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90-401: Christa Edith Muller-Sieburg (19 February 1952 – 12 January 2013) was a German-American immunologist and hematologist, whose work became central to the understanding of the clonal heterogeneity of hematopoietic stem cells (HSCs). Muller-Sieburg is known for her contributions to the purification of hematopoietic stem cells , the characterization of individual stem cell clones and her revision of

180-448: A 40% decrease in bone marrow cell number that includes several hematopoietic lineages. Expansion potential of hematopoietic progenitor cells is also reduced. These characteristics correlate with reduced ability to repair double-strand breaks in hematopoietic tissue. Deficiency of NHEJ factor 1 in mice leads to premature aging of hematopoietic stem cells as indicated by several lines of evidence including evidence that long-term repopulation

270-524: A disease and identification of chemical compounds (or antibodies) that bind to those proteins and inhibit or enhance their function. Such compounds become candidate drugs for the treatment of the disease. Several compounds developed either at the Institute or by biopharmaceutical companies are now in clinical trials. Pioneering studies at the Institute showed that simple sugars such as D-mannose, L-fucose and D-galactose are effective therapies for

360-443: A donor) or syngeneic (from an identical twin). It is most often performed for patients with certain cancers of the blood or bone marrow , such as multiple myeloma or leukemia . In these cases, the recipient's immune system is usually destroyed with radiation or chemotherapy before the transplantation. Infection and graft-versus-host disease are major complications of allogeneic HSCT. In order to harvest stem cells from

450-567: A faster-growing few , substantiating a novel theory of ageing which could enable healthy aging . Of note, the shift in clonal diversity during aging was previously reported in 2008 for the murine system by the Christa Muller-Sieburg laboratory in San Diego, California. A cobblestone area-forming cell (CAFC) assay is a cell culture-based empirical assay. When plated onto a confluent culture of stromal feeder layer ,

540-423: A follow-up study in 2000, Muller-Sieburg and co-workers showed that the genetic control of HSC frequency is mostly cell-autonomous. By 2008, Scfr1 had become integrated into the group of genes and gene networks that specify "stemness" and cell fate decisions. The last 15 years of her life, Muller-Sieburg worked on the clonal fabric of hematopoiesis, making pioneering contributions to the foundations and practice of

630-420: A fraction of hematopoietic stem cells creep between the gaps (even though the stromal cells are touching each other) and eventually settle between the stromal cells and the substratum (here the dish surface) or trapped in the cellular processes between the stromal cells. Emperipolesis is the in vivo phenomenon in which one cell is completely engulfed into another (e.g. thymocytes into thymic nurse cells ); on

720-436: A heterogeneous cell population with respect to their differentiation and proliferation behaviors. As a consequence of this clonal heterogeneity principle, whole blood represents as a mixture of "bloods" originating from many active stem cell clones. Within each clonal blood, all HSCs form a homogeneous core population whose members have the same lifespan and carry the memory of the differentiation and self-renewal capacities of

810-431: A highly specific role in the repair of double-strand breaks by NHEJ. Lig4 deficiency in the mouse causes a progressive loss of hematopoietic stem cells during aging. Deficiency of lig4 in pluripotent stem cells results in accumulation of DNA double-strand breaks and enhanced apoptosis. In polymerase mu mutant mice, hematopoietic cell development is defective in several peripheral and bone marrow cell populations with about

900-540: A hospital which had received significant donations from T. Denny Sanford previously, allowing it to create the Sanford Children's Health Research Center, which has sites in Sioux Falls, South Dakota , and La Jolla, California, the latter within the campus of the institute. In 2008, Sanford Burnham Prebys was awarded a $ 97.9 million grant by NIH to establish a high-throughput screening center. In 2010,

990-428: A key element of idiotype network theory postulated by Niels Kaj Jerne , namely the enigmatic shift from one to another class of immunoglobulins produced by the same clone on B-lymphocytes. By making sequential sub-lines from an original hybridoma line, she discovered immunoglobulin class switch and described it in her 1983 paper published with Klaus Rajewsky . The following year, they co-authored an important paper on

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1080-725: A leading scientist in the field of experimental hematology, led to her appointment as a professor and head of the stem cell program at the Sidney Kimmel Cancer Center, La Jolla in 1998, and, subsequently, as a professor at the Sanford Burnham Medical Research Institute (later: Sanford Burnham Prebys ), from 2009 until her death. During her research career Muller-Sieburg published more than 50 articles in peer-reviewed journals, wrote several invited book chapters, and co-authored one book on hematopoietic stem cells. Muller-Sieburg

