DATE

Joyce E. Jones

Executive Secretary

U.S. Department of Health & Human Services

Exchange Visitor Waiver Review Board

200 Independence Avenue, SW

HHS Building, Room 627H

, DC 20201

Re: Request for HHS waiver on behalf of , Ph.D.

To Whom It May Concern:

I am writing this letter to request that the Department of Health and
Human Services act as an Interested Government Agency in recommending a
waiver of the two year home residency requirement on behalf of Dr. ,
Senior Research Fellow in the Division of Molecular Genetics at the
University of in Seattle.

**[1. Description of Program]{.underline}**

For the last thirty years, my office has been working on the development
of therapeutics for sickle cell disease and homozygous beta (β)
thalassemia based on the induction of fetal hemoglobin. In the 1970s, I
provided the experimental evidence that fetal hemoglobin can be induced
when the adult erythropoiesis is perturbed. I further demonstrated that
this could be achieved with cytotoxic drugs. These studies resulted in
the introduction of a cytotoxic drug called hydroxyurea, which was used
in the treatment of sickle cell disease. Hydroxyurea is now used
extensively in the treatment of sickle cell patients in the United
States and worldwide.

Sickle cell disease is common among the African-American population. It
is estimated that one of 400-500 African-American liveborns are
homozygous for the sickle hemoglobin and will develop sickle cell
disease. The World Health Organization (WHO) estimates that every year,
about 100,000 children with sickle cell anemia are born worldwide.
Thalassemia is common among individuals of Mediterranean and Asiatic
descent. WHO estimates that each year, approximately 120,000 children
with thalassemia syndrome are born. Currently, the only cure for both
sickle cell disease and thalassemia is bone marrow transplantation, a
procedure that has significant mortality and is available only to a
minority of patients who have a compatible donor. However, it is well
established that both sickle cell disease and homozygous β thalassemia
can be cured if we can induce the production of large amounts of fetal
hemoglobin in these patients. This is because both sickle cell disease
and β thalassemia are a result of mutations that affect the adult
hemoglobin gene. Therefore, replacement of adult hemoglobin with fetal
hemoglobin will abolish the deleterious effects of the abnormal genes.

While hydroxyurea has had some success in treating sickle cell disease,
there are a significant number of patients who fail to respond to the
hydroxyurea treatment. There are also questions about the safety of
lifelong treatment with a cytotoxic drug. Furthermore, hydroxyurea
treatment is not effective for patients with thalassemia. Therefore, it
is of utmost importance that new inducers of fetal hemoglobin be
developed. The program in which Dr. is engaged focuses on the
development of a new class of therapeutics that can potentially
stimulate the production of fetal hemoglobin in both sickle cell disease
and thalassemia. This program is supported by grants from the National
Institutes of Health (NIH), National Heart, Lung, and Blood Institute,
HL20899-225, Cellular Mechanisms and NIH, National Institute of Diabetes
and Digestive and Kidney Diseases, DK45365-06, Molecular Control of
Globin Gene Switching.

Specifically, the focus of this program is the investigation of
compounds that affect gene expression by acting directly on the fetal
globin gene chromatin. These compounds have been synthesized by our
medicinal chemist collaborators in the United States and Germany. Dr. is
playing a critical role with her investigation on the effects of these
compounds on the fetal hemoglobin genes of established cell lines and of
primary erythropoietic cells. In the next stage of her research, she
will conduct pre-clinical studies using transgenic mice carrying the
human fetal globin gene and non-human primates.

**[2. Exchange Visitor's Essentiality to Program and Her Unique
Capabilities]{.underline}**

Dr. was recruited to our laboratory as an expert in cell biology and
molecular biology. Since joining my group, Dr. has been a major
contributor to the success of our program. She is a creative and
original thinker with native intelligence, bright ideas, and excellent
research experience. She has exhibited extraordinary capacity in solving
many problems in experiments. Above all, Dr. has a rare combination of
profound knowledge in many disciplines, including clinical medicine,
hematology, immunology, molecular biology, and cell biology. She has
integrated these disciplines intuitively in her research and achieved
outstanding results.

