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Infertility is a major reproductive health issue that affects about 12% of women of reproductive age in the United States. Aneuploidy in eggs accounts for a significant proportion of early miscarriage and in vitro fertilization failure. Recent studies have shown that genetic variants in several genes affect chromosome segregation fidelity and predispose women to a higher incidence of egg aneuploidy. However, the exact genetic causes of aneuploid egg production remain unclear, making it difficult to diagnose infertility based on individual genetic variants in mother’s genome. Although, age is a predictive factor for aneuploidy, it is not a highly accurate gauge because aneuploidy rates within individuals of the same age can vary dramatically.
Researchers described a technique combining genomic sequencing with machine-learning methods to predict the possibility a woman will undergo a miscarriage because of egg aneuploidy—a term describing a human egg with an abnormal number of chromosomes. The scientists were able to examine genetic samples of patients using a technique called “whole exome sequencing,” which allowed researchers to home in on the protein coding sections of the vast human genome. Then they created software using machine learning, an aspect of artificial intelligence in which programs can learn and make predictions without following specific instructions. To do so, the researchers developed algorithms and statistical models that analyzed and drew inferences from patterns in the genetic data.
As a result, the scientists were able to create a specific risk score based on a woman’s genome. The scientists also identified three genes—MCM5, FGGY and DDX60L—that when mutated and are highly associated with a risk of producing eggs with aneuploidy. So, the report demonstrated that sequencing data can be mined to predict patients’ aneuploidy risk thus improving clinical diagnosis. The candidate genes and pathways that were identified in the present study are promising targets for future aneuploidy studies. Identifying genetic variations with more predictive power will serve women and their treating clinicians with better information.
Thriving Vaccines and Research: Weizmann Institute Coronavirus Research Development
Reporter:Amandeep Kaur, B.Sc., M.Sc.
In early February, Prof. Eran Segal updated in one of his tweets and mentioned that “We say with caution, the magic has started.”
The article reported that this statement by Prof. Segal was due to decreasing cases of COVID-19, severe infection cases and hospitalization of patients by rapid vaccination process throughout Israel. Prof. Segal emphasizes in another tweet to remain cautious over the country and informed that there is a long way to cover and searching for scientific solutions.
A daylong webinar entitled “COVID-19: The epidemic that rattles the world” was a great initiative by Weizmann Institute to share their scientific knowledge about the infection among the Israeli institutions and scientists. Prof. Gideon Schreiber and Dr. Ron Diskin organized the event with the support of the Weizmann Coronavirus Response Fund and Israel Society for Biochemistry and Molecular Biology. The speakers were invited from the Hebrew University of Jerusalem, Tel-Aviv University, the Israel Institute for Biological Research (IIBR), and Kaplan Medical Center who addressed the molecular structure and infection biology of the virus, treatments and medications for COVID-19, and the positive and negative effect of the pandemic.
The article reported that with the emergence of pandemic, the scientists at Weizmann started more than 60 projects to explore the virus from different range of perspectives. With the help of funds raised by communities worldwide for the Weizmann Coronavirus Response Fund supported scientists and investigators to elucidate the chemistry, physics and biology behind SARS-CoV-2 infection.
Prof. Avi Levy, the coordinator of the Weizmann Institute’s coronavirus research efforts, mentioned “The vaccines are here, and they will drastically reduce infection rates. But the coronavirus can mutate, and there are many similar infectious diseases out there to be dealt with. All of this research is critical to understanding all sorts of viruses and to preempting any future pandemics.”
The following are few important projects with recent updates reported in the article.
Mapping a hijacker’s methods
Dr. Noam Stern-Ginossar studied the virus invading strategies into the healthy cells and hijack the cell’s systems to divide and reproduce. The article reported that viruses take over the genetic translation system and mainly the ribosomes to produce viral proteins. Dr. Noam used a novel approach known as ‘ribosome profiling’ as her research objective and create a map to locate the translational events taking place inside the viral genome, which further maps the full repertoire of viral proteins produced inside the host.
She and her team members grouped together with the Weizmann’s de Botton Institute and researchers at IIBR for Protein Profiling and understanding the hijacking instructions of coronavirus and developing tools for treatment and therapies. Scientists generated a high-resolution map of the coding regions in the SARS-CoV-2 genome using ribosome-profiling techniques, which allowed researchers to quantify the expression of vital zones along the virus genome that regulates the translation of viral proteins. The study published in Nature in January, explains the hijacking process and reported that virus produces more instruction in the form of viral mRNA than the host and thus dominates the translation process of the host cell. Researchers also clarified that it is the misconception that virus forced the host cell to translate its viral mRNA more efficiently than the host’s own translation, rather high level of viral translation instructions causes hijacking. This study provides valuable insights for the development of effective vaccines and drugs against the COVID-19 infection.
Like chutzpah, some things don’t translate
Prof. Igor Ulitsky and his team worked on untranslated region of viral genome. The article reported that “Not all the parts of viral transcript is translated into protein- rather play some important role in protein production and infection which is unknown.” This region may affect the molecular environment of the translated zones. The Ulitsky group researched to characterize that how the genetic sequence of regions that do not translate into proteins directly or indirectly affect the stability and efficiency of the translating sequences.
Initially, scientists created the library of about 6,000 regions of untranslated sequences to further study their functions. In collaboration with Dr. Noam Stern-Ginossar’s lab, the researchers of Ulitsky’s team worked on Nsp1 protein and focused on the mechanism that how such regions affect the Nsp1 protein production which in turn enhances the virulence. The researchers generated a new alternative and more authentic protocol after solving some technical difficulties which included infecting cells with variants from initial library. Within few months, the researchers are expecting to obtain a more detailed map of how the stability of Nsp1 protein production is getting affected by specific sequences of the untranslated regions.
