The use of somatic cell gene therapy by Drs. French Anderson, Michael Blaese and Steven Rosenberg, for the treatment of adenosine deaminase deficiency is clearly the development and use for the first time of techniques for this kind of genetic therapy. It is too early to claim any definite results but preliminary indications are that the children with adenosine deaminase are doing better with the treatment than prior to it. The use of lac cells to deliver potent toxins to tumors is at a very early stage, but clearly this represents a significant clinical application of ideas and techniques that have been generated in the last ten years.

The development of prototypic vaccines for vaccination to prevent AIDS has proceeded rapidly. In particular, clinical trials are beginning on the use of the vaccinia virus to carry important genetic elements, not only of the HIV virus, but of other infectious agents. This represents a culmination of the work of NIH scientists, but principally of Dr. Bernard Moss who, over the last 15 years, has studied the use of vaccinia virus for a variety of vaccinations.

In other related work, early methods of using antibodies and other cellular proteins that will deliver toxins directly, and almost uniquely, to the tumor cells, has been progressing and several of these preparations are in beginning clinical trials. This represents the use of the most recent techniques in recombinant DNA methodology and in toxin production, a major clinical problem.

In yet another field, magnetic resonance imaging, the NIH has one of the premier installations of its kind for this purpose. It should be noted that the history of magnetic resonance research, which started out as nuclear magnetic resonance, began more than 30 years ago in the laboratories of NIH. Without this background, it would have been difficult for the NIH to develop clinical magnetic resonance imaging as rapidly as it has.

Most recently, with respect to spectroscopic magnetic resonance imaging, the NIH has been at the forefront. Dr. Robert Balaban and colleagues have made fundamental contributions to our knowledge of how energy transport is regulated in the mitochondria. Installation of a new large bore high field magnet is planned within the next six months.

HUMAN GENE THERAPY

Question. I was pleased to hear about initial success Drs. Anderson and Blaese have had in using gene therapy to treat Severe Combined Immune Deficiency (SCID).

As I understand it, NIH usually pays for drugs taken by patients in clinical protocols. However, I'm troubled by reports that NIH may not treat the 10 other children suffering from SCID due to the expense of PEG-ADA, the drug that must be administered in conjunction with gene therapy. It will take two years to treat all SCID children, and the annual cost of the drug is $200,000 per child, for an additional cost of $2 million.

Will the Director's discretionary fund be used to purchase the necessary amount of PEG-ADA so that the therapy is available to these children?

Answer. It is true that NIH usually pays for the therapeutic agent taken by patients who are part of an approved experimental clinical protocol. That is, the cost for the research protocol is born by NIH. However, NIH does not reimburse for normally prescribed treatment that is not research, and therefore, not part of the approved experimental protocol.

In the case of the SCID patients, PEG-ADA is the normally prescribed treatment, and these patients are prescribed PEG-ADA whether or not they are accepted into the gene-therapy protocol. With regard to the acceptance of SCID patients for the gene-therapy protocol, PEG-ADA is already prescribed in all these patients, and is not a variable under study in the approved protocol.

The approved protocol for gene-therapy requires that SCID patients meet certain medical and scientific criteria to be eligible for the protocol. For example, the patient's cells must be transducable; that is, the gene therapy must "fit" the cells. In addition, the patients must be able to meet certain physical requirements, including the ability to visit NIH every two weeks for treatment. It is intended that all patients that meet the medical and scientific criteria of the protocol will be entered into the study. Therefore, the NIH's ability to pay for PEG-ADA is not a factor in admitting patients into the gene-therapy protocol.

QUESTIONS SUBMITTTED BY SENATOR HARRY REID

NEUROLOGY RESEARCH

Question. What evidence is there that this experiment is instrumental in the advancement of treatment and cures of diseases which relate to human or non-human animals?

[Background information - In justifying his

experimentation, Charles Larson states that "It is
important to study the neural control of vocalization
in order to understand the human speech production
process itself and to learn how neurological
disorders such as Huntington's disease, Parkinsonism,
and spastic dysphonia affect vocalization." However,
experts in the fields of neurobiology, clinical
neurology, primate communication, and other fields in
human and veterinary medicine have provided
substantial evaluations to the contrary. These
evaluations conclude that, at best Professor Larson's
grant is a waste of tax monies and, at worst, comes
very close to scientific misfeasance. Considering
the obvious exaggeration and the questionability of
the project goals which allude to these specific
human diseases, by what criteria has the National
Institutes of Health (NIH) funded Professor Larson's
project?

In Professor Larson's experimentation, the region of
the brain stimulated is the periaqueductal gray area
(PAG). In a specific paper published in 1985 while
his project was being funded by the NIH, Professor
Larson says, "It has also been suggested that human
speech, being propositional in nature, is
fundamentally different from most types of animal
vocalizations and is controlled by different neural
mechanisms." In the same paper, he also says, "the
extent to which the PAG may be involved in normal
human speech remains to be determined," and "the PAG
may not be crucial for normal speech." In view of
the marginal and speculative nature of the PAG's
relationship to human speech and the general belief
that the diseases enumerated in Professor Larson's
justification for his grant are related to areas of
the brain other than the PAG, is not his statement of
justification an attempt to suggest that his research
has a relationship to human health that is, in fact,
probably non-existent?

