ANTHROPOLOGY PROGRAM
ROOM 20B-131
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
77 MASSACHUSETTS AVENUE
CAMBRIDGE, MASSACHUSETTS 02139-4307

June 24, 1999

Dr Joshua Lederberg
Sackler Foundation Scholar
The Rockefeller University
1230 York Avenue

New York, NY 10021-6399

Dear Dr Lederberg,

I would like to tell you about a new research project and conference that is hoped will
assist in developing a solution to the problem of infectious disease treatment in an age of
antibiotic and multiple drug resistance (and please excuse the length of this unsolicited
letter, but I hope you will find it of value). The project and upcoming conference are
based on preliminary research which indicates that a particular form of hyperthermia
appears to be as or more effective than antibiotics in treating a number of infectious
organisms, including, according to preliminary indications, Staphylococcus aureus. A
second line of research, carried out by scientists from Rockefeller, Yale, and several other
universities and institutions, including the Max Planck Institute, has demonstrated that a
form of hyperthermia which possesses the same properties as that used effectively against
a number of micro-organisms in the laboratory can be produced, perhaps surprisingly,
through a set of behavioral medicine techniques. According to our initial data and
analysis, induction and maintenance of a “mild” or fever-like hyperthermia effect for a
specific duration (roughly from one to several hours) at the site of an infectious
challenge, can lead to the enhancement of the oxygen-dependent antimicrobial capacity
of phagocytic cells (Knighton et al 1986; Kurz et al 1996; Von Furth and Van den Berg
1996; Allen et al 1997), the production of immune-augmenting cytokines (Downing et al
1988; Hasday 1997), and enhancement of the performance of the natural killer (NK) cell
system (Downing et al 1988; Burd et al 1998), with potentially substantial and medically
important microbicidal effects, unanticipated by previous researchers.

The behavioral medicine research of the Rockefeller University and other scientists
follows in a distinguished historical lineage that derives from Pavlov and from the North
American behaviorist tradition developed by Skinner and others, and demonstrates that
individuals may learn to achieve “acquired (voluntary) control of peripheral vascular
responses” (Lynch and Schuri 1977; Miller 1989) through the development of an
integrated set of self-conditioning, somatosensory discrimination, and other behavioral
techniques. These researchers found that techniques consisting of focused attention to
heat-related cognitions (efferent function) could, with practice, lead further to an actual
‘tise in temperature, through activation of the corticofugal-peripheral nervous system
pathways controlling vasomotor tone (Kunzendorf 1990; Kojo 1985, 1990; Lynch and
Schuri 1977). The initial modest changes could be perceived (afferent function) and
amplified, with or without the aid of technical feedback devices (ie, “biofeedback”;
Miller 1989; Kojo 1985, 1990; Piedmont 1981), to a level within the upper physiologic or
febrile range (approximately 37 to 40 degrees C). Although this latter line of research

was not specifically designed to investigate the use of behavioral hyperthermia-inducing
techniques for prevention or treatment of infection, my colleagues and I have begun to
synthesize the results of this research with other very recent clinical and microbiological
studies on the potentially powerful microbicidal effects of hyperthermia.

How exactly would these vasomotor and consequent temperature changes mediate
microbicidal effects? Briefly, our analysis, based on direct and indirect evidence, from in
vitro and in vivo studies on animals and humans, indicates the following. Moderate,
febrile hyperthermia significantly increases the oxygen available for phagocytic cells,
which often falls below critical levels (ie, below approximately 40 mm Hg) in the
hypoxic microenvironments of wounds and sites of infections (Knighton et al 1984, 1986,
anid references therein). Increases in tissue oxygen tension which can be induced through
hyperthermia have been found to enhance microbicidal performance to the extent of
producing an antibiotic effect equivalent to or greater than that provided by standard
antibiotic medication (eg, ampicillin), in studies directly comparing the two treatment
conditions (Knighton et al, “Oxygen as an Antibiotic: A Comparison of the Effects of
Inspired Oxygen Concentration and Antibiotic Administration on In Vivo Bacterial
Clearance,” Archives of Surgery, 1986; also Knighton et al 1984; Rabkin & Hunt 1987;
in these studies it was found that by increasing local temperature to an average 38.0
degrees C for an average of 42 minutes it was possible to achieve the same increase in
oxygen tension, of between 20 and 40 mm Hg, produced by the increased oxygenation
responsible for the antibiotic effect).