The landscape of elimination
The article reported that the body’s immune system consists of two main factors- HLA (Human Leukocyte antigen) molecules and T cells for identifying and fighting infections. HLA molecules are protein molecules present on the cell surface and bring fragments of peptide to the surface from inside the infected cell. These peptide fragments are recognized and destroyed by the T cells of the immune system. Samuels’ group tried to find out the answer to the question that how does the body’s surveillance system recognizes the appropriate peptide derived from virus and destroy it. They isolated and analyzed the ‘HLA peptidome’- the complete set of peptides bound to the HLA proteins from inside the SARS-CoV-2 infected cells.
After the analysis of infected cells, they found 26 class-I and 36 class-II HLA peptides, which are present in 99% of the population around the world. Two peptides from HLA class-I were commonly present on the cell surface and two other peptides were derived from coronavirus rare proteins- which mean that these specific coronavirus peptides were marked for easy detection. Among the identified peptides, two peptides were novel discoveries and seven others were shown to induce an immune response earlier. These results from the study will help to develop new vaccines against new coronavirus mutation variants.
Gearing up ‘chain terminators’ to battle the coronavirus
Prof. Rotem Sorek and his lab discovered a family of enzymes within bacteria that produce novel antiviral molecules. These small molecules manufactured by bacteria act as ‘chain terminators’ to fight against the virus invading the bacteria. The study published in Nature in January which reported that these molecules cause a chemical reaction that halts the virus’s replication ability. These new molecules are modified derivates of nucleotide which integrates at the molecular level in the virus and obstruct the works.
Prof. Sorek and his group hypothesize that these new particles could serve as a potential antiviral drug based on the mechanism of chain termination utilized in antiviral drugs used recently in the clinical treatments. Yeda Research and Development has certified these small novel molecules to a company for testing its antiviral mechanism against SARS-CoV-2 infection. Such novel discoveries provide evidences that bacterial immune system is a potential repository of many natural antiviral particles.
Resolving borderline diagnoses
Currently, Real-time Polymerase chain reaction (RT-PCR) is the only choice and extensively used for diagnosis of COVID-19 patients around the globe. Beside its benefits, there are problems associated with RT-PCR, false negative and false positive results and its limitation in detecting new mutations in the virus and emerging variants in the population worldwide. Prof. Eran Elinavs’ lab and Prof. Ido Amits’ lab are working collaboratively to develop a massively parallel, next-generation sequencing technique that tests more effectively and precisely as compared to RT-PCR. This technique can characterize the emerging mutations in SARS-CoV-2, co-occurring viral, bacterial and fungal infections and response patterns in human.
The scientists identified viral variants and distinctive host signatures that help to differentiate infected individuals from non-infected individuals and patients with mild symptoms and severe symptoms.
In Hadassah-Hebrew University Medical Center, Profs. Elinav and Amit are performing trails of the pipeline to test the accuracy in borderline cases, where RT-PCR shows ambiguous or incorrect results. For proper diagnosis and patient stratification, researchers calibrated their severity-prediction matrix. Collectively, scientists are putting efforts to develop a reliable system that resolves borderline cases of RT-PCR and identify new virus variants with known and new mutations, and uses data from human host to classify patients who are needed of close observation and extensive treatment from those who have mild complications and can be managed conservatively.
Moon shot consortium refining drug options
The ‘Moon shot’ consortium was launched almost a year ago with an initiative to develop a novel antiviral drug against SARS-CoV-2 and was led by Dr. Nir London of the Department of Chemical and Structural Biology at Weizmann, Prof. Frank von Delft of Oxford University and the UK’s Diamond Light Source synchroton facility.
To advance the series of novel molecules from conception to evidence of antiviral activity, the scientists have gathered support, guidance, expertise and resources from researchers around the world within a year. The article reported that researchers have built an alternative template for drug-discovery, full transparency process, which avoids the hindrance of intellectual property and red tape.
The new molecules discovered by scientists inhibit a protease, a SARS-CoV-2 protein playing important role in virus replication. The team collaborated with the Israel Institute of Biological Research and other several labs across the globe to demonstrate the efficacy of molecules not only in-vitro as well as in analysis against live virus.
Further research is performed including assaying of safety and efficacy of these potential drugs in living models. The first trial on mice has been started in March. Beside this, additional drugs are optimized and nominated for preclinical testing as candidate drug.
Use of 3D Bioprinting for Development of Toxicity Prediction Models
Curator: Stephen J. Williams, PhD
SOT FDA Colloquium on 3D Bioprinted Tissue Models: Tuesday, April 9, 2019
The Society of Toxicology (SOT) and the U.S. Food and Drug Administration (FDA) will hold a workshop on “Alternative Methods for Predictive Safety Testing: 3D Bioprinted Tissue Models” on Tuesday, April 9, at the FDA Center for Food Safety and Applied Nutrition in College Park, Maryland. This workshop is the latest in the series, “SOT FDA Colloquia on Emerging Toxicological Science: Challenges in Food and Ingredient Safety.”
Human 3D bioprinted tissues represent a valuable in vitro approach for chemical, personal care product, cosmetic, and preclinical toxicity/safety testing. Bioprinting of skin, liver, and kidney is already appearing in toxicity testing applications for chemical exposures and disease modeling. The use of 3D bioprinted tissues and organs may provide future alternative approaches for testing that may more closely resemble and simulate intact human tissues to more accurately predict human responses to chemical and drug exposures.
