.
    Dr. Weldon. The current vaccine that is available right 
now, what is in that vaccine?
    Dr. Friedlander. I know that there is protective antigen in 
there, and it's reported that there are small amounts of the 
lethal factor as well.
    Dr. Weldon. OK.
    Dr. Friedlander. I don't know the actual composition.
    Dr. Weldon. Very good.
    Both of you gentlemen encouraged the further research for 
the development of these drugs that can be used against the 
toxins. In the first panel, during the questioning, I mentioned 
that I saw this as being complementary, and I think you made 
this statement very eloquently, Dr. Friedlander, in managing 
these diseases. As I understand it, the current drug that's on 
the market for treating septic shock, the one that was just 
released----
    Dr. Friedlander. Yes.
    Dr. Weldon [continuing]. What is the name of that product?
    Dr. Friedlander. It's activated protein C.
    Dr. Weldon. Activated protein C. That's fairly expensive, 
correct?
    Dr. Friedlander. I'm not sure what the cost is.
    Dr. Weldon. You're not sure? One of the issues that will 
come into play in its clinical application is, does the patient 
really need it, because of the huge amount of cost associated 
with administering it. Do you see that as a hurdle for the 
application of some of the technologies you're developing right 
now for the development of these products?
    Dr. Friedlander. I think it is. As was alluded to before, I 
think in the first panel, one of the problems with developing 
very narrowly focused therapeutics is the marketplace, and 
that's difficult to support other than through the government, 
I think. The advantages of having a broad-based therapeutic 
that crosses several potential bioterrorist agents, as Dr. 
Thomas mentioned, for example, offers an advantage in that 
regard, in the sense that there's a larger market for it. If 
you had a very narrow-targeted therapeutic, the commercial 
market and big pharma would be less interested.
    Dr. Weldon. So if it's got a clinical application, and it's 
in the treatment of cancer, for example----
    Dr. Friedlander. Yes.
    Dr. Weldon [continuing]. It could make it very easy to 
bring something like this to market? Based on the testimony we 
heard in the first panel, I think there's some real potential 
clinical applications in treating other diseases with the use 
of these products.
    Would both of you say the level of funding, excusing you 
from this question, has been adequate so far for the type of 
research that needs to be done in this arena? I guess you don't 
really want to answer that either because you work for the 
Federal Government, right?
    Mr. Leppla. Yes.
    Mr. Balhorn. Well, I do, too.
    Dr. Weldon. Oh, you work for the Federal Government also? 
OK, well, forget about that question then.
    Well, I want to thank all of you. I will yield to the 
gentleman from Connecticut for questioning.
    Mr. Shays. Thank you. Mr. Chairman, I'm usually not 
speechless, but at this hearing I have been, and I'm not sure 
if it was I needed more sleep or just was not catching on 
quickly to the dialog or compelling myself to. Maybe it was 
some of my old classes that came back to haunt me here, the 
memory of them. I felt like I was back in school.
    I guess what I'm trying to think of is the bottom line for 
me is that we have the potential that anthrax could be used as 
a weapon against our military forces or our community at large, 
and that we need, in the case of not providing a prophylactic 
of vaccine, that we need to treat, and be able to effectively 
treat, those who have contracted anthrax.
    Now, Dr. Friedlander, I'm well aware of the government's 
program to basically vaccine, and I do have my differences with 
that program. But what I'm interested to know from the three of 
you, and I would have asked the earlier panel, if I had gotten 
back in time, I want to know your reaction when you started to 
see that we were under attack by anthrax--letters, shutting 
down, we shut down a government building. My building was shut 
down for 5 weeks. We shut down another government building for 
3 months. There was even talk at one point, and it was serious, 
that there was even question whether they would have to tear 
down the building. I mean, that's absurd, but it was real-live 
talk. Then we began to wonder the potential of what we were 
looking at.
    So I want to know how you reacted and what clicked in, and 
did you say, you know, we've got some answers here? Are we 
seeing the ingenuity of the American people at work in what 
we've seen in the previous panel and this panel? So walk me 
through some of the things that I can grasp a little better.
    Why don't we start with you, Mr. Balhorn? How did you react 
when you started to see this happen?
    Mr. Balhorn. Well, I think probably my first reaction, and 
probably the same reaction that many people have, was those of 
us that have sort of thought about this and worked in this area 
for a number of years were never totally convinced that 
biological weapons could actually, or would actually, be used. 