Furthermore, the same magnitude and duration of temperature increase has been found to
enhance the recruitment, migration, and cytokine expression of NK cells substantially
(for example, in one study such a temperature increase raised the level of interferon
synthesis 10-fold (Downing et al 1988; Hasday 1997). Recent research has shown that a
variety of “activating factors” — including inflammatory substances released at the site of
an infectious challenge (such as the superantigen staphylococcus enterotoxins),
cytokines, and heat — may not only significantly up-regulate NK cytolytic function, but
substantially “expand [its] target cell repertoire” as well (D’Orazio & Stein-Streilein
1989; Salazar-Mather et al 1996; Robertson & Ritz 1990), Moreover, NK cells also
secrete cytokines that may in turn significantly up-regulate other immune cells, including
macrophages (Herberman 1985; Gomez et al 1985) and neutrophils (Klempner et al
1979). Such experiments involving activating factors have led to fundamental revisions in
the understanding of the role of the NK cell in the immune system (Whiteside &
Herberman 1990), and research in progress right now is identifying the potentially
extremely important role that hyperthermia can play as an NK-activating factor, with
respect to a previously unsuspected wide range of diseases and pathogenic conditions (eg,
Burd et al 1998; Bushell et al, in preparation).
Indeed, the new emerging understanding of the significance and mechanisins of “the NK
system” (Whiteside & Herberman 1990) are reflected in the recent spate of studies
showing the potentially important and even critical role of the system in host defense
against a previously unsuspected wide range of diseases. These include a variety of
diseases produced by bacterial pathogens (Garcia-Penarrubia 1991; Greenberg 1989),
possibly including S aureus (D’Orazio & Stein-Streilein 1996), and mycobacteria,
including mycobacterium avium (Bermudez & Young 1991), and even tuberculosis
(Ratcliffe et al 1994; Bushell et al, in preparation; and see below); parasitic disease,
including leishmaniasis (Maasho et al 1998) and schistosomiasis (Wynn et al 1994); and
fungal infection (Murphy 1989) as well as viral diseases such as HIV/AIDS (Chehimi et
al 1992). And, since the behavioral techniques for inducing “moderate” hyperthermia,
presently to be described, appear to provide a superior form of “heat delivery system,” it
is reasonable to hypothesize that such techniques may stimulate and augment NK system
function with potentially clinically significant effects. In fact, preliminary research on the
use of such techniques in the treatment of pulmonary tuberculosis — one of the few
instances in which such techniques have been formally utilized in the treatment of
infectious disease — found, in several detailed case studies, the resolution of symptoms,
including cavitation, associated with behaviorally-induced “hyperemia” of the lungs,
Which were confirmed radiologically (Luthe 1963; see also Linden 1990). In light of the
fact that NK cells produce a powerful and rapidly-acting macrophage activating factor
(which was tested on alveolar macrophages; Gomez et al 1985; Greenberg 1989;
Robertson & Ritz 1990; Bermudez & Young 1991), as well as other relevant cytokines,
We are considering the possibility of further research into this enticing subject (see
below).

Other significant antimicrobial effects of moderate hyperthermia also include, of course,
its limiting effects on the replication of a number of organisms, including certain gram-
negative bacteria, parasites such as leishmania, and many viruses (Cunha 1998; Davis &
Phair 1997; Navin et al 1990).

Several different behavioral techniques have been found that generate the temperature
changes necessary to produce a hyperthermia effect of the same magnitude used
effectively for microbicidal purposes, including biofeedback (French et al 1973) and the
use of focused states of absorption (Benson et al 1982), but there is a common
denominator to the techniques, one that involves the use of heat cognitions, particularly
the multisensory imagery of warmth (Bushell et al, in preparation). The heat cognitions
apparently trigger a centrifugal cortical-subcortical pathway linked to peripheral
sympathetic and parasympathetic fibers which control vasomotor tone (Kunzendorf 1990;
Kojo 1985, 1990; Lynch and Schuri 1977). Experimental research into the psychophysics
of thermal sensation have shown that changes in local temperature as miniscule as 0.0017
degrees C/sec can be sensed by subjects in experimental research (Hensel 1973, 1981;
Kojo 1990), and both the magnitude and locus of temperature change can thereby be
consciously regulated according to this incoming information (within limits).