A synopsis of the schedule and related works from the speakers is given below:
8:40 AM–9:20 AM
Overview and Challenges of Bioprinting
Sharon Presnell, Amnion Foundation, Winston-Salem, NC
9:20 AM–10:00 AM
Putting 3D Bioprinting to the Use of Tissue Model Fabrication
Y. Shrike Zhang, Brigham and Women’s Hospital, Harvard Medical School and Harvard-MIT Division of Health Sciences and Technology, Boston, MA
10:00 AM–10:20 AM
Break
10:20 AM–11:00 AM
Uses of Bioprinted Liver Tissue in Drug Development
Jean-Louis Klein, GlaxoSmithKline, Collegeville, PA
11:00 AM–11:40 AM
Biofabrication of 3D Tissue Models for Disease Modeling and Chemical Screening
Marc Ferrer, National Center for Advancing Translational Sciences, NIH, Rockville, MD
Dr. Sharon Presnell was most recently the Chief Scientific Officer at Organovo, Inc., and the President of their wholly-owned subsidiary, Samsara Sciences. She received a Ph.D. in Cell & Molecular Pathology from the Medical College of Virginia and completed her undergraduate degree in biology at NC State. In addition to her most recent roles, Presnell has served as the director of cell biology R&D at Becton Dickinson’s corporate research center in RTP, and as the SVP of R&D at Tengion. Her roles have always involved the commercial and clinical translation of basic research and early development in the cell biology space. She serves on the board of the Coulter Foundation at the University of Virginia and is a member of the College of Life Sciences Foundation Board at NC State. In January 2019, Dr. Presnell will begin a new role as President of the Amnion Foundation, a non-profit organization in Winston-Salem.
Integrating Kupffer cells into a 3D bioprinted model of human liver recapitulates fibrotic responses of certain toxicants in a time and context dependent manner. This work establishes that the presence of Kupffer cells or macrophages are important mediators in fibrotic responses to certain hepatotoxins and both should be incorporated into bioprinted human liver models for toxicology testing.
Abstract: Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM). Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first timedemonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.
A great interview with Dr. Presnell and the 3D Models 2017 Symposium is located here:
Please clickhere for Web based and PDF version of interview
Some highlights of the interview include
Exciting advances in field showing we can model complex tissue-level disease-state phenotypes that develop in response to chronic long term injury or exposure
Sees the field developing a means to converge both the biology and physiology of tissues, namely modeling the connectivity between tissues such as fluid flow
Future work will need to be dedicated to develop comprehensive analytics for 3D tissue analysis. As she states “we are very conditioned to get information in a simple way from biochemical readouts in two dimension, monocellular systems” however how we address the complexity of various cellular responses in a 3D multicellular environment will be pertinent.
Additional challenges include the scalability of such systems and making such system accessible in a larger way
Shrike Zhang, Brigham and Women’s Hospital, Harvard Medical School and Harvard-MIT Division of Health Sciences and Technology
Dr. Zhang currently holds an Assistant Professor position at Harvard Medical School and is an Associate Bioengineer at Brigham and Women’s Hospital. His research interests include organ-on-a-chip, 3D bioprinting, biomaterials, regenerative engineering, biomedical imaging, biosensing, nanomedicine, and developmental biology. His scientific contributions have been recognized by >40 international, national, and regional awards. He has been invited to deliver >70 lectures worldwide, and has served as reviewer for >400 manuscripts for >30 journals. He is serving as Editor-in-Chief for Microphysiological Systems, and Associate Editor for Bio-Design and Manufacturing. He is also on Editorial Board of Bioprinting, Heliyon, BMC Materials, and Essays in Biochemistry, and on Advisory Panel of Nanotechnology.
Skardal A, Murphy SV, Devarasetty M, Mead I, Kang HW, Seol YJ, Shrike Zhang Y, Shin SR, Zhao L, Aleman J, Hall AR, Shupe TD, Kleensang A, Dokmeci MR, Jin Lee S, Jackson JD, Yoo JJ, Hartung T, Khademhosseini A, Soker S, Bishop CE, Atala A.
Sci Rep. 2017 Aug 18;7(1):8837. doi: 10.1038/s41598-017-08879-x.
Bhise NS, Manoharan V, Massa S, Tamayol A, Ghaderi M, Miscuglio M, Lang Q, Shrike Zhang Y, Shin SR, Calzone G, Annabi N, Shupe TD, Bishop CE, Atala A, Dokmeci MR, Khademhosseini A.
Biofabrication. 2016 Jan 12;8(1):014101. doi: 10.1088/1758-5090/8/1/014101.
Marc Ferrer, National Center for Advancing Translational Sciences, NIH
Marc Ferrer is a team leader in the NCATS Chemical Genomics Center, which was part of the National Human Genome Research Institute when Ferrer began working there in 2010. He has extensive experience in drug discovery, both in the pharmaceutical industry and academic research. Before joining NIH, he was director of assay development and screening at Merck Research Laboratories. For 10 years at Merck, Ferrer led the development of assays for high-throughput screening of small molecules and small interfering RNA (siRNA) to support programs for lead and target identification across all disease areas.
At NCATS, Ferrer leads the implementation of probe development programs, discovery of drug combinations and development of innovative assay paradigms for more effective drug discovery. He advises collaborators on strategies for discovering small molecule therapeutics, including assays for screening and lead identification and optimization. Ferrer has experience implementing high-throughput screens for a broad range of disease areas with a wide array of assay technologies. He has led and managed highly productive teams by setting clear research strategies and goals and by establishing effective collaborations between scientists from diverse disciplines within industry, academia and technology providers.
Ferrer has a Ph.D. in biological chemistry from the University of Minnesota, Twin Cities, and completed postdoctoral training at Harvard University’s Department of Molecular and Cellular Biology. He received a B.Sc. degree in organic chemistry from the University of Barcelona in Spain.
Wilson KM, Mathews-Griner LA, Williamson T, Guha R, Chen L, Shinn P, McKnight C, Michael S, Klumpp-Thomas C, Binder ZA, Ferrer M, Gallia GL, Thomas CJ, Riggins GJ.
SLAS Technol. 2019 Feb;24(1):28-40. doi: 10.1177/2472630318803749. Epub 2018 Oct 5.
The CRISPR-Cas9 system has proven to be a powerful tool for genome editing allowing for the precise modification of specific DNA sequences within a cell. Many efforts are currently underway to use the CRISPR-Cas9 system for the therapeutic correction of human genetic diseases. CRISPR/Cas9 has revolutionized our ability to engineer genomes and conduct genome-wide screens in human cells.