There was always some concern about it's a threat that we worry 
about, but there wasn't any certainty associated with it.
    I think a lot of us that understand the biochemistry, the 
biology of this, of these agents, also know how easy it is to 
do this. So the event itself showed that we really are in a new 
world, that biological weapons are a serious threat.
    Mr. Shays. Let me just say, easy for you, but, I mean, some 
of what we heard was that this was sophisticated, not easy to 
do, and therefore--so put it in what context. It is easy----
    Mr. Balhorn. Well, I guess easy in the context of 
designing--it's probably not a good example, but say if you 
wanted to develop a nuclear weapon, there are certain things 
you would have to have. Plutonium is one of them. It's 
difficult to get. It's something that's fairly limited and 
complicated and takes certain experts to deal with.
    In biology you have the same field of--you know, you have 
expertise. But we've progressed in teaching even our students 
certain aspects in biology that they can carry out as college 
students or even high school students in some special courses. 
A lot of these things are what can be, what are used to produce 
some of these compounds, just growing bacteria in culture and 
isolating spores, things like that.
    So in that concept----
    Mr. Shays. Easy, OK.
    Mr. Balhorn. In that respect.
    So I think the main thing was that it convinced me and 
others that it is a real threat and there needs to be a 
concerted effort to minimize those specific types of threat 
agents that might be used.
    Mr. Shays. But, I mean, when the Twin Towers were hit after 
having 19 hearings on terrorism, I found myself, as the 
buildings were going down or shortly afterwards, saying to 
myself out loud, my gosh, there's no red line; there's no line 
that terrorists won't cross.
    Mr. Balhorn. That's right.
    Mr. Shays. So they answered the one question that I had 
wondered: Would they use biological chemicals, potentially 
nuclear weapons? And the answer was a hearty yes; a very 
frightened yes is the way I should say it.
    But now you're an expert in this field, and things didn't 
actually unfold the way we anticipated. For instance, under the 
program the military had, we were going to vaccinate everyone 
because my committee had been told continually that inhaled 
anthrax was death; there was no cure; there was no way to deal 
with it.
    So what was happening here? I mean, we did cure people who 
had inhaled it. So what happened?
    Mr. Balhorn. Well, I think Dr. Friedlander could probably 
answer that better than I could.
    Mr. Shays. But what happened in your own mind? Were you 
surprised that all of a sudden we were able to deal with 
inhaled anthrax?
    Mr. Balhorn. No, I wasn't. I mean, I'm aware that you can 
be infected by a variety of pathogens and there are treatments 
for them. It often depends on how you contract it, the level 
that the organism is reproduced to before you actually get 
treated, and the susceptibility of the individual. Every 
individual is slightly more susceptible.
    Mr. Shays. I don't know where you were in our hearings, but 
one of the whole justifications for the military's program of 
vaccination was that we on this side of the table were being 
irresponsible to suggest that there not be a vaccination 
program, because if you contracted anthrax through a weaponized 
program of inhaling it, that you were dead. So you're telling 
me you're not surprised. I was surprised, but I'm not an 
expert, only because I listened to the experts who told me I 
should be surprised.
    Mr. Balhorn. I guess probably there are very few things 
where you with certainty can say that, if you are exposed to it 
in terms of biological, that it will kill you for certain, 
because of the way individuals respond and the conditions under 
which they contract it.
    Mr. Shays. Well, we lost five people. So five people did 
die from it.
    Mr. Balhorn. Yes, right. So, yes, I was surprised at such a 
small number.
    Mr. Shays. Yes.
    Mr. Balhorn. But what went through my mind was that we can 
accelerate the pace; we need to, and that although there were 
fewer people--you know, more people survived than we thought. I 
think we were very lucky.
    Mr. Shays. Yes, I kind of tuned out when you were taking 
the diagrams and when the first panel was here. I apologize, 
but I kind of did. But I was trying to think of the bottom 
line. The bottom line is, though, that both panels--and I would 
like to come to the next two panelists--the bottom line was 
that we were talking more of a cure rather than a prophylactic, 
is that correct?
    Mr. Balhorn. Not necessarily, because many of these 
compounds can be used as a prophylactic, where you could, if 
you expect someone might have been exposed recently, they could 
be treated in advance.
    Mr. Shays. OK, well, but they were exposed. In other words, 
so there's an interim. In other words, there's a prophylactic 
before it catches on?