The results can be surprisingly impressive with respect to the agility, dexterity, precision,
‘and power of the behaviorally-mediated temperature regulating system, in terms of the
range of local (and regional) temperature variables potentially accessible to conscious
control. In the words of the Rockefeller University researchers, who provide a
comprehensive and detailed summary of a body of research into the phenomenon of
behavioral control of temperature:

{In one representative study]... 19 out of 21 individuals learned increases or decreases in hand temperature
in four to six training sessions of 15 minutes each.... [and] (1) most subjects learn with as little as one hour
of practice; (2) many subjects can increase or decrease temperature at “will” and can transfer the body
locus of temperature change with little decrement in performance once training is complete; (3) feedback is
needed only during the early stages of training [but see below]; (4) with extended practice, the locus of
control is gradually reduced to the location of the transducer responsible for feedback; (5) retention is
nearly perfect after four to five months without practice; (6) control of variations in temperature as great as
9.86 degrees C (17.75 degrees F) are possible...

To this list of impressive features can be added still others: substantial temperature
increases can be generated through such behavioral techniques rapidly, such as 10 to 15
degree F increases within 1-2 minutes (Sargent et al 1972; Miller 1975; Schwartz 1984);
increases as great as 26 degrees F, and up to 104 degrees F, have been reported in the
literature (Schwartz 1984); subjects can maintain stable increases for considerable
periods (Taub 1977), including for over several! hours (Benson et al 1982), and while
simultaneously engaged in other tasks (Benson et al 1982; Taub 1977); feedback from
special technical devises are in many cases not necessary, and may even interfere with
acquisition of the skill (Miller 1989; Kojo 1985, 1990; Piedmont 1981; Engel 1986); the
techniques can apparently produce temperature increases over most cutaneous and
superficial tissues that have been tested, including arms, legs, hands, feet, digits,
forehead, earlobes, mouth, and trunk (Taub 1977; Benson et al 1982), and deep tissues,
including at least several visceral organs (eg, kidney, colon, lungs), are also accessible
(Miller 1969, 1975, 1989; Luthe 1963, 1969; Ikemi et al 1965, 1966); children appear to
be particularly adept at acquiring the skills (Lynch, Hama, Kohn, & Miller 1976).

The question of course naturally arises: if “moderate” hyperthermia does indeed possess a
significant microbicidal potential, then why is this knowledge not more widespread and
developed? There are at least several reasons for this. In the first place, as you and others
have pointed out, the antibiotic revolution in infectious disease medicine has essentially
eclipsed other frameworks and approaches to the subject. Unfortunately, as you and
others have also pointed out, this one-sided orientation has, to indulge a metaphor,
generated its own “germs” of destruction, in that its exclusivity has left us under-prepared
for the emergence of MDR infectious organisms. Secondly, the development of a viable
and effective heat delivery system for therapeutic hyperthermia has been significantly
hampered by formidable technical problems, which some researchers have summed up
with the phrase “the biology is with us but the physics is against us”: problems with
focusing applied heat with precision, differences in the conductance properties of
adjacent tissues, problems with development of noninvasive thermometry, and side
effects such as acute discomfort, pain and even tissue damage, have all contributed to
what is in many ways a veritable technological impasse (Myerson et al 1997;
Seegenschmiedt & Vernon 1995; Navin et al 1990; Neva et al 1984). (A third reason for
the relative lack of interest in hyperthermia as an anti-microbial treatment modality, I
believe, is based on the fact that many medical researchets are tot fainiliar with the very
recent research demonstrating its potential as a significant stimulatory agent for natural
immune system function, including in particular the NK system, as discussed above).

It is perhaps surprising, then, that what appear to be correctives for such “high tech”
problems would come from the domain of behavioral medicine. However, as the
Rockefeller University researchers emphasize in their comprehensive and detailed
reviews of studies on the behavioral control of vasomotor function, blood flow, and
temperature, the techniques can produce changes characterized by precision and
“specificity” (Miller 1975) in terms of both magnitude and anatomical location, dexterity,
anid prolonged stability, if desired, and can be successfully directed to deep as well as
superficial tissues, learned rapidly, etc.