CRISPR–Cas9 induces a p53-mediated DNA damage response and cell cycle arrest in immortalized human retinal pigment epithelial cells, leading to a selection against cells with a functional p53 pathway. Inhibition of p53 prevents the damage response and increases the rate of homologous recombination from a donor template. These results suggest that p53 inhibition may improve the efficiency of genome editing of untransformed cells and that p53 function should be monitored when developing cell-based therapies utilizing CRISPR–Cas9.
Whereas some cell types are amenable to genome engineering, genomes of human pluripotent stem cells (hPSCs) have been difficult to engineer, with reduced efficiencies relative to tumour cell lines or mouse embryonic stem cells. Using hPSC lines with stable integration of Cas9 or transient delivery of Cas9-ribonucleoproteins (RNPs), an average insertion or deletion (indel) efficiency greater than 80% was achieved. This high efficiency of insertion or deletion generation revealed that double-strand breaks (DSBs) induced by Cas9 are toxic and kill most hPSCs.
The toxic response to DSBs was P53/TP53-dependent, such that the efficiency of precise genome engineering in hPSCs with a wild-type P53 gene was severely reduced. These results indicate that Cas9 toxicity creates an obstacle to the high-throughput use of CRISPR/Cas9 for genome engineering and screening in hPSCs. As hPSCs can acquire P53 mutations, cell replacement therapies using CRISPR/Cas9-enginereed hPSCs should proceed with caution, and such engineered hPSCs should be monitored for P53 function.
CRISPR-based editing of T cells to treat cancer, as scientists at the University of Pennsylvania are studying in a clinical trial, should also not have a p53 problem. Nor should any therapy developed with CRISPR base editing, which does not make the double-stranded breaks that trigger p53. But, there are pre-existing humoral and cell-mediated adaptive immune responses to Cas9 in humans, a factor which must be taken into account as the CRISPR-Cas9 system moves forward into clinical trials.
Below, we report on the State of the Science for Overcoming Obstacles in Oncolytic Virus Delivery and provide the source for all the references used
ONCOLYTIC VIROTHERAPY FOR PANCREATIC CANCER
Adenovirus
ONYX-015 was the first TOV used in a clinical trial for pancreatic cancer. ONYX-015 was administered intratumourally under endoscopic ultrasound-guidance into patients with locally advanced adenocarcinoma of the pancreas or metastatic disease in phase I/II trials[132]. The treatment was well-tolerated in most patients, however no objective responses were seen with ONYX-015 as a single agent and only 2/21 patients experienced mild responses when combined with gemcitabine[132]. A second adenovirus vector carries a deletion in the E1A gene[133]. E1A normally binds to the retinoblastoma protein, forcing cells to prematurely enter the S phase of the cell cycle. Since most pancreatic cancers harbor a mutation in CDKN2A[134], the E1A protein is unnecessary for entry of the TOV into cancer cells. Furthermore a double-deleted (E1A and E1B19) adenovirus demonstrated increase potency and selectivity in pancreatic cancer models[135,136]. This demonstrates that TOVs can be genetically engineered to increase selectivity and efficacy while maintaining their potency. Adenovirus selectivity has also been improved by engineering tumour-specific promoters such as a human CEA promoter[137] or by substituting the adenovirus serotype 5 fiber knob with the fiber knob from serotype 3[138]. The potency of TOVs can also be improved further by engineering them with therapeutic genes that stimulate the immune system and/or improve direct oncolysis. Adenovirus ZD55-IL-24 expressing IL-24 locally in pancreatic tumours in immune competent mice inhibited tumour growth and induced a stronger T cell response compared to its backbone virus, as measured by IL-6 and IFN-γ levels[139].
HSV
Two oncolytic HSV-1 vectors are currently in clinical trials for the treatment of pancreatic cancer. HF10 is a non-engineered, naturally occurring oncolytic HSV that demonstrated regression in 1/6 of the patients treated[140,141]. OncoVex GM-CSF is a ∆34.5 and ICP47-deleted mutant expressing GM-CSF, whereby the deletions allow for tumour-selective replication and inhibition of protein-kinase R activation, respectively[142]. Phase I/II trials in various solid tumours demonstrated OncoVex GM-CSF to be well-tolerated at high and repeated doses[143,144]. A phase I clinical trial with OncoVex GM-CSF in patients with unresectable pancreatic cancer is underway.
Poxviruses
The most widely studied poxvirus is VV, which is highly immunogenic and produces a strong cytotoxic T cell response[145] and circulating neutralizing antibodies which can be detected decades later[146]. For its crucial role in the eradication of smallpox, much has been learned about its potential role in immunotherapy today. The Lister strain of vaccinia remarkably showed no replication degradation even under the hypoxic conditions of PDAC[147]. A second Lister strain, thymidine kinase-deleted replicating VV armed with IL-10 demonstrated superior and long-lasting antitumour immunity in both a subcutaneous pancreatic cancer model and a Kras-p53 mutant-transgenic pancreatic cancer model after systemic delivery compared to its unarmed backbone virus[148]. Myxoma virus, a rabbit-specific poxvirus combined with gemcitabine resulted in 100% long-term survival in Pan02-engrafted immunocompetent intraperitoneal dissemination models of pancreatic cancer[149]. The only poxvirus to be tested in clinical trials is a non-replicative VV that expresses the pancreatic TAAs CEA and MUC-2[150]. The vaccine also includes a triad of costimulatory molecules, B7.1 (CD80), ICAM-1 (intra-cellular adhesion molecule-1) and LFA-3 (leukocyte function-associated antigen-3) (TRICOM) (PANVAC-VF)[150]. GM-CSF was also used as an adjuvant following each vaccination of PANVAC-VF. Phase I trials demonstrated antigen-specific antitumour responses in 62.5% of patients enrolled and antibody responses against VV was observed in all ten patients, which was associated with an increase in survival (15.1 mo vs 3.9 mo)[48]. A phase III clinical trial for the treatment of metastatic pancreatic cancer after failing treatment with gemcitabine, however, was terminated after failing to reach its primary efficacy endpoint[151].