1170-701: A mathematician whom she had met in 1972 while studying at the University of Cologne. Muller-Sieburg died on 12 January 2013 of a squamous cell carcinoma , after nine years of illness, during which time she was still actively working. In 1983, Muller-Sieburg and her husband, Hans B. Sieburg, moved to the United States of America, both as fellows of the Deutsche Forschungsgemeinschaft ( German Research Foundation ) at Stanford University . There, Muller-Sieburg began her research at

1260-581: A set of rare genetic disorders. Some are currently in clinical trials. Sanford Burnham Prebys has working relationships with the University of California, San Diego , The Scripps Research Institute , the Salk Institute for Biological Studies , and the Mayo Clinic . Sanford Burnham Prebys also collaborates with pharmaceutical companies to move research breakthroughs from the lab out to

1350-550: A state of quiescence , or reversible growth arrest. The altered metabolism of quiescent HSCs helps the cells survive for extended periods of time in the hypoxic bone marrow environment. When provoked by cell death or damage, Hematopoietic stem cells exit quiescence and begin actively dividing again. The transition from dormancy to propagation and back is regulated by the MEK/ERK pathway and PI3K/AKT/mTOR pathway . Dysregulation of these transitions can lead to stem cell exhaustion, or

1440-436: Is a key determinant of the ability of stem cells to maintain themselves against physiological stress over time. Rossi et al. found that endogenous DNA damage accumulates with age even in wild type Hematopoietic stem cells, and suggested that DNA damage accrual may be an important physiological mechanism of stem cell aging. A study shows the clonal diversity of hematopoietic stem cells gets drastically reduced around age 70 to

1530-454: Is a subtype of HSC. (This sense of the term is different from colony-forming units of microbes, which is a cell counting unit.) There are various kinds of HSC colony-forming units: The above CFUs are based on the lineage. Another CFU, the colony-forming unit–spleen (CFU-S), was the basis of an in vivo clonal colony formation, which depends on the ability of infused bone marrow cells to give rise to clones of maturing hematopoietic cells in

1620-427: Is accompanied by extensive practical laboratory training under the supervision of faculty. In January 2020, Sanford Burnham Prebys reported $ 117M in annual revenue.   The sources of funding in 2019 were: 58% federal; 22% private philanthropy; 8% biopharma partnerships; 8% licensing & other and 4% other grants. Philanthropy has played a major role in the growth and expansion of the institution. Donations from

1710-865: Is also listed in the top 2% of research institutions globally by the amount of citations. In terms of nonprofit/non-government institutes in the field of biomedical science, it is ranked #6 nationally. Since its inception in 1976, the institute has grown from a small building in West San Diego to a campus in La Jolla containing an accredited graduate school with more than 350 postdocs, graduate students, and interns mentored per year. Current Institute educational programs serve trainees with professional development programs, postdoctoral scientific training and graduate programs in Biomedical Sciences. The Sanford Burnham Prebys educational system partners with

1800-505: Is an established as therapy for chronic myeloid leukemia, acute lymphatic leukemia, aplastic anemia, and hemoglobinopathies, in addition to acute myeloid leukemia and primary immune deficiencies. Hematopoietic system regeneration is typically achieved within 2–4 weeks post-chemo- or irradiation therapy and HCT. HSCs are being clinically tested for their use in non-hematopoietic tissue regeneration. DNA strand breaks accumulate in long term hematopoietic stem cells during aging. This accumulation

1890-551: Is associated with a broad attenuation of DNA repair and response pathways that depends on HSC quiescence. Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template. The NHEJ pathway depends on several proteins including ligase 4 , DNA polymerase mu and NHEJ factor 1 (NHEJ1, also known as Cernunnos or XLF). DNA ligase 4 (Lig4) has

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1980-560: Is composed of many individual bloods were obtained by single-cell experiments using limiting dilution for cell sorting and serial transplantation. In this approach, an initial transplant containing one hematopoietic stem cell extracted from lineage negative (Lin-) blood cells is used to rescue a lethally irradiated host with mono-clonal blood. The results from these serial transplantation experiments, lasting from 7 months up to five years, led Muller-Sieburg to quantitatively analyze sets of stem cell kinetics with H. Sieburg. These analyses led to

2070-540: Is defective and worsens over time. Using a human induced pluripotent stem cell model of NHEJ1 deficiency, it was shown that NHEJ1 has an important role in promoting survival of the primitive hematopoietic progenitors. These NHEJ1 deficient cells possess a weak NHEJ1-mediated repair capacity that is apparently incapable of coping with DNA damages induced by physiological stress, normal metabolism, and ionizing radiation. The sensitivity of hematopoietic stem cells to Lig4, DNA polymerase mu and NHEJ1 deficiency suggests that NHEJ

2160-455: Is defined as the repopulation kinetic of the HSC. The reconstitution kinetics are very heterogeneous. However, using symbolic dynamics , one can show that they fall into a limited number of classes. To prove this, several hundred experimental repopulation kinetics from clonal Thy-1 SCA-1 lin (B220, CD4, CD8, Gr-1, Mac-1 and Ter-119) c-kit HSC were translated into symbolic sequences by assigning