    Mr. Balhorn. Right.
    Mr. Shays. OK. But, in other words, we're not going to 
vaccinate all the American people.
    Mr. Balhorn. Right.
    Mr. Shays. We're not even going to vaccinate all the 
military forces, I don't believe.
    Mr. Balhorn. Right.
    Mr. Shays. Unless we develop a new vaccine. But if we 
suspect--and the bottom line is we can pretty much determine if 
someone's been exposed? It was kind of curious, I'd just say 
this to you: You know, we were asking people to come and be 
tested on whether they had contracted anthrax, and the place we 
invited them to go was the Hart Building. I told my staff, I 
said, you know, be tested; don't go there; that's crazy.
    Mr. Balhorn. Well, one of the difficulties is being able to 
detect with certainty that they've been exposed, because the 
symptoms, the very early symptoms, are a lot like flu. So I 
think one of the things that is difficult in this case is they 
can progress to a certain stage before the individual is aware.
    But there are a variety of new technologies that are being 
developed where you can detect infections. The DNA-based 
technologies have been around for quite some time, allowing us 
to detect the organism. In some cases, or in many cases 
actually, when an individual takes a chemical into their body 
or they are infected by an organism, their body produces 
antibodies; they start producing them fairly quickly. Once 
people are starting to use those technologies of looking for 
the antibodies that are present, or the products that the cell 
produces in response to the presence of the organism--so, 
currently, I don't know of any method where we can detect 
shortly after someone's been exposed.
    Mr. Shays. I want to go on to the next panelist, but 
there's so many hearings that we've had on this, and you just 
trigger one thing after another. I mean, for us and our panel, 
when we were looking at anthrax as a prophylactic to our 
military, we were basically told, this is the story; this is 
the way it is, and this is what we've got to do. Iraq has 
weaponized anthrax. Our troops are going to be in that theater. 
We have to protect them.
    Yet, you were working before, and working after, September 
11th dealing with anthrax, experimenting with it, correct? Or 
aren't I correct?
    Mr. Balhorn. Me personally?
    Mr. Shays. Yes.
    Mr. Balhorn. No, we have not. So what we're doing is we're 
designing reagents for detecting botulinum toxin, but we've 
moving on to anthrax, yes.
    Mr. Shays. OK. Mr. Leppla, or Doctor, I want to know how 
you responded to September 11th. I want to know if you were 
involved in the anthrax program before September 11th at all. I 
want to know what your reaction was when you saw these letters 
going out. I want to know what you suspected. I just want to 
know your reaction.
    Mr. Leppla. Well, as an intramural researcher at NIH, I 
have been working on very basic aspects of anthrax toxin for 20 
years, initially at USAMRIID and then at NIH. But NIH, of 
course, is not a front-line responder to public health 
emergencies.
    Mr. Shays. Right.
    Mr. Leppla. So there were no immediate changes in our 
activities. I was called occasionally for advice on reagent 
availability and things like this, but I haven't had a role in 
responding to the emergency aspects of this. NIH traditionally 
has looked for medical therapies, and in this case I think has 
not traditionally had a role in vaccine development for 
anthrax, but has now, of course, mounted that.
    Mr. Shays. 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?
    Mr. Leppla. That's a policy issue that's well beyond my 
area of expertise. I mean, I have worked with the protective 
antigens for many years. So it's my understanding, and view 
from reading the publicly available literature, that the 
vaccine has been carefully evaluated by the FDA. So I thought 
the DOD was certainly on reasonable grounds in deciding to 
administer this licensed vaccine to the military.
    Mr. Shays. No troubles on the fact that military personnel 
were required to do it, even under threat of being dishonorably 
discharged?
    Mr. Leppla. Well, again, that's an area beyond my----
    Mr. Shays. Do you work for, are you working for the 
government now?
    Mr. Leppla. I work for the NIH.
    Mr. Shays. Is that why you're reluctant to answer the 
question?
    Mr. Leppla. It's----
    Mr. Shays. I'm going to respect your reason, but I'm 
dumbfounded by it, why someone who obviously has expertise 
would not have an opinion.
    Mr. Leppla. Well, my expertise is in basic research. I 
mean, I do have a--and I'm not involved in any way in 
evaluating the vaccine or I don't have access to the data that 
the DOD has collected on----
    Mr. Shays. Well, we had people who were much more 
inquisitive than you sitting before us in previous hearings. 