Other pre-clinical TOVs for pancreatic cancer therapy
Parvovirus, measles virus and reovirus have also demonstrated pre-clinical activity in pancreatic cancer models. Parvoviruses particularly demonstrated enhanced IL-2-activated NK responses against PDAC cells[152,153]. An armed measles virus (MV), MV-purine nucleoside phosphorylase (PNP)-anti-prostate stem cell antigen, that expresses the prodrug convertase PNP, which then activates the prodrug fludarabine, was shown to enhance the oncolytic efficacy of the virus in gemcitabine-resistant PDAC cells[154]. Reovirus is another promising TOV for pancreatic cancer therapy, particularly because its selectivity depends on the cellular activity of Ras, which is constitutively active in pancreatic cancer[155]. Reolysin® (Oncolytics Biotech Inc., Calgary, AB, Canada) a reovirus administered intraportally resulted in decreased metastatic tumour volumes in the liver of immunocompetent animal models[156,157]. A phase II study of Reolysin® in combination with gemcitabine in patients with advanced PDAC has been completed (clinicaltrials.gov: NCT00998322). A two-armed randomized phase II study of carboplatin and paclitaxel plus Reolysin®vs carboplatin and paclitaxel alone in recurrent or metastatic pancreatic cancer is currently being conducted by the United States National Cancer Institute (NCI-8601/OSU-10045).
A understanding how antitumour immunity is regulated allows us to recognize barriers against effective immunotherapy delivery and furthermore, allow for the development of rational combination therapies aiming targeting these mechanisms[108,158,159]. This approach allows therapies to work synergistically and also has the potential to benefit a broader patient population[108]. Tumours have evolved to avoid immune recognition and/or destruction at every stage in the antitumour response, therefore targeting more than one immune resistance mechanism will enhance antitumour immunity.
An important immunological barrier in cancer immunotherapy is the tolerance towards self-antigens. Tumours downregulate their antigenicity through various mechanisms in response to selective pressure by the immune system, a process called “immunoediting”[37]. Therefore, in order to raise an effective antitumour response, the immunological tolerance must be broken to allow tumour antigen-specific cytotoxic T cell responses[158]. This can be achieved by increasing the tumour load and/or enhance antigen presentation[108]. TOVs can initiate selective infection and replication in the tumour bed, exposing TAA, disrupting the immunotolerance employed by the tumour while re-engaging adaptive immune effector responses[39]. Combining an agent that can cause disruption to the tumour bed i.e., an oncolytic virus, with a novel antitumour immunomodulating agent such as anti-PD-1/PD-L1 antibodies can maximize immune-stimulating and immune-recruiting inflammatory responses[39]. Specifically, TOV lysis induces the release of tumour antigens into the microenvironment, which are then cross-presented to T cells in the draining lymph nodes by APCs[159] (Figure (Figure1).1). This allows T cell infiltration to the tumour bed. Next, T cell dysfunction must be reversed[108,158]. Immune checkpoint inhibitors alleviate immunosuppression, allowing the elimination of the tumour by the adaptive immune system[70]. TOVs in combination with immune checkpoint inhibitors can therefore potentiate and activate the immune system synergistically, ultimately creating a pro-inflammatory environment. Pre-existing TILs are strong prognostic predictors in cancer[106]. This is extremely relevant for tumours with poor immune-cell infiltration, such as pancreatic cancer, which would depend on TOV-infection mediated lymphocyte infiltration for an enhanced response to immune checkpoint blockade. Zamarin et al[160] demonstrated constrained replication of an intratumoural-injected Newcastle disease virus in a B16 melanoma model. Lymphocytic infiltrates, however, were detected in both TOV-injected and non-TOV-injected tumours, and rendered the tumours sensitive to CTLA-4 blockade. The antitumour activity was dependent on CD8+ T cells, NK cells and type I and II IFNs[160]. Ipilimumab with or without talimogene laherparapvec, is in early clinical testing in patients with unresected melanoma (clinicaltrials.org: NCT01740297). Interestingly, an MV engineered to express CTLA-4 or PD-L1 antibodies delayed tumour progression and prolonged median OS in B16 melanoma models[161]. Finally, TOVs have demonstrated a tolerable toxicity profile, whereby flu-like symptoms are the most common adverse events, and in fact, most of the side effects seen so far in the combination regiment are related to the immune checkpoint blockade inhibitor[162]. Dias et al[163] suggested an oncolytic adenovirus expressing CTLA-4 locally might reduce systemic side effects normally induced with anti-CTLA-4 antibodies alone.
OVERCOMING OBSTACLES IN ONCOLYTIC VIRUS DELIVERY
The main issue with virotherapy is systemic delivery for targeting metastatic cancer cells. Intravenous administration is more practical, especially for treatment of a tumour in a hard-to-reach location such as the pancreas, and with the majority of patients presenting with advanced or metastatic disease. However, nonimmune human serum and existing anti-TOV antibodies may neutralize the TOV in the bloodstream. Furthermore, non-specific hepatic and splenic sequestration of the TOV and ineffective extravasation into the tumours are important issues[164]. Currently, studies in pre-clinical models aim to overcome these obstacles. These include chemical modification of viral coat proteins by conjugation of biocompatible polymers e.g. polyethylene glycosylation[165,166], using mesenchymal stem cell carrier systems to deliver the TOV to the tumour bed[167–169], and increasing vessel permeabilization[170,171].