2250-426: Is incompatible with the evidence of clonal hematopoiesis involving the heterogeneous core populations of HSCs. Specifically, her data argue that self-renewal does not contribute to the heterogeneity of the adult HSC compartment but, rather, all HSCs in a clone follow a predetermined fate, consistent with the generation-age hypothesis. By extension, the self-renewal and differentiation behavior of HSCs in adult bone marrow

2340-454: Is more predetermined than stochastic. Almost a decade later, in a review paper, Timm Schroeder summarized these essential findings in the succinct phrase "subtypes, not unpredictable behavior". The dependence on epigenetically determined initial conditions placed hematopoiesis mathematically into the category of chaotic systems with deterministic evolution. This view was supported by Muller-Sieburg's finding in collaboration with H. Sieburg that

2430-557: Is not stochastically regulated or dependent on differences in environmental influence. My-bi HSC self-renew longer than balanced or Ly-bi HSC. The myeloid bias results from reduced responsiveness to the lymphopoetin interleukin 7 (IL-7). Subsequently, other groups confirmed and highlighted the original findings. For example, the Eaves group confirmed in 2007 that repopulation kinetics, long-term self-renewal capacity, and My-bi and Ly-bi are stably inherited intrinsic HSC properties. In 2010,

2520-482: Is recognized for its NCI-designated Cancer Center , its drug discovery center ( Conrad Prebys Center for Chemical Genomics ) and the Sanford Children’s Health Research Center . It also has strategic partnerships with the biotech and pharmaceutical industry. Sanford Burnham Prebys is one of seven fundamental research institutes in the United States and runs an NCI-designated cancer center. It

2610-402: Is the mixture of blood cells contributed by distinct hematopoietic stem cell clones during the organism's lifetime. The process of blood formation ( hematopoiesis ) acts on the fixed repertoire of heterogeneous stem cell clones. According to the dogmatic view of stem cell homogeneity the lifespan of individual HSCs (defined as the time period for which an HSC can divide without differentiation)

2700-1271: Is the process by which all mature blood cells are produced. It must balance enormous production needs (the average person produces more than 500 billion blood cells every day) with the need to regulate the number of each blood cell type in the circulation. In vertebrates, the vast majority of hematopoiesis occurs in the bone marrow and is derived from a limited number of hematopoietic stem cells that are multipotent and capable of extensive self-renewal . Hematopoietic stem cells give rise to different types of blood cells, in lines called myeloid and lymphoid . Myeloid and lymphoid lineages both are involved in dendritic cell formation. Myeloid cells include monocytes , macrophages , neutrophils , basophils , eosinophils , erythrocytes , and megakaryocytes to platelets . Lymphoid cells include T cells , B cells , natural killer cells , and innate lymphoid cells . The definition of hematopoietic stem cell has developed since they were first discovered in 1961. The hematopoietic tissue contains cells with long-term and short-term regeneration capacities and committed multipotent , oligopotent , and unipotent progenitors. Hematopoietic stem cells constitute 1:10,000 of cells in myeloid tissue . HSC transplants are used in

2790-405: Is the property which distinguishes hematopoietic stem cells from all other blood cell types. For their work on hematopoietic stem cell purification, Muller-Sieburg and collaborators were awarded a United States patent. Muller-Sieburg was one of the first to recognize the need of maintaining HSC multi-lineage and self-renewal potentials while propagating HSCs in vitro . A sequence of publications in

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2880-509: Is thought to occur in the stem cell niche in the bone marrow, and it is reasonable to assume that key signals present in this niche will be important in self-renewal. There is much interest in the environmental and molecular requirements for HSC self-renewal, as understanding the ability of HSC to replenish themselves will eventually allow the generation of expanded populations of HSC in vitro that can be used therapeutically. Hematopoietic stem cells, like all adult stem cells , mostly exist in

2970-655: Is very small. By corollary, this result shows that the hematopoietic stem cell compartment is also heterogeneous by dynamical criteria. It was originally believed that all hematopoietic stem cells were alike in their self-renewal and differentiation abilities. This view was first challenged by the 2002 discovery by the Muller-Sieburg group in San Diego, who illustrated that different stem cells can show distinct repopulation patterns that are epigenetically predetermined intrinsic properties of clonal Thy-1 Sca-1 lin c-kit HSC. The results of these clonal studies led to

3060-498: The B cell precursor problem. The results of their collaboration were reported in a joint paper, describing for the first time the isolation of an early committed pre-pre-B cell along with the discovery of a hematopoietic stem cell population expressing low levels of Thy-1 antigen. The marker Thy-1(low) was crucial to establishing the exclusion criteria for the purification of HSCs. In 1986, Muller-Sieburg and her husband moved to La Jolla , California , where she continued her work on