We've had some people who have suggested that their biggest 
concern--we asked one individual who is an editor of a major 
medical magazine, a doctor, we asked him what was the question 
we should have asked him, and he said, well, my biggest concern 
is that a cottage industry operation of a few scientists could 
develop a biological agent that had been altered to the point 
that there would be no antidote and that we could wipe out 
mankind as we know it. That was a pretty strong statement for 
someone. He didn't need to say that, but he said it because he 
felt that we should know that's a real concern.
    When you know that, you then say, well, I understand maybe 
why we make arrests, why we might have tribunals, why we're 
calling this a war, and why we're working as hard as we can to 
shut down the terrorists before they annihilate the human race. 
I'm just curious as to what your--I'm not a scientist; you 
are--whether you had similar emotions or whether you kind of 
yawned and said, well, you know, this doesn't seem to be all 
that big a deal. What was your reaction? When you saw letters 
that saw 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?
    Mr. Leppla. Well, of course, I had all the same concerns of 
any other citizen, but in terms of my job responsibilities, it 
was not something that was part of my job function. So as a 
witness here representing in some way NIH, I'm not sure that my 
personal views are----
    Mr. Shays. OK, I'm going to respect that.
    Dr. Friedlander----
    Dr. Friedlander. Yes?
    Mr. Shays [continuing]. Thank you for your service to your 
country. Our spontaneous applause is heartfelt, and that you 
would spend your last day with this committee is probably one 
of the highest compliments you could pay us. [Laughter.]
    I would like to just ask you a few questions. I would like 
to ask you how confident you are about data from animal studies 
about the safety and efficacy of vaccines and anti-toxins in 
humans.
    Dr. Friedlander. I think it's prudent to look at all the 
data that one has in trying to make an assessment. As someone 
alluded to earlier, for some diseases it's very difficult to 
test in the human population. So you have to take a look at all 
the best data that you have and come up with the best medical 
assessment as to the risk and the benefit.
    Mr. Shays. When I was growing up and they were developing a 
small pox vaccine, polio, and so on, we would basically test it 
on animals and then humans, animals first to determine safety, 
and then humans to determine efficacy, and we could determine 
that there would be some population that a certain percentage 
would contract the disease. Therefore, we could then begin to 
know the efficacy of particular vaccines. But we don't have 
that, the ability to do this in this kind of instance, do we?
    Dr. Friedlander. That's correct, and I think the FDA is 
trying to deal with that in the best way that they can. I don't 
know the current status of that, but----
    Mr. Shays. But it does suggest to me, not being a 
scientist, obviously, but that any universal requirement to 
take a vaccine that hasn't been tested in terms of efficacy 
with humans, you really have to be very cautious, correct?
    Dr. Friedlander. Well, I think that's correct, and I think 
the same argument holds with any therapeutic drug that's being 
considered for the same diseases.
    Mr. Shays. What was your reaction when you saw what was 
happening with anthrax? You've heard the question I've asked. 
Walk me through September, after September 11th, and how you 
reacted.
    Dr. Friedlander. Well, I think the world changed, and I 
think there was a sense of urgency, a sense of concern that was 
unprecedented, and involving the CDC and I think NIH, as well 
as DOD.
    Mr. Shays. When we talk about the five people who have been 
literally murdered from anthrax being sent in the mail, this 
weaponized anthrax, tell me how we and how you work through the 
fact that we are part of the Biological Weapons Convention of 
1972, and in there the protocol is very clear: Offensive use of 
biological agents is prohibited; any research for offensive use 
is prohibited, but defensive is not.
    So you have been involved in, obviously, on the defensive 
side of biological agents. You do have to create the weapon, 
though, to know how to defend against it. Just walk me through 
the challenge that exists.
    Dr. Friedlander. I'm not sure I can do that. I've not been 
involved in any research along those lines. It's been geared 
over the years----
    Mr. Shays. Are you indirectly involved?
    Dr. Friedlander. No.
    Mr. Shays. So Fort Detrick does not get involved in 
anything of that----
    Dr. Friedlander. I can't speak for Fort Detrick.
    Mr. Shays. Are we walking on sensitive ground in terms of 
classified versus non-classified?
    Dr. Friedlander. No, I think you have to address that with 
the Medical Research and Materiel Command.
    Mr. Shays. So you haven't been involved in any way with the 
anthrax program?
    Dr. Friedlander. No, that's not what I said, no. I have 
been, but only from the perspective of developing 
countermeasures.