In PDAC, however, the biggest hurdle may not be the host immune system, but the TME. The TME has played a significant role in not only acting as a physical barrier to deliver treatments, but it also in the development of resistance to conventional drugs. The TME remains a problem for successful TOV treatment. The TOV must be able to spread in the hypoxic and densely stromal-rich TME in order to attract enough attention to induce antitumour immunity[172]. Breaching the stromal barrier in PDAC is needed for TOVs to access the cancer cells[173]. Paradoxically, a recent study by Ilkow et al[174] demonstrated that the cross-talk between CAFs and cancer cells actually lead to increased permissibility of TOV-based therapeutics. Tumour cells producing TGF-α reprogrammed CAFs, dampening levels of anti-viral transcripts. This allowed the cells to be more sensitive to VV, vesicular stomatitis virus and maraba MG1 TOVs. The reprogrammed CAFs produced fibroblast growth factor (FGF)-2 which suppressed levels of retinoic acid-inducible gene I and increased the susceptibility of the tumour cells to virus[175]. This study also demonstrated that an FGF2-expressing TOV has improved therapeutic efficacy by sensitizing the tumour cells to virotherapy and is particularly relevant to pancreatic cancers, where CAFs are a major component of the tumour stroma[175]. It is important to note that not only the patient’s existing immune system may impede successful TOV therapy, but that the enhanced antitumour response by combinatory approaches (e.g., the inclusion of immune-checkpoint inhibitors) may also impede successful TOV infection, spread and engagement of the immune system. This stresses the importance of determining strategic combinations, dosing and timing schedules in future studies.
CONCLUSION
The poor prognosis of pancreatic cancer due in part to the limited efficacy of conventional and targeted therapies, appeals for a novel strategy to treat this disease. It has become very clear that the immune system has the greatest potential to selectively destroy tumours, and when it is strategically induced, a durable benefit can be achieved. Past and present studies have defined means for tumour escape from immune surveillance and have developed immunotherapies to counteract these mechanisms. However, with the various escape strategies leading to low immunogenicity and highly immunosuppressive tumour beds, a successful control of tumour growth by immunotherapy does not come without various obstacles and challenges. Future steps include the development of immune-monitoring strategies for the identification of biomarkers, to establishment guidelines to assess clinical end points of immunotherapy and finally to evaluate combination therapeutic strategies to maximize clinical benefit[176]. The ability of TOVs to stimulate inflammation, deliver genes and immunomodulatory agents as well as reduce tumour burden by direct cell lysis, allows them to be important therapeutic vectors for a highly immunosuppressed tumour such as PDAC. Immune checkpoint blockade agents can then reverse T cell anergy and further boost OV-induced responses. As this combinatory approach may exist as a double-edged sword, it is crucial to determine appropriate timing, dosing and sequence schedules of each agent.
SOURCE & REFERENCES
World J Gastroenterol. 2016 Jan 14; 22(2): 748–763.
Recently a German inventor, Clemens Bimek, developed a novel, reversible, hormone free, uncomplicated and lifelong contraceptive device for controlling male fertility. His invention is named as Bimek SLV, which is basically a valve that stops the flow of sperm through the vas deferens with the literal flip of a mechanical switch inside the scortum, rendering its user temporarily sterile. Toggled through the skin of the scrotum, the device stays closed for three months to prevent accidental switching. Moreover, the switch can’t open on its own. The tiny valves are less than an inch long and weigh is less than a tenth of an ounce. They are surgically implanted on the vas deferens, the ducts which carry sperm from the testicles, through a simple half-hour operation.
The valves are made of PEEK OPTIMA, a medical-grade polymer that has long been employed as a material for implants. The device is patented back in 2000 and is scheduled to undergo clinical trials at the beginning of this year. The inventor claims that Bimek SLV’s efficacy is similar to that of vasectomy, it does not impact the ability to gain and maintain an erection and ejaculation will be normal devoid of the sperm cells. The valve’s design enables sperm to exit the side of the vas deferens when it’s closed without any semen blockage. Leaked sperm cells will be broken down by the immune system. The switch to stop sperm flow can be kept working for three months or 30 ejaculations. After switching on the sperm flow the inventor suggested consulting urologist to ensure that all the blocked sperms are cleared off the device. The recovery time after switching on the sperm flow is only one day, according to Bimek SLV. However, men are encouraged to wait one week before resuming sexual activities.
Before the patented technology can be brought to market, it must undergo a rigorous series of clinical trials. Bimek and his business partners are currently looking for men interested in testing the device. If the clinical trials are successful then this will be the first invention of its kind that gives men the ability to control their fertility and obviously this method will be preferred over vasectomy.
For the millions of people living with HIV worldwide, a life-long commitment to antiretroviral drugs is a must. Without these drugs, reservoirs of HIV hiding within resting T cells throughout the body can easily resurge and cause disease. In a study published yesterday (October 20) in Nature Communications, researchers from the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, described a bispecific antibody-like protein that attacks those reservoirs by coaxing HIV out of hiding and targeting infected cells for destruction.
“In order to kill the [infected] cell, the cell has to be activated,” said study coauthor John Mascola, director of NIAID’s Vaccine Research Center. This is because HIV has a way of hiding out inside inactive CD4+ T cells where the virus adopts a dormant-like state known as latency. In this state, the virus is impervious to antiretroviral drugs as well as antibodies that might otherwise alert other immune cells to the virus’ presence inside an infected cell. “By definition, latently-infected cells don’t express virus proteins,” Oliver Schwartz, the head of the virus and immunity laboratory at the Pasteur Institute in Paris, who was not involved in the work, told The Scientist.
Mascola and his colleagues designed a protein that activates latently-infected T cells by targeting a protein found on the surface of all T cells called CD3. Engagement of CD3 signals infected CD4+ T cells to start dividing, which revamps HIV’s replication machinery causing the virus to make proteins that appear on the surface of the infected cell. Mascola’s team tested the protein, called VRC07-αCD3, on T cells donated by HIV patients on antiretroviral therapies. The researchers found that VRC07-αCD3 caused the T cells to display Env, indicating that latent virus had become reactivated.