3150-811: The University of Cologne . She completed her studies under the guidance of Klaus Rajewsky in 1978 with a diploma thesis in immunology entitled "Investigations concerning the Class Specificity of the Fc-Receptor on Murine Lymphocytes Using Monoclonal Antibodies" at the Institut für Genetik. She received her doctorate in the natural sciences in 1983 with a dissertation entitled "Regulation of the Expression of Idiotopic Antibodies by Isotype Variants of Monoclonal Anti-Idiotopic Antibodies" (advisor: Klaus Rajewsky ). Muller-Sieburg married Hans B. Sieburg,

3240-569: The Western Association of Schools and Colleges . Sanford Burnham Prebys also employs postdoctoral fellows; there are typically around 125 postdocs training at the Institute at any time. The graduate school is focused in biomedical research and is supplemented by the technologies developed to facilitate breakthroughs in medical practice. The program offers a foundation in biomedical science with project opportunities in biology, chemistry, bioinformatics and engineering, with focus on one of

3330-415: The liver or spleen and develop. This enables Hematopoietic stem cells to be harvested directly from the blood. Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells , usually derived from bone marrow, peripheral blood, or umbilical cord blood. It may be autologous (the patient's own stem cells are used), allogeneic (the stem cells come from

3420-501: The 1980s, the Institute became known for its work on fibronectin and other extracellular matrix components, and cell adhesion . Some of the highlights include the discovery of the RGD tripeptide as the cell attachment site in fibronectin, fibrinogen, and other adhesive proteins, and the discovery of integrins, the cell surface receptors that recognize the RGD sequence in matrix proteins. In

3510-453: The 1990s established Muller-Sieburg as a pioneer of stromal-stem cell culture methodology. In the course of this work, Muller-Sieburg noticed that the frequency of HSCs - a measure of proliferative capacity - is under genetic control. In a 1996 landmark study, she and collaborators reported the discovery of the hematopoietic stem cell frequency gene on chromosome 1 in the murine system, which they named Scfr1 (stem cell frequency regulator 1). In

3600-407: The 1990s, Institute scientists made important contributions to research on programmed cell death prominence with the discovery of several previously unknown pro- and anti-apoptotic proteins, namely caspases , IAPs, and Bcl-2 family members. The demonstration by Institute scientists that cells deprived of attachment to extracellular matrix commit suicide by apoptosis , named Anoikis , connected

3690-461: The Goodell group provided additional insights about the molecular basis of lineage bias in side population (SP) SCA-1 lin c-kit HSC. As previously shown for IL-7 signaling, it was found that a member of the transforming growth factor family (TGF-beta) induces and inhibits the proliferation of My-bi and Ly-bi HSC, respectively. From Greek haimato- , combining form of haima 'blood', and from

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3780-758: The Latinized form of Greek poietikos 'capable of making, creative, productive', from poiein 'to make, create'. Sanford Burnham Prebys 32°54′04″N 117°14′31″W  /  32.901192°N 117.241937°W  / 32.901192; -117.241937 Sanford Burnham Prebys is a 501(c)(3) non-profit medical research institute focused on basic and translational research, with major research programs in cancer, neurodegeneration, diabetes, infectious, inflammatory, and childhood diseases. The institute also specializes in stem cell research and drug discovery technologies. The institute employs more than 500 scientists and staff at its campus in La Jolla, California. It

3870-660: The Sanford Burnham Prebys Science Network, the Office of Education, Training & International Services to cover an array of scientific career and professional development topics. William H. Fishman , M.D., Ph.D., and his wife, Lillian Waterman Fishman, founded the La Jolla Cancer Research Foundation in 1976 after retiring from Tufts University School of Medicine . The Foundation focused on onco-development,

3960-680: The Whittaker Corporation and the California Foundation enabled the acquisition a five-acre site on the La Jolla mesa. Donations from philanthropists and the institute's namesakes—T. Denny Sanford, Malin and Roberta Burnham, and Conrad Prebys—have helped to ensure the institute's continued growth. The Institute initially focused on the commonalities between cancer and fetal development, known as onco-developmental biology. Significant early discoveries include development of monoclonal antibody -based ‘two-site’ ELISA . In

4050-511: The blood of another individual HSC by (a) the lifespan of the underlying stem cell population and (b) the composition by blood cell types relative to each other. Her discovery demonstrated that, in fact, the opposite of the dogmatic view of stem cell homogeneity is the case. Namely, she showed that whole blood is the poly-clonal mixture of the hematopoietic systems generated and maintained by individual stem cells actively functioning during any given period of time. These results that whole blood