    Mr. Shays. Well, then, walk me through that. Walk me 
through that.
    Dr. Friedlander. Specifically----
    Mr. Shays. Yes. Tell me what kinds of things you've been 
required to do.
    Dr. Friedlander. Well, I started working on anthrax a long 
time ago, when we were----
    Mr. Shays. One of the reasons why I'm asking the question, 
obviously, is that there's concern that the anthrax that we've 
had to deal with has been anthrax that may have been developed 
by our own personnel, be they military or not, and obviously an 
aberration, someone who's simply taken their solemn 
responsibilities and flipped it on end and turned against our 
own country. But walk me through it.
    Mr. Chairman, do I have 5 more minutes?
    Mr. Burton [resuming Chair]. I beg your pardon?
    Mr. Shays. Do I have 5 more minutes?
    Mr. Burton. Sure, we'll give you 5 more minutes. I have 
another meeting I want to go to, and I'm going to ask one 
question.
    Mr. Shays. Well, I'm going to just then yield to you.
    Mr. Burton. OK, and then what I'll do is I'll let you have 
the Chair and then you can finish in 5 minutes.
    Mr. Shays. Yes, and I'll be finished, so I won't keep them 
much longer.
    Mr. Burton. I just have one question, and that is for you, 
Dr. Friedlander. I'm sorry to lose you. I hear you're retiring, 
and I hear you have done very fine things for this country. So 
I wish you the best for the future.
    Dr. Friedlander. Thank you.
    Mr. Burton. 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 whatsoever about 
that?
    Dr. Friedlander. No. I think that's an issue for the FBI so 
far as I know.
    Mr. Burton. For the FBI?
    Dr. Friedlander. It's my understanding that they're 
investigating, they're in charge of the investigation----
    Mr. Burton. Is the military doing anything like 
investigating whether or not there were any leaks or anybody 
down there that was previous personnel that might have been 
involved in that?
    Dr. Friedlander. I'm not involved in that at all. So far as 
I know, the FBI is in charge of the investigation.
    Mr. Burton. OK, very good.
    Mr. Shays, can you take the chair then?
    Oh, let me just, before I leave, because I'm going to turn 
the Chair over to Mr. Shays and he can conclude the meeting, I 
hope that you will remember what I suggested to the first 
panel. That is, any ideas that you have on what should be done 
in the area of funding, research, creating research teams, or 
anything that needs to be done to speed up the process of 
coming up with countermeasures or vaccines or other substances 
to ward off chemical or biological attacks, we'd like to have 
that submitted to our committee, in addition to NIH.
    I know NIH is looking at this, and I know they're working 
very diligently to come up with these vaccines and 
countermeasures, but one of the reasons I'm asking for that, 
and I think Mr. Shays would like to have it, as well as the 
rest of the committee, is we're the ones that help get the 
funding for these various research projects. Because time is of 
the essence, we need to have that information, so that we can 
make a determination on how much money is necessary, and if we 
have to go to the President and ask him to go along with 
additional appropriations for this research, we want to do 
that, because we don't want to be caught flat-footed if there's 
an attack. OK? So if you could get that for us, we would really 
appreciate it.
    Mr. Shays.
    Mr. Shays [assuming Chair]. Can I just sit here with the 
gavel?
    Mr. Burton. If you'd like, I'll throw it to you.
    Mr. Shays. No, don't throw it. [Laughter.]
    Because I'm not going to be that long. Thank you, Mr. 
Chairman. Thank you, sir.
    Dr. Friedlander, this is a serious question. It is trying 
to understand how one divides, knows when they are doing 
defensive versus offensive. In order to do defensive--and let 
me just preface something, so you don't try to anticipate 
something you don't need to anticipate.
    I happen to believe in the protocol of 1972. I also happen 
to believe in the administration's rejection of the Convention 
that somehow attempted to allow for surveillance in a way that 
I thought was ineffective that was rejected this last fall with 
a variety of nations. It was too ironic for me that Iran and 
Iraq were part of the Convention that was trying to determine 
how we were going to oversee the potential of offensive use of 
chemical weapons, and the hypocrisy of that was more than I 
could stand.
    But tell me what you do. You take anthrax that is produced 
by our country. It has to be weaponized and then you try to 
determine how you deal with this weaponized anthrax? All I'm 
trying to understand is, you have to make the weapon in order 
to know how to defend against it, isn't that true?