In recent years, researchers have come up with a handful of approaches to activate latent HIV, such ashistone deacetylase inhibitors, which increase viral gene expression. VRC07-αCD3, however, doesn’t just activate latent HIV—it also binds Env on the surface of infected CD4+ T cells and tags the cells for killing by another sort of cell called CD8+ killer T cells. Using T cells in culture, Mascola’s team demonstrated that the CD3-binding region of the protein triggers killer CD8+ T cells to lyse CD4+ T cells expressing Env.
The NIAID study was preceded by one in The Journal of Clinical Investigation that described a similar protein with dual specificities for CD3 and Env, but with a slightly different structure. Both designs share features that allow the proteins to activate latent cells, tag Env, and activate and bring killer CD8+ T cells into close proximity of their infected targets.
The dual specificity for CD3 and Env also provides a layer of safety: it ensured the killer CD8+ T cells only acted in full force when HIV was present. “That was an encouraging part of the data,” Mascola said.
Schwartz said this feature potentially addresses the concern that nonspecific activation of large numbers of T cells could elicit a dangerous overactivation of the immune system called a cytokine storm.
Mascola and his colleagues tested the safety of VRC07-αCD3 in five HIV-infected Rhesus macaques by giving the animals six doses over the course of three weeks. The monkeys were also on antiretroviral drugs, and the virus remained undetectable throughout the treatment. Although the monkeys tolerated the drug well, VRC07-αCD3 did activate T cells and caused serum cytokine levels to increase. “So this type of treatment is not risk-free,” Caltech virologist Pamela Bjorkman, who was not involved in the work, wrote in an email to The Scientist.
Mascola said his group plans to continue testing VRC07-αCD3 in macaques and in humanized mice to work out a balance between T cell activation and HIV killing. However, neither model “really tells you what’s going to happen in people,” he said. “We’ll have to proceed slowly in the clinic.”
A. Pegu et al., “Activation and lysis of human CD4 cells latently infected with HIV-1,”Nature Communications, 6:8447 doi:10.1038/ncomms9447, 2015.
Lucy Shapiro (born July 16, 1940, New York City) is an American developmental biologist. She is a professor of Developmental Biology at the Stanford University School of Medicine. She is the Ludwig Professor of Cancer Research and the director of the Beckman Center for Molecular and Genetic Medicine.[1] She founded a new field in developmental biology, using microorganisms to examine fundamental questions in developmental biology. Her work has furthered understanding of the basis of stem cell function and the generation of biological diversity.[2] Her ideas have revolutionized understanding of bacterial genetic networks and helped researchers to develop novel drugs to fight antibiotic resistance and emerging infectious diseases.[3] In 2013, Dr. Shapiro was presented with the 2011 National Medal of Science, which is given to individuals who have demonstrated “an outstanding breadth of knowledge in their field.”[3][4]
Lucy
Shapiro, PhD
Stanford University
Virginia and D.K. Ludwig Professor
Professor, Developmental Biology
Director of the Beckman Center for Molecular and Genetic Medicine
Stanford University, Palo Alto, California, USA
The Ludwig Institute for Cancer Research Ltd is an international not-for-profit organization with a 40-year legacy of pioneering cancer discoveries. The Institute provides its scientists from around the world with the resources and the flexibility to realize the life-changing potential of their work and see their discoveries advance human health. This philosophy, combined with robust translational programs, maximizes the potential of breakthrough discoveries to be more attractive for commercial development.
The Ludwig Institute conducts its own research and clinical trials, making it a bridge from the most basic questions of life to the most pressing needs of cancer care. Since its inception, the Institute has invested more than $1.7 billion of its own resources in cancer research, and has an endowment valued at $1.2 billion. The Institute’s assets are managed by the LICR Fund.
Dr. Lucy Shapiro, DF, Ph.D serves as Virginia and D.K. Ludwig Professor of Cancer Research in the Department of Developmental Biology and Director of the Beckman Center for Molecular and Genetic Medicine at the Stanford University School of Medicine where she has been a faculty member since 1989. Dr. Shapiro founded Stanford University’s Department of Developmental Biology in 1989 and served as its Chairperson from 1989 to 1997.
Lucy Shapiro Ph.D.
Co-Founder, Co-Chair of Scientific Advisory Board, Director and Member of Nominating & Corporate Governance Committee,Anacor Pharmaceuticals, Inc.
Age
Total Calculated Compensation
This person is connected to 46 board members in 3 different organizations across 6 different industries.
Using her unique worldview as both artist and scientist, Shapiro revolutionized the field of developmental biology and set the stage for the new field of systems biology.
Lucy Shapiro
Stanford developmental biologist Lucy Shapiro, PhD, whose unique worldview has revolutionized the understanding of the bacterial cell as an engineering paradigm, will be the commencement speaker for the School of Medicine Class of 2015.
The diploma ceremony will be held June 13 from 11 a.m. to 1 p.m. on Alumni Green, followed by a luncheon at 1 p.m. on the Dean’s Lawn.
Shapiro, the Virginia and D. K. Ludwig Professor, has spent her career on the leading edge of developmental biology. She is the recipient of numerous awards, including the National Medal of Science in 2012 and the 2014 Pearl Meister Greengard Prize, which celebrates the achievements of outstanding women in science.
Shapiro, director of the Beckman Center for Molecular and Genetic Medicine, has been a faculty member since 1989, when she founded the medical school’s Department of Developmental Biology.
A painter who studied both biology and the fine arts as an undergraduate, Shapiro said that she sees science as part of the world of art. She began her career as a scientist focused on finding new ways of looking at and understanding living things, much as an artist does. She started by hunting for the simplest organism she could find — a bacterial cell — and then studying its molecular mechanisms. Her research into the genetic circuitry of these cells paved the way for new antibiotics. Her use of the microorganism as a model also set the stage for the emerging field of systems biology.
