[House Hearing, 107 Congress]
[From the U.S. Government Publishing 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
79-590 WASHINGTON : 2002
____________________________________________________________________________
For Sale by the Superintendent of Documents, U.S. Government Printing Office
Internet: bookstore.gpo.gov Phone: toll free (866) 512-1800; (202) 512-1800
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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
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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:]
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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:]
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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:]
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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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