Given her combined expertise in clinical medicine, hematology,
immunology, as well as her rare knowledge of cell biology and molecular
biology technologies, Dr. has taken a lead role in this project. For
instance, Dr. is the only researcher in my group investigating the in
vitro and in vivo effects of potential inducers of fetal hemoglobin
synthesis. Indeed, she is the only one in this laboratory capable of
doing this work, which requires a background in drug action, cell
biology, and molecular biology, plus experience and knowledge of
molecular biology and cell biology techniques, such as the luciferase
analysis method.

The most important accomplishment Dr. has contributed to our study is
her discovery that several of the new compounds she investigated, such
as suberoylanilide hydroxamic acid (SAHA), Depsippeptide (FR901228),
N-Hydroxy-7-(4-dimethylaminobenzoyl)-aminoheptanamide (M344), Scriptaid
(HR13), (S)-Octanedioic acid hydroxyamide
(1-phenethylcarbamoyl-2-phenyl-ethyl)-amide (SW68), (S)-Octanedioic acid
(1-benzylcarbamoyl-2-phenyl-ethyl)-amide hydroxyamide(SW70),
(S)-3-(4-Methoxy-phenyl)-2-(7-hydroxycarbamoyl-heptanoylamino)-propionic
acid methyl ester (SW99),
(S)-3-Phenyl)-2-(7-hydroxycarbamoyl-heptanoylamino)-propionic acid
methyl ester (M232), and
(S)-2-(7-Hydroxycarbamoyl-heptanoylamino)-3-thiophen-2-yl-propionic acid
methyl ester (SW86), have the ability to induce fetal hemoglobin in
primary human erythroid cells. She found that at least six of these new
compounds, specifically suberoylanilide hydroxamic acid (SAHA),
Depsippeptide (FR901228),
N-Hydroxy-7-(4-dimethylaminobenzoyl)-aminoheptanamide (M344), Scriptaid
(HR13), (S)-Octanedioic acid hydroxyamide
(1-phenethylcarbamoyl-2-phenyl-ethyl)-amide (SW68), and (S)-Octanedioic
acid (1-benzylcarbamoyl-2-phenyl-ethyl)-amide hydroxyamide (SW70), are
exceptional because they can induce fetal hemoglobin in very low
concentrations. Therefore, her findings raise great hopes that the
compounds may prove very active in vivo. Currently, Dr. is continuing
her screening of the new compounds and is investigating several in vitro
tested *γ *inducers in vivo in a transgenic mice system. In the next
step of this investigation, after the required quantities of these
compounds are synthesized, Dr. will conduct pre-clinical studies using
mice and primates.

Indeed, Dr. has already received recognition for her findings in this
study. Within a few months of joining this program, Dr. presented an
abstract of her findings at the *Annual Meeting of the American Society
of Hematology*. Also, her paper, entitled "*Hydroxamide Derivatives Of
Short-Chain Fatty Acids Are Potent Inducers Of Fetal Hemoglobin
Production*," will published in the forthcoming volume of [Experimental
Hematology]{.underline}. In this paper, Dr. discussed her investigation
in which she applied the luciferase system to test the short-chain fatty
acid-derived hydroxamic acids, butyryl-hydroxamate, and
propionyl-hydroxamate, which are inducers of *γ*-globin gene expression.
Two other hydroxamic acid derivatives, suberoylhydroxamic acid (SBHA)
and suberoylanilide hydroxamic acid (SAHA), which were previously shown
to inhibit histone deacetylase and induce terminal erythroid maturation,
were also studied. Dr. 's findings in this study are important because
she found that hydroxamate based histone deacetylase inhibitors
represent a new class of fetal hemoglobin inducers.

In addition, Dr. will also submit a second paper, entitled "*Induction
Of γ Gene Expression By Amide Analogues Of Trichostatin A.*," to
[Blood]{.underline}. This paper discusses Dr. 's application of the
luciferase system to test the *γ*-globin gene expression induced by the
function of a series of amide analogues of Trichostatin A. She also
studied these inducers in primary human erythroid cells. In this study,
Dr. discovered that several of these new compounds have the ability to
induce fetal hemoglobin in very low concentrations.