    Dr. Friedlander. I think that's true.
    Mr. Shays. Yes.
    Dr. Friedlander. I mean, I'm not sure, I think the research 
that's been ongoing has--there has not been--I'm not sure that 
work, in terms of the evaluation of vaccines, for example, that 
we've done over the years at USAMRIID has used anthrax spores 
to test essentially.
    Mr. Shays. But has some of what has been discussed today 
been actively pursued in your facilities?
    Dr. Friedlander. Some of the approaches to treatment you 
mean?
    Mr. Shays. Yes, yes.
    Dr. Friedlander. Some of them have, yes.
    Mr. Shays. But, in order to do that, you have to deal with 
an aerosoled anthrax, correct?
    Dr. Friedlander. Yes.
    Mr. Shays. Yes. So can I make an assumption that, if we 
think a particular country is developing a particular type of 
weaponized biological agent, that we have to take that 
weaponized biological agent in order to know how to respond 
defensively to it?
    Dr. Friedlander. Well, I can't quite answer that. I mean, 
there may be some differences. The ways in which we test it are 
by aerosolizing liquid spores, and that's different than what 
was in the envelopes.
    Mr. Shays. You mean that particular----
    Dr. Friedlander. The method of producing spores.
    Mr. Shays. OK, refresh me. How was the method----
    Dr. Friedlander. Well, we use the liquid formulation in the 
testing of vaccines and antibiotics, for example.
    Mr. Shays. Let me just ask each of the panelists--first, 
preface it by saying, I have a basic theory that if you unleash 
American or just human ingenuity, but it seems best in the 
United States because we seem to unleash it better, that when 
we're confronted with challenges, that we, through the private, 
public, government sectors, can sometimes find very clever, 
very simple responses to what we thought were impossible tasks 
before people began to think it through.
    The reason, my motivation in asking you what you were 
thinking was, did you all come and say, after September 11th, 
and after you started seeing what we were faced with as a 
country, did you start to redesign your activities and your 
research and your thought process to say, you know, we can make 
a contribution here? That's the assumption I have made. Is that 
an incorrect assumption?
    Mr. Balhorn. My answer is yes, because I'll give you one 
example. The technologies that we were developing, are 
developing, or are using, they haven't changed as a result of 
that event, but what has changed is the fact that what we were 
developing and are currently funded for are detection reagents, 
the first line of defense, trying to find out where it is, 
who's been exposed to it, and so forth.
    But what convinced me, what I was convinced of after that 
was that we really could apply the same methods to development 
of therapeutics to save those people that were exposed. So it 
did have an impact, and I think it's something that--well, 
basically, that's it.
    Mr. Shays. So then one of the reasons why we are having 
this hearing was to put on the record a response and give it 
some attention. That's been part of the motivation of this 
hearing. One of the things that is troubling to me as a Member 
of Congress is that there's probably two or three people a 
week, sometimes one, sometimes more than three--and when I say 
``people,'' organizations, groups of people--who come to me and 
say they have an answer for this particular problem, whether 
it's detecting explosives on planes. We are becoming a little 
frustrated--I don't like to use that word often--because we 
refer them to whom? We refer them to the Office on Homeland 
Security, and we know that's becoming a bottomless pit, of 
which there's no capacity yet to know and evaluate good ideas 
and bad ideas, to know what are bad and reject and what are 
good and accept.
    One of the things that concerns me is, and one of the 
reasons we're having this hearing, I think, is to make sure 
that we are a force that is contributing to catching these good 
ideas and seeing how they can be implemented.
    Dr. Leppla, are you being asked to evaluate a lot of 
different private sector ideas? Are you having more people 
contact you? What's happened that's different in your life 
since September 11th?
    Mr. Leppla. Certainly a great deal is different, yes. I 
mean, I often say anthrax was an orphan disease in the middle 
eighties when a few of us were working on it, not very many 
people were aware of it, or considered it a significant 
problem. Clearly, the situation is very different now.
    I'm one person in the field, but I'm still getting many 
calls from academics or small companies or large companies who 
wish to contribute in some way to research on anthrax 
therapies. Many of these have very impressive technologies. The 
NIAID hasn't, although I'm not a member of the NIAID, they 
clearly have been very responsive in putting out a number of 
new funding opportunities. I know just in the last month two 
deadlines have passed for submission of both SBIR and RO-1 
grants from universities. My impression is they've had 
tremendous response to those requests for proposals.