4140-494: The bone marrow before birth. Hematopoietic stem cell transplantation remains a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases. As survival following the procedure has increased, its use has expanded beyond cancer to autoimmune diseases and hereditary skeletal dysplasias ; notably malignant infantile osteopetrosis and mucopolysaccharidosis . Stem cells can be used to regenerate different types of tissues. HCT

4230-422: The cell adhesion and apoptosis fields. These findings essentially explained why normal cells stay in their appropriate place, whereas cancer cells spread and metastasize. Reduced integrin function in malignant cells makes it possible for them to leave their original tissue and increased expression of anti-apoptotic proteins prevents anoikis, enabling cancer invasion and metastasis. Several drugs have been brought to

4320-555: The cells that are floating loosely on top of the stromal cells are spherical and thus refractile. However, the cells that creep beneath the stromal cells are flattened and, thus, not refractile. The mechanism of pseudoemperipolesis is only recently coming to light. It may be mediated by interaction through CXCR4 (CD184) the receptor for CXC Chemokines (e.g., SDF1 ) and α4β1 integrins . Hematopoietic stem cells (HSC) cannot be easily observed directly, and, therefore, their behaviors need to be inferred indirectly. Clonal studies are likely

4410-498: The central open problems in hematopoiesis research, namely HSC “ fate decisions ". In vivo , at multiple million cell scales, " fate decisions " must occur reasonably fast and reliably to uphold all blood functions for extended periods of time. Muller-Sieburg's work showed that hematopoietic " decisions " occur on a largely deterministic basis, which is consistent with the demands for speed and reliability expected for host survival. Hematopoietic stem cells Haematopoiesis

4500-669: The characterization and maintenance of hematopoietic stem cells at the Eli Lilly Research Institute led by Dr. Jacques M. Chiller, while Hans Sieburg initially joined the laboratory of Melvin Cohn at the Salk Institute for Biological Studies and later, became faculty at the University of California, San Diego . In 1989, Muller-Sieburg became an independent group leader at the Medical Biology Institute in La Jolla, where she expanded her work on

4590-454: The circulating peripheral blood, blood donors are injected with a cytokine , such as granulocyte-colony stimulating factor (G-CSF), that induces cells to leave the bone marrow and circulate in the blood vessels. In mammalian embryology, the first definitive Hematopoietic stem cells are detected in the AGM ( aorta-gonad-mesonephros ), and then massively expanded in the fetal liver prior to colonising

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4680-406: The clinic for the treatment of cancer and other diseases based on the fundamental RGD/ integrin and apoptosis studies at the institute. More recently, the institute has expanded its research to several additional areas, including neuroscience , cardiovascular diseases , rare diseases of sugar and phosphate metabolism. The common trend is discovery of proteins that are linked to the development of

4770-424: The clonal composition of the HSC population, as manifested in the shift in bias classes of HSCs. Specifically, the proportion of the myeloid-biased HSCs is increased compared to the proportion of lymphoid-biased HSCs, while the proportion of balanced HSCs is near unchanged. This important conclusion may have significant implications to understanding the causes of the age-related immune deficiencies. Muller-Sieburg

4860-414: The clonal lifespan of HSCs can be predicted from repopulation kinetics. Muller-Sieburg's experimental work, therefore, establishes hematopoiesis as a new highly non-trivial challenge in chaos theory. Muller-Sieburg expanded her clonal studies to explore the correspondence between the long-term limit behavior of the hematopoietic process and the longevity of the host organism. Specifically, she wondered about

4950-435: The closest technique for single cell in vivo studies of HSC. Here, sophisticated experimental and statistical methods are used to ascertain that, with a high probability, a single HSC is contained in a transplant administered to a lethally irradiated host. The clonal expansion of this stem cell can then be observed over time by monitoring the percent donor-type cells in blood as the host is reconstituted. The resulting time series

5040-663: The combination of several different cell surface markers (particularly CD34 ) are used to separate the rare hematopoietic stem cells from the surrounding blood cells. Hematopoietic stem cells lack expression of mature blood cell markers and are thus called Lin-. Lack of expression of lineage markers is used in combination with detection of several positive cell-surface markers to isolate hematopoietic stem cells. In addition, hematopoietic stem cells are characterised by their small size and low staining with vital dyes such as rhodamine 123 (rhodamine ) or Hoechst 33342 (side population). Hematopoietic stem cells are essential to haematopoiesis,

5130-833: The country and in neighboring institutions to ensure the translational and human relevance of the research. Understanding how cells discriminate between functional and nonfunctional proteins. Discoveries about the damaging impact of oxidative stress on protein structure and function in the neurodegenerative diseases of Alzheimer's and Parkinson's, metabolic diseases of diabetes and liver failure, and inflammatory disease and cancer. Findings are translated into new therapies that improve protein folding and preserve cell function in diseases that have global health impact. Using model organisms—mice, fish, flies, worms and human stem cells to Research of new genetic disorders and improving understanding of those with previous knowledge. Using zebrafish, mouse models, patient cells and stem cell technologies, probe