Dr. 's abilities and expertise is critical to the development of new
therapeutics for sickle cell disease and homozygous β thalassemia. Her
insightful knowledge, broad experience, and excellent expertise in cell
biology and molecular biology techniques make her an indispensable
member of our team. It was impossible for us to find any person with her
qualifications and experience from recruitment advertisements that were
placed on the internet. Dr. 's work is essential to successful induction
of fetal hemoglobin and to the design and development of effective
treatment for sickle cell disease and thalassemia. Thus, the continued
presence of Dr. in this country and the continued progress of her
research are in the direct interest of the United States. Our country
would benefit immensely by her expertise in cell biology and molecular
biology. Moreover, Dr. is deeply devoted to her research. Her work will
have a significant impact in relieving the suffering of the millions of
patients who have sickle cell disease and thalassemia.

**[3. Information Regarding Current Personnel]{.underline}**

My program on the cellular and molecular control of fetal hemoglobin
synthesis has three components. The first component focuses on the
delineation of the molecular basis of the phenomenon of hemoglobin
switching (i.e., the change from fetal to adult hemoglobin during
development) using transgenic mouse models and chromatin
immunoprecipitation assays. Two faculty members (associate and assistant
professors), three postdoctoral fellows, and two technicians work on
this project. Except for the technicians, all are Ph.D. molecular
biologists. Because Dr. has the ability to perform primary human
erythroid cells cultures, she assists the associate professor
dynamically observe the human *γ* and β hemoglobin expression lever in
primary human erythroid cells. Through this observation, she will
develop a model for future study of hemoglobin switching.

The second component focuses on the investigation of two transcriptional
factors that are potentially involved in the control of fetal globin
genes. One assistant professor, one postdoctoral fellow, one Ph.D.
student, and one technician work on this project. The scientists are all
Ph.D. molecular biologists. Dr. plays a vital role in this investigation
because she is an expert and has extensive experience in using the
luciferase analysis system.

The third component is the development of therapeutics for the induction
of fetal hemoglobin synthesis. The compounds being developed are
inhibitors of the enzyme histone deacetylase. They are synthesized by
our collaborators in the Department of Medical Chemistry of the
University of Münster, Germany and in the Department of Chemistry of
California State University, Fresno. Dr. is the only person in my
laboratory investigating the effects of these compounds in the induction
of fetal hemoglobin in vitro and in vivo. Nobody else in this group has
the expertise required to perform Dr. 's research, which is critical to
the overall success of the program.

**[4. Recruitment Efforts]{.underline}**

While Dr. is indispensable to this nationally important research, we
were greatly concerned that she may be required to return to China for
two years, as required by her current J-1 visa. In order to avoid a
significant loss in the progress of our work, we placed two
advertisements for the position on the internet, one on the Career
Network website and the other on the [Science Magazine]{.underline}
website. Approximately 150 scientists applied for the position,
including those from the United States, China, Japan, and India.
However, the advertisement failed to yield applicants possessing the
requisite experience and leadership qualifications necessary to carry on
these studies.

**[5. Future of Program if Waiver is Not Granted]{.underline}**

As noted above, Dr. has a unique combination of expertise in clinical
medicine, drug actions, as well as cell and molecular biology. Perhaps
even more significantly, she is a self-starter who accomplishes a
tremendous amount in a short period of time, and has already
tremendously furthered our research. Indeed, it took me three years to
fill the position Dr. occupies. Recently, we have had great difficulty
recruiting qualified scientists in the hemoglobin field, and I find it
very unlikely that I will be able to recruit a research scientist
possessing the qualifications of Dr. . Therefore, if the waiver is not
granted, the program will end with Dr. 's departure. It will be a pity
to have this program discontinued because its successful completion will
have a major impact on the development of new therapeutics for sickle
cell disease and thalassemia.