Perhaps even more surprising is the fact that the potential anti-microbial properties of
such behavioral techniques apparently have been exploited for some time, particularly by
several cultures that possess what might be thought of as highly developed, sophisticated
systems of “traditional behavioral medicine.” These cultures, including India, China, and
Tibet, possess long-standing traditions of “behavioral medicine” which have explicitly
considered behaviorally-generated heat as a form of medicine, to be used therapeutically,
including specifically against infectious disease (eg, Clifford 1984). Moreover, the ability
to generate heat with precision, dexterity, and prolonged stability (ie, for as long as
several hours), has been strikingly demonstrated in a study of Tibetan practitioners of a
particular form of heat-producing behavioral technique, a study which was conducted by
Herbert Benson and colleagues from Harvard Medical School (Nature 295: 234-6, 1982;
although the study was not concerned with the use of the technique for infection-fighting
purposes).

Because of the exciting and compelling nature of the above evidence, and because of the
re-emerging problem of MDR pathogens, my colleagues and I decided to attempt to
initiate a program devoted to this multifaceted subject, one that would integrate research
and conference interaction between colleagues. In this endeavor I have been joined by Dr
Thomas K Hunt, Professor of Surgery and Director of the Wound Healing Laboratory,
University of California at San Francisco Medical Center, who is one of the original
(post-WWII) pioneering investigators into the role of temperature and oxygen in host
defenses against wound-infecting organisms; Dr Ronald B Herberman, Director of the
Cancer Institute, University of Pittsburgh, who is the actual discoverer of the NK cell,
and who has conducted a sizeable body of research into both the anti-neoplastic and anti-
microbial (eg, Levy SM, RB Herberman, et al 1991) properties of the NK system; and Dr
N Herbert Spector, former director of labs and programs at the Walter Reed Institute,
NSF, and NIH, who has been credited as one of the founders of the field that investigates
immune and nervous system interactions (American College of Allergy and Immunology
News, November 1993) for his pioneering early experiments that established a
connection between the hypothalamus and certain immune variables (Spector et al 1974,
1975), as well as other achievments (Spector et al 1995; Spector 1996, 1997). And,
‘furthermore, because of the evidence for the use of behaviorally-induced hyperthermia
for mictobicidal purposes in the Indd-Tibetan tradition, we sought aid fortunately
obtained the formal participation of the Dalai Lama of Tibet in our project. The Dalai
Lama is a leader in cross cultural dialogue, as well as in the dialogue between modern
Western science and information systems found in other traditions and cultures, as
evidenced by his past participation in conferences with medical and neuroscientists at
Harvard Medical School, MIT, and the Centre Nationale de la Recherche Scientifique in
Paris.

Based on that conference and other preliminary and follow-up work, we are in the
process of designing several studies. In one we will be investigating the potential
microbicidal effect of the hyperthermia-generating behavioral medicine techniques
against S aureus, through a methodology that will be employing skin chamber assays,
and subcutaneous oxygen and temperature monitoring. This study is directly tied to one
of Hunt’s studies, just getting underway, which will be investigating the possible
development of resistance to oxygen-based killing mechanisms in S aureus. In another
study, which is still in initial stages, we hope to investigate the potential effects of the
techniques against tuberculosis, which follows on work already done some time ago in
Germany (see above). These studies are attempts to answer the call issued by a number of
infectious disease specialists (eg, Kernodle and Kaiser 1995, 1997; Ratcliffe et al 1994)
for the investigation and development potential “immunostimulatory agents” in the battle
against dangerous antibiotic resistant pathogens.

We also currently wish to plan our next conference. We would be preatly honored if you

would consider participating in our conference. We would be more than happy to
schedule it to accommodate your busy schedule (as well as the schedule of the Dalai a
Lama, of course). Likewise we would be greatly honored and grateful if you would

consider offering any opinions, information, feedback, etc, regarding the development of

our conference or research program.

Again, I would like to apologize for the length of this unsolicited letter, and for any
undue repetition of information familiar to you. Nevertheless, I hope you will have found
it of some value. We look forward to hearing from you at your earliest convenience.

Sincerely,

WEE C

William C. Bushell, PhD
Visiting Research Scientist

Mailing Address and Telephone:
280 Riverside Drive, #2K
New York, NY 10025

(212) 932-1452
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