5220-457: The discovery of quantitative determinants of clonal heterogeneity and the confirmation of Muller-Sieburg's conjecture that specific purification methods might restrict the repertoire of purified HSC, emphasizing that caution be taken in interpreting experimental results from a specific set of HSCs to be true for all HSCs This work laid the clonal foundations of modern hematology. Based on her experimental data, Muller-Sieburg suggested to replace

5310-485: The dogmatic view of the homogeneity of the stem cell population with the new concept of clonal diversity within the population of hematopoietic stem cells. She showed that the heterogeneity of the differentiation potential of adult hematopoietic stem cells is epigenetically fixed before birth and that no new heterogeneity of differentiation potential is introduced by self-renewal in postnatal hematopoiesis. Muller-Sieburg showed definitively that, therefore, an organism's blood

5400-591: The formation of the cells within blood. Hematopoietic stem cells can replenish all blood cell types (i.e., are multipotent ) and self-renew. A small number of hematopoietic stem cells can expand to generate a very large number of daughter hematopoietic stem cells. This phenomenon is used in bone marrow transplantation , when a small number of hematopoietic stem cells reconstitute the hematopoietic system. This process indicates that, subsequent to bone marrow transplantation, symmetrical cell divisions into two daughter hematopoietic stem cells must occur. Stem cell self-renewal

5490-744: The founder HSC. By comparing the intra-clonal kinetics of the leukocyte sub-populations, Muller-Sieburg showed that all hematopoietic stem cells belong to and stay for life in one of three classes of repopulation kinetics : Myeloid-biased (My-bi), Balanced or Lymphoid-biased (Ly-bi). Thus, an unexpected organization of HSC differentiation behaviors was discovered, leading to the principle of lineage bias established by Muller-Sieburg in collaboration with Hans Sieburg. Most theories of hematopoiesis assume that self-renewal and differentiation of hematopoietic stem cells (HSCs) are randomly regulated by intrinsic and environmental influences. Opposite to this "stochastic" view, Muller-Sieburg showed that random regulation

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5580-450: The gradual loss of active Hematopoietic stem cells in the blood system. Hematopoietic stem cells have a higher potential than other immature blood cells to pass the bone marrow barrier , and, thus, may travel in the blood from the bone marrow in one bone to another bone. If they settle in the thymus , they may develop into T cells . In the case of fetuses and other extramedullary hematopoiesis . Hematopoietic stem cells may also settle in

5670-438: The growth and metastasis of solid and hematologic malignancies. Focus on the microbiome, cell migration/invasion, cell signaling, angiogenesis and immunology. In addition to its research mission, Sanford Burnham Prebys has a broad educational mission. Established in 2005, the institute's Graduate School of Biomedical Sciences offers a Ph.D. degree in Biomedical Sciences. In 2015, Sanford Burnham Prebys achieved accreditation with

5760-400: The institute adopted the name Sanford-Burnham Medical Research Institute following a $ 50 million pledge of support from Sanford. An anonymous gift of $ 275 million was made in 2014, which was later cut to $ 200 million. In 2015, the institute changed its name again to Sanford Burnham Prebys Medical Discovery Institute following a $ 100 million gift from philanthropist Conrad Prebys . This

5850-585: The laboratory of Irving Weissman at the Stanford University Medical Center , while H. Sieburg worked and taught at the Stanford Mathematics Department. Muller-Sieburg's research at Weissman's lab was focused on the identification of a common cell precursor for both T cells and B cells . She worked closely with Cheryl Ann Whitlock, who came to Weissman's lab from Owen Witte 's lab also to work on

5940-440: The longer-lived myeloid-biased HSCs, which accumulate in the aged organism. Importantly, myeloid-biased (My-bi) HSCs from young and aged sources behave similarly in all aspects tested, indicating that organism aging does not change individual HSCs. Rather, aging (defined as "the totality of observable effects in an entity surviving in the long-term time limit relative to the behavior of the same observables at earlier times") changes

6030-468: The main foundations of biomedical science within a laboratory specializing in the area. It is a small program with eight openings per year and a steady state of thirty students. Entering graduate students are admitted to their thesis labs on day one and do not perform laboratory rotations. The graduate school has a short time to degree, averaging 4.7 years. In. the first two years, students complete five core courses, six tutorials and one elective. Instruction

6120-400: The normal life expectancy of the host. These results allowed Muller-Sieburg to establish the clonal lifespan as a quantitative measure of the reliability of self-renewal capacity. At the same time, consistent with clonal heterogeneity, she showed that the differentiation capacity of individual HSCs is (a) limited and (b) dependent on the clone founder. Therefore, Muller-Sieburg also established