**[6. Long Range Plans for Exchange Visitor]{.underline}**

As Dr. is indispensable to our research program, if the waiver is
granted, we would propose the nomination of Dr. for a junior faculty
appointment at the level of acting instructor or acting assistant
professor. These are yearly renewable appointments, which are approved
by the Dean of the Medical School on the recommendation of the faculty.

**[7. Exchange Visitor's Qualifications]{.underline}**

Dr.  has a strong combination of both clinical and basic science
expertise in hematology, molecular biology, cell biology, and
immunology. She is credited with significant research on the effects of
compounds, such as suberoylanilide hydroxamic acid (SAHA),
N-Hydroxy-7-(4-dimethylaminobenzoyl)-aminoheptanamide (M344), Scriptaid
(HR13), (S)-Octanedioic acid hydroxyamide
(1-phenethylcarbamoyl-2-phenyl-ethyl)-amide (SW68), and (S)-Octanedioic
acid (1-benzylcarbamoyl-2-phenyl-ethyl)-amide hydroxyamide(SW70), on the
fetal hemoglobin genes of established cell lines and primary
erythropoietic cells. Indeed, this research has already received
recognition through her poster presentation at the *43^rd^ Annual
Meeting of the* *American Society of Hematology (2000)*. In addition,
her paper entitled "*Hydroxamide Derivatives of Short-Chain Fatty Acids
Are Potent Inducers of Fetal Hemoglobin*" has recently been accepted for
publication in [Experimental Hematology]{.underline}. She will also
shortly be submitting a second paper entitled "*Induction of γ Gene
Expression by Amide Analogues of Trichostatin A.*" to
[Blood]{.underline}. The timeline for acceptance for publication in
[Blood]{.underline} is three months. Moreover, based on this work we are
applying for a patent, entitled "*Induction of fetal hemoglobin by
histone deacetylase inhibitors*." This will include a class of compounds
that are inhibiters of histone deacetylase, which can induce human γ
hemoglobin synthesis, and thus have the potency of treating sickle cell
disease and the β thalassemia syndromes.

Prior to joining my program, Dr. held a number of leading positions at
institutions in the China and France. For example, as an Associate
Professor and Head of the Stem Cell Laboratory at the Institute of
Transfusion Medicine in Beijing, Dr. supervised the work of sixteen
fellows, including Ph.D. and master's candidates and one postdoctoral.
This laboratory focused on studying the proliferation, expansion, and
orderly differentiation of hematopoietic stem cells, mesenchymal stem
cells, embryonic stem cells, cell therapy, and gene therapy. During Dr.
's tenure as head of the laboratory, the laboratory made a number of
important findings. For example, they induced nerve cells and bone
cells, which have potency for bioengineering, from the bone marrow
mesenchymal stem cells isolated from cord blood. They also studied the
expansion of hematopoietic stem cells from the stem cells isolated from
cord blood, and induced specifically differentiate into red blood cells,
white blood cells, and megakaryocytes. Dr. personally presented some of
these findings at the *First Chinese Cord Blood Biology Conference*, the
*Chinese National Experimental Hematology Conference*, and the *Chinese
National Hematology Conference*. She has also published these findings
in several prominent journals, including [Basic Medical Sciences and
Clinics]{.underline}. In support of this research, Dr. 's laboratory was
the recipient of several grants, including those from the National Key
Basic Research Project, the National High Technology Project, and the
Institute for the Study of Biology for the clinical application of
dendritic cells. Moreover, Dr. was one of ten finalists from thousands
of scientists representing all of China in the "outstanding scientist"
competition.