    So a great many people out there are wanting to contribute, 
and I'm glad in a little way to be able to advise them or 
provide them with reagents. So things are very different.
    Mr. Shays. Thank you.
    With the power invested in me here, I'm going to invite 
anyone who was in the previous panel, if they have a closing 
comment that they want to make, any last thought that they 
would like to make, and I would also invite--is there anyone 
from the previous panel that wishes we had asked a question 
that they had prepared to answer and not been able to answer it 
because they weren't asked? And anyone on this panel that would 
like to ask a question that we didn't ask that they would like 
to answer?
    First, let me start with that: Is there anyone on this 
panel that has a question that they would like to ask 
themselves and then answer, that you'd like to put on the 
record? I'm not trying to be cute, but that you'd like to put 
on the record. Is there anything else?
    Mr. Balhorn. Well, I'd like to make a comment and sort of 
echo--a couple of comments of what Dr. Friedlander said. You've 
asked a number of questions about the vaccine and the 
difficulties associated with that. I think it's important to 
point out and reiterate that any drug or treatment that we 
develop has to go through the same kind of testing, and can 
have potential problems. So by talking about designing, even 
using computers, molecules that bind the special sites, and 
they only bind to one protein, in practice that turns out not 
to be the case and they have to be tested.
    So these things also, I think it's important to say, take 
time, not that it has to take 10 to 12 years to accomplish what 
you want. It can take a few years, but it's not something that 
can be done in 6 months or 8 months. So I think it's really 
important that you and your committee have an impact on 
basically the basic science and funding for the basic science 
that needs to go into this.
    Anthrax is the first one that you're considering, but there 
are a number of potential targets or agents that can be used as 
bioweapons. A lot of the methods we've talked about translate 
directly into producing, you know, inhibitors for those as 
well.
    So I think it's really important to think ahead. We've seen 
that bioweapons will be used. They may not come back and use 
the same one next time. So we need to think a little bit about 
what are the next potential ones and put an effort toward 
solving those.
    What you worry about is that there are a lot of different 
agents. You can also keep in mind, help yourself in terms of 
working toward that is that all of these agents are actually 
threats to the community outside bioterrorism. In some cases 
like anthrax it's a very small threat, but you've talked about 
Ebola. That's a threat that shows up repeatedly as well. So I 
think there's a benefit of that, besides the applications to 
things like cancer research.
    Mr. Shays. Some of the most impressive meetings that I've 
had overseas have been with the World Health Organization and 
people who literally go to very dangerous spots in the world, 
not knowing what kind of pathogen they're dealing with, but 
they go there, in some cases I feel unarmed and unprotected, to 
try to understand what's happening.
    One of the things in my previous work as chairman of the 
Human Resources Committee overseeing HHS and CDC, and so on, is 
the incredible new threats that may develop that aren't man-
made but just a result of human contact and interaction, and so 
on. What I wrestle with, as a public official, is the ethics of 
the government mandating vaccines where we know that there will 
always be some that will respond in a negative way, and then 
what obligation do we have to those who respond negatively? In 
other words, there's always going to be a certain percentage, 
and the fact that they are under command and under threat of 
court marshall, and the concept that seems to be evolving in 
some of the military, that we are going to protect our military 
by just injecting them with more vaccines. So we all are 
wrestling with a lot of things.
    But the one thing I am pretty certain of is there's a lot 
of ingenuity out in our country, and there's a lot we can 
learn. I'm just hoping that the government has the ability to 
accept good ideas and reject bad ones. It used to be the large 
ate the small; now it's the fast eat the slow. I don't think 
our government can move quickly sometimes.
    So, Dr. Friedlander, do you have any other comment that you 
would like to make?
    Dr. Friedlander. No, thank you.
    Mr. Shays. I do appreciate your being here very much.
    Dr. Friedlander. Thank you.
    Mr. Shays. Is there anyone from the other panel that would 
like to make a closing comment?
    [No response.]
    If not, we'll call this hearing adjourned. Thank you very 
much.
    [Whereupon, at 1:35 p.m., the committee was adjourned, to 
reconvene at the call of the Chair.]
    [The prepared statement of Hon. Wm. Lacy Clay follows:]
    [GRAPHIC] [TIFF OMITTED] T9590.085
    
    [GRAPHIC] [TIFF OMITTED] T9590.086
    
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