6210-1008: The notion of lineage bias . Using the ratio ρ = L / M {\displaystyle \rho =L/M} of lymphoid (L) to myeloid (M) cells in blood as a quantitative marker, the stem cell compartment can be split into three categories of HSC. Balanced (Bala) hematopoietic stem cells repopulate peripheral white blood cells in the same ratio of myeloid to lymphoid cells as seen in unmanipulated mice (on average about 15% myeloid and 85% lymphoid cells, or 3 ≤ ρ ≤ 10). Myeloid-biased (My-bi) hematopoietic stem cells give rise to very few lymphocytes resulting in ratios 0 < ρ < 3, while lymphoid-biased (Ly-bi) hematopoietic stem cells generate very few myeloid cells, which results in lymphoid-to-myeloid ratios of ρ > 10. All three types are normal types of HSC, and they do not represent stages of differentiation. Rather, these are three classes of HSC, each with an epigenetically fixed differentiation program. These studies also showed that lineage bias

6300-464: The other hand, when in vitro , lymphoid lineage cells creep beneath nurse-like cells , the process is called pseudoemperipolesis . This similar phenomenon is more commonly known in the HSC field by the cell culture terminology cobble stone area-forming cells (CAFC) , which means areas or clusters of cells look dull cobblestone -like under phase contrast microscopy, compared to the other hematopoietic stem cells, which are refractile. This happens because

6390-464: The pathological mechanisms of genetic disorders to address unanswered questions. This research has led to diagnostic tests and novel therapies for patients. Research to understand the regulation and interplay of host immune responses and microbial pathogenesis; also studying viral-host interactions, innate and humoral immunity, inflammation and T cell checkpoint regulation. This research provides therapeutic opportunities to address medical needs, including

6480-409: The placenta, yolk sac, embryonic head, and fetal liver. Stem and progenitor cells can be taken from the pelvis, at the iliac crest, using a needle and syringe. The cells can be removed as liquid (to perform a smear to look at the cell morphology) or they can be removed via a core biopsy (to maintain the architecture or relationship of the cells to each other and to the bone). A colony-forming unit

6570-472: The possible dualism of "aged organism" and "old HSCs". Following her own, strict biological definition of HSC aging as intrinsic to the hematopoietic system, she showed that the answer to the dualism problem lies in the long-term dynamics of clonal aging of individual HSCs in the context of the clonal composition of an aging hematopoietic system. The clonal analysis of repopulating HSCs demonstrated that lymphoid-biased (Ly-bi) HSCs are lost earlier compared to

6660-594: The process of hematopoiesis . Muller-Sieburg was a co-discoverer of the negative marker set of hematopoietic stem cells that led to the modern purification techniques widely used in hematopoietic stem cell research today. She was the first to demonstrate the biased differentiation behavior of individual stem cell clones, thereby sparking a novel and entirely original view of hematopoiesis . Muller-Sieburg received her Abitur in 1972 in Bonn , West Germany . The same year, she moved to Köln to begin her studies in biology at

6750-494: The purification and maintenance of hematopoietic stem cells via long-term bone marrow cultures – a technique she had developed in collaboration with Cheryl Whitlock, George F Tidmarsh and Irving Weissman at Stanford. By using this technique, Muller Sieburg and Elena Deryugina identified the growth factor, namely macrophage-colony stimulating factor (M-CSF) as a cytokine critical for the maintenance of stromal cell support for hematopoietic stem cells. Muller-Sieburg's recognition as

6840-426: The regulation of the isotype switch by anti-idiotype antibodies. This ground-breaking paper was recognized and cited by Niels K. Jerne in his Nobel Prize acceptance lecture on 8 December 1984. Muller-Sieburg accomplished separation of whole bone marrow into two fractions, the adherent and non-adherent fractions, and demonstrated that the latter fraction was the one that comprised B cell precursors. She found that it

6930-437: The science of blood. Based on her 1996 studies of the heterogeneity of the hematopoietic microenvironment, Muller-Sieburg increasingly doubted the then pervasive belief that "all stem cells are created equal", a view that, if true, would imply that blood is mono-clonal. To gain clarity, she followed the kinetics of individual HSCs and showed that blood generated by one individual hematopoietic stem cell differs significantly from

7020-423: The spleens of irradiated mice after 8 to 12 days. It was used extensively in early studies, but is now considered to measure more mature progenitor or transit-amplifying cells rather than stem cells . Since hematopoietic stem cells cannot be isolated as a pure population, it is not possible to identify them in a microscope. Hematopoietic stem cells can be identified or isolated by the use of flow cytometry where