Dr. was selected for this esteemed position based on her history of
excellence. For example, during her postdoctoral research at the Faculty
Medicine St. Antoine in Paris, she led a critically important study on
*"In Vitro Generation of Dendritic Cells from Human Blood Monocytes of
Healthy Donors and Patients in Experimental Conditions Compatible for
their use In Cell Therapy*." This research was supported by an important
grant of 90,000 Francs from the Foundation of Claude-Bernard Paris. The
significant results of this study were presented as a poster in the
*European Macrophage Study Conference* in Paris. Additionally, Dr.
played an indispensable role in and led the work of a technician and a
DEA student in a study on the "*Generation of Dendritic Cells from CD34+
Cells and Monocytes of the Same Patient in the View of their Antitumor
Vaccination*," which was supported by a grant of 120,000 Francs from the
Foundation of la Recherche Medical Paris. With this study, Dr. was the
first to show that dendritic cells from monocytes were as good as
dendritic cells derived from stem cells. This is significant because
obtaining dendritic cells from monocytes is much faster and accomplished
with less cytokines than from stem cells. Indeed, Dr. 's findings
received recognition through publication the [Journal of Hematotherapy
and Stem Cell Research]{.underline} and the [Chinese Journal of
Experimental Hematology]{.underline}.

Similarly impressive is the work Dr. performed as an Assistant Professor
at the Institute of Radiation Medicine in Beijing, where she led the
work of five scientists in critical research supported by the Foundation
of China National Nature Science, entitled "*Construction, Expression
and Biologic Activity of Recombinant Human Fusion Protein TPO/GM-CSF*."
Through this research, Dr. recreated a recombinant cytokine, which can
stimulate both leucocytes and thrombocyte production, to treat
leucopoenia and thrombopenia, and reduce the mortality of irradiation of
injury. Indeed, Dr. was successful in cloning this recombinant
cytokine's gene, evidencing that it can stimulate both thrombocyte and
white blood cells production and, as shown in the in-radiated mouse
model, improve the survival rate. In addition, she also found that due
to the structural homology of TPO and EPO, the cloned cytokine not only
stimulates the production of both leucocytes and thrombocytes, but also
the production of erythrocytes. This work was published in the [Journal
of Hematotherapy and Stem Cell Research]{.underline}. Moreover, Dr.
received a patent for the rhTPO/GM-CSF cytokine in China, where she was
also honored with a prestigious award. Dr. was one of a few scientists
selected to receive an award in recognition for her significant
contributions to the progress of science and technology in Chinese
military medicine science.

The major impact of Dr. 's work is clearly reflected in her numerous
important papers that have appeared in major peer-reviewed medical
journals over the past twelve years. These include a number of first
author publications in American, European, and Chinese journals,
including [Foreign Medicine]{.underline}, the [Bulletin of the Academy
of Military Medical Sciences]{.underline}, the [Chinese Journal of
Hematology]{.underline}, [Shanxi Leukemia]{.underline}, the [Chinese
Journal of Experimental Hematology]{.underline}, the [Chinese Journal of
Clinical Oncology]{.underline}, [Progress in Physiology
Science]{.underline}, the [Chinese Journal of Radiologic Medicine and
Protection]{.underline}, the [Journal of Hematotherapy and Stem Cell
Research]{.underline}, [Basic Medical Sciences and Clinics]{.underline},
and [Experimental Hematology]{.underline}. She will also submit a paper
to the prestigious journal [Blood]{.underline}. Moreover, the
recognition Dr. received also comes in the form of prestigious honors
and awards, as well as membership in prominent medical and scientific
societies. For example, Dr. received a first class award from both the
Institute of Transfusion Medicine and the Institute of Radiation
Medicine in Beijing. She was among the ten candidates selected from 250
applicants at the Institute of Radiation Medicine, and was one of a
handful of applicants selected from a class of 2,000 at the Institute of
Transfusion Medicine. Dr. was also one of six individuals to receive a
highly competitive award from the Chinese Medicine Society, which was
presented to her at the *Annual Meeting of the Chinese Medicine
Society*. Furthermore, Dr. was presented an award for her vital
contributions to science and technology for the advancement of Chinese
military medicine sciences. In addition, based on recommendations and
her vital contributions to the field, Dr. was granted membership in the
International Society of Experimental Hematology, the American Society
of Gene Therapy, and the American Society of Hematology.

Thank you for your time and attention to this matter.

Sincerely,