Additionally, Professor Larson, himself, admits that
the PAG is not the only area involved in vocalization
and that the PAG may be only a link between the
limbic system of the brain and laryngeal and
respiratory systems. The limbic system is heavily
involved with emotions and the PAG itself is involved
with pain mechanisms. As the animals involved in
this study are clearly under a great deal of
emotional stress and experiencing pain, how can
Professor Larson know which of the effects he is
studying are due to pain and stress and which to
vocalization? At best, are not the results altered
in unknown ways by the stress the animal is
undergoing? Therefore, is there not significant
doubt that Professor Larson's data applies even to
the macaques involved, much less to humans?]

Answer. The merit of Dr. Larson's research and design was evaluated by the Sensory Disorders and Language Study Section that includes foremost experts in the study of voice, speech and language. The proposal received a favorable review and a high funding priority.

In the judgment of the expert review panel, the proposal demonstrated a strong and balanced approach to identifying the relationships among periaqueductal gray, nucleus retro-ambiguus and laryngeal motor neurons and should provide basic information regarding motor control of vocalization and offer greater insight into understanding disorders of motor speech control. It was considered important from the standpoint of understanding normal mechanisms of voice and speech. The investigators have shown that there are several functional types of cells among the periaqueductal gray neurons that are related to vocalization and have begun to define the properties of these cells. They have also obtained evidence that stimulation of different parts of the periaqueductal gray area may elicit different types of vocalizations and have begun to study patterns of muscle activity related to periaqueductal gray neuron stimulation.

They have obtained evidence, supported by data from other neuroanatomical laboratories, that the periaqueductal gray neurons project to the nucleus retro-ambiguus, instead of directly to the nucleus ambiguus.

Dr. Larson's research reflects a careful and meticulous approach to an important issue, accompanied by appropriate and adequate treatment of the animals involved in his research. This research is important to our understanding of the muscles and movements involved in vocalization, and has direct relevance to voice disorders, such as spasmodic dysphonia and speech disorders like the ones associated with Parkinson's disease. Continuation of this research is critical to our understanding of neurologically-based speech disorders and will ultimately have an impact upon our treatment of those affected.

Question. How is continued funding of this grant justified in light of the flawed aspects of this experiment and the minimal results produced to date?

[Background information - Professor Larson cites a number of papers substantiating the relationships between the PAG and vocalization in a variety of animal species. As his results to date seem not to show much more than what is already known and copiously published, does not Professor Larson's research largely duplicate existing results? Is it not a waste of taxpayer money and productive of unnecessary animal suffering to fund this duplicative work?

In spite of the rather lengthy experimentation
Professor Larson has performed, his results seem
minimal almost to the point of triviality. Why is
the NIH rewarding such unproductive experimentation
by extending this grant? It seems, too, that the
taxpayers have been funding and funding generously,
Professor Larson's career since his days as a
graduate student 20 years ago with very little, if
anything, to show for that funding. Why does the NIH
allow this to continue? What are the NIH standards
for extending or terminating grants?]

Answer. The project will attempt to improve the understanding of mechanisms of vocal control by studying brainstem neuronal activity. This research is a part of a body of basic scientific research that provides important information in determining the pathophysiology of voice and speech disorders that cannot be conducted on human subjects, but may provide greater insight into human disorders. Charles Larson is recognized as one of the world's foremost authorities on the neural bases of vocalization. Over the last twenty years he has published more than twenty articles on related research.

Question. What assurances are there that the macaques involved in Professor Larson's experiments are being humanely treated as stipulated in the Animal Welfare Act?

[Background information

Exactly how has Professor Larson assured that each and every animal used in each and every one of his experiments no pain or discomfort? Detailed anesthetic protocols for the past 2 years, as well as photocopies of the notes substantiating these protocols and purchase orders of the pharmacologic agents used should be provided. What post-operative analgesic medicine is used? Photocopies of notes substantiating the use of these medications and purchase orders of the pharmacologic agents used in any post-surgery procedure should be provided.

What are the qualifications of all personnel administering and monitoring anesthetic protocols and performing surgical procedures?

Why cannot local citizens have contact with the
community representative serving on Northwestern
University's Animal Care and Use Committee, or even
know that person's name, despite numerous requests
from local residents and the Evanston, Illinois City
Council? Is not this withholding of information an
arrogant violation of the Animal Welfare Act as
amended by the Dole-Brown Amendment?]

Answer. Review groups at NIH and at Northwestern University have carefully considered this research and had no concerns regarding Dr. Larson's treatment of his animal subjects; the issue of pain was specifically addressed by the reviewers. The consideration of the treatment of animal subjects is a threetiered process. The Northwestern University Animal Care and Use Committee formally assures the NIH, under procedures outlined in both the Department of Agriculture Animal Welfare Act as amended and the Public Health Service Policy on Humane Care and Use of Laboratory Animals, that animal protocols regarding surgical procedures, medication, and recovery issues were judged to be appropriate. Additionally, the NIH Study Section, after receiving this clearance, reviewed and evaluated the scientific appropriateness as well as the issues related to animal care and use and made this report to the Institute prior to final consideration of the grant application. The final tier of the review is each Institute's own National Advisory Council.

Northwestern does not release the names of any of the committee members fearing for the safety of the individuals and their families due to death threats received in 1989 that were investigated by the FBI and other law enforcement organizations. However, Northwestern University does provide opportunities to address concerns to the committee members by communicating in care of the committee. The records about purchases and procedures would be the property of Northwestern University and requests for those kinds of materials should be directed to the Vice President for Research and Dean of the Graduate School, Dr. David H. Cohen. Questions about the Act can be answered most thoroughly by the Department of Agriculture, Animal and Plant Health Inspection Service, Regulatory Enforcement and Animal Care Office.