7110-525: The study of developmental biology in conjunction with oncology . In 1996, the foundation was renamed the Burnham Institute in honor of San Diego businessman Malin Burnham after he joined with an anonymous donor to contribute $ 10 million; in 2006, it was renamed the Burnham Institute for Medical Research. In 2007, T. Denny Sanford gave the institute $ 20 million through Sanford Health ,

7200-599: The study of the biology of ageing that includes the Salk Institute for Biological Studies and the University of California, San Diego is made up of Sanford Burnham Prebys and the San Diego Nathan Shock Center. There are seven research programs at Sanford Burnham Prebys: Insights into the complex system of networks and mechanisms that tumors use to survive and proliferate. Findings build dialogue with clinicians and physician scientists across

7290-556: The symbols "+", "-", "~" whenever two successive measurements of the percent donor-type cells have a positive, negative, or unchanged slope, respectively. By using the Hamming distance , the repopulation patterns were subjected to cluster analysis yielding 16 distinct groups of kinetics. To finish the empirical proof, the Laplace add-one approach was used to determine that the probability of finding kinetics not contained in these 16 groups

7380-624: The top 3% of research institutes in the United States in National Institutes of Health grant funding. Research staff in Sanford Burnham Prebys’ laboratories numbers over 520 including postdoctoral researchers; an additional 30 graduate students and 164 administrative and support personnel to bring the total number of employees to over 500. The institute is home to six research centers: A partnership for

7470-467: The treatment of cancers and other immune system disorders due to their regenerative properties. They are round, non-adherent, with a rounded nucleus and low cytoplasm-to-nucleus ratio. In shape, hematopoietic stem cells resemble lymphocytes . The very first hematopoietic stem cells during (mouse and human) embryonic development are found in aorta-gonad-mesonephros region and the vitelline and umbilical arteries. Slightly later, HSCs are also found in

7560-427: The treatment of endemic and pandemic infectious diseases, autoimmune disorders, cancer and inflammatory diseases. Focus on RNA biology and the signaling pathways that regulate cell growth and cell fate; what drives cancer cell growth, to lead to treatments for brain, breast and prostate cancers, as well as melanoma and leukemia. Studies the interplay between cancer cells, the microenvironment and immune cells regulates

7650-441: The variability in differentiation capacity as a quantitative measure of clonal heterogeneity and clonal lifespan. Furthermore, Muller-Sieburg's clonal experiments showed that the life of a hematopoietic stem cell (clone) is highly dependent on the initial conditions given by the epigenetically fixed differentiation and self-renewal capacities of each clone founding HSC. Muller-Sieburg showed that murine hematopoietic stem cells form

7740-771: Was an early adopter and promoter of the use of abstract mathematics in the field of experimental hematology. In collaboration with Hans Sieburg, this approach proved particularly fruitful in her experimental studies of  HSC clonality. For example, the classification of kinetics or the prediction of lifespans from short initial kinetics or the reliability of self-renewal required symbolic computation , reliability theory and functional programming . Muller-Sieburg generously provided data for other modeling studies and engaged in correspondence discussions of deep principles of modeling hematopoiesis. The important outcomes of Muller-Sieburg's clonal diversity experiments are time-series, which are invaluable in computational research addressing one of

7830-548: Was assumed to be approximately the same. However, Muller-Sieburg experiments demonstrated that the longevity of hematopoietic stem cell clones differed dramatically. Specifically, she showed that clonal bloods became deficient in one or more cell types – a definitive observable of the extinction of their clone-maintaining stem cell population – after significantly different lengths of time. Some of these clone-maintaining hematopoietic stem cells survived multiple sequential in vitro - in vivo transplantations, which exceeded several times

7920-466: Was eventually shortened to its current name, Sanford Burnham Prebys In 2022, David Brenner, M.D., former vice chancellor for Health Sciences at UC San Diego , was named president and chief executive office of the institute. Sanford Burnham Prebys was founded with its primary focus on cancer research. The Institute ranks consistently among the world's top 25 organizations for its research impact, according to Thomson Scientific data. It also ranks among

8010-712: Was frequently invited to national and international conferences and symposia. Muller-Sieburg gave her last invited lecture "The Life of a Hematopoietic Stem Cell" at the Keystone Symposium "The Life of a Stem Cell: From Birth to Death" in March 2012. In 2013, the Christa Muller-Sieburg award was named after her by the International Society of Experimental Hematology. While working at the University of Cologne , Muller-Sieburg addressed

8100-543: Was not the B220 -positive fraction that contained B-cell precursors as was expected, but the B220 -negative fraction. She confirmed that B220+ cells were too late in the lineage to make B cells let alone T cells and myeloid cell types. Importantly, this B220-negative population was enriched for cells that were capable of reconstituting all types of blood cells for life when transplanted into lethally irradiated hosts ("complete repopulation capacity"). Complete repopulation capacity

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