She has served in advisory roles in both the Clinton and George W. Bush administrations on the threat of infectious disease in developing countries. She has said that increasing levels of both antibiotic resistance and novel infectious agents are likely to be a larger threat to the world than bioterrorism. Shapiro also started a biotech company to test and develop antibiotic and antifungal medications.
Use science to make world a better place, graduates told
At the medical school’s commencement, Lucy Shapiro described how years of solitary work in the laboratory led her to influence public policy and battle the growing threat of infectious disease on the global stage.
JUN 152015
Commencement speaker Lucy Shapiro discussed how she raised alarms about the threat of emerging infectious diseases, drug-resistant pathogens “and a poor to nonexistent drug pipeline.” Norbert von der Groeben
Developmental biologist Lucy Shapiro, PhD, told the 2015 School of Medicine graduates how, as a basic scientist who spent most of her life studying single-celled bacteria, she stepped out of her laboratory and onto the global stage to try to help the world avert a potential disaster.
“About 15 years ago, I sat up and looked around me and found that we were in the midst of a perfect storm,” said Shapiro, the Virginia and D. K. Ludwig Professor, speaking at the school’s commencement June 13 on Alumni Green. “There was a global tide of emerging infectious diseases, rampant antibiotic and antiviral resistance amongst all pathogens and a poor to nonexistent drug pipeline.
“For me the alarm bells went off, and I was convinced that I had to try and do something. Let me tell you the story of how I stepped out of my comfort zone. I launched a one-woman attack.”
She took any speaking engagement she could get to educate the public about antibiotic resistance; walked the corridors of power in Washington, D.C., lobbying politicians about the dangers of emerging infectious diseases; and used discoveries from her lab on the single-celled Caulobacter bacterium to develop new, effective disease-fighting drugs.
Bench-to-bedside for a better world
A recipient of the National Medal of Science, Shapiro exhorted the graduates to be unafraid of breaking out of their comfort zones and to use science to improve the human condition. Bridging the gap between the lab and the clinic can make the world a better place, she said.
Lloyd Minor, MD, dean of the School of Medicine, also emphasized the importance of bench-to-bedside work in his remarks to the graduates. There has never been a better time for shepherding advances in basic research into the clinic, he said.
Kristy Red-Horse, assistant professor of biology, hoods Katharina Sophia Volz, the first-ever graduate of the Interdepartmental Program in Stem Cell Biology and Regenerative Medicine. Norbert von der Groeben
“You are beginning your careers at an unprecedented time of opportunities for biomedical science and for human health,” he said.
This year’s class of 195 graduates comprised 78 students who earned PhDs, 78 who earned medical degrees and 39 who earned master’s degrees. It included Katharina Sophia Volz, the first-ever graduate of the Interdepartmental Program in Stem Cell Biology and Regenerative Medicine — the first doctoral program in the nation focusing on stem cell science and translating it to patient care.
Volz, whose work in the lab has opened the doors to improvements in clinical care for heart patients, said Stanford Medicine is the place to be for scientists who want to make a difference in the world.
“Everybody here is reaching for the stars. We can do the best work here of anywhere,” said Volz, 28, a native of Ulm, Germany, the birthplace of Albert Einstein. She has worked in 10 different labs across the globe. Her father and mother, Johannes and Luise Volz, traveled from Germany to celebrate with her.
“I’ve never been in a more supportive environment,” said Volz, who discovered the progenitors to the muscle layer around the coronary arteries, a finding with implications for regenerative medicine and finding treatments for coronary artery disease.
Well-wishers, garlands and fussy babies
Some in the crowd of well-wishers, seated under a giant white tent, held garlands of flowers for the graduates, while toddlers ran around the lawn and babies fussed and cried. The two student speakers added humor and pathos to the occasion, with memories of their years of hard work and discovery.
“I’d like to run one last experiment,” said Francisco Jose Emilio Gimenez, a PhD graduate in biomedical information. “Who here had serious doubts they would ever finish their PhD?”
Brook Barajas, who earned a PhD in cancer biology, holds her 15-month-old son Sebastian. Norbert von der Groeben
The dozens of hands shooting up from the stage were followed by laughter from the crowd.
Meghan Galligan, a medical degree graduate, said she was both nervous to be in front of the crowd and concerned about whether her puffy black graduation cap would stay put. “I’m wearing a French pastry hat and worried it’s going to fall off,” she said.
Her years of education to become a physician changed the day she entered clinical care training. “From the day we started clinics, we would really never be the same as those bright-eyed individuals who gathered here for orientation,” she said. “How could we be after gaining such privileged access into the human condition?”
Role as government adviser
Shapiro’s desire to improve the human condition led her out of the lab to the nation’s capital. She has since served in advisory roles in the administrations of Bill Clinton and George W. Bush on the threat of infectious disease in developing countries. Now director of the Beckman Center for Molecular and Genetic Medicine at Stanford, Shapiro has been a faculty member since 1989. She was founding chair of the Department of Developmental Biology and also started a biotech company in Palo Alto to test and develop antibiotics and antifungals.
Her lab at Stanford made breakthroughs in understanding the genetic circuitry of simple cells, setting the stage for the development of new antibiotics. Shapiro told the audience that over the 25 years that she has worked at the School of Medicine, she has seen a major shift in the connection between those who conduct research in labs and those who care for patients in clinics.
“We have finally learned to talk to each other,” Shapiro said. “I’ve watched the convergence of basic research and clinical applications without the loss of curiosity-driven research in the lab or patient-focused care in the clinic.”
Monica Eneriz-Wiemer, who earned a medical degree, hugs her mother Gloria Eneriz on June 13 before the School of Medicine’s diploma ceremony. Norbert von der Groeben
This new connection, she said, is key to the future of global health.
“This is no ordinary time, from shattering political unrest in the Middle East and North Africa and the consequent flood of immigrant populations that serves as a petri dish for infectious pathogens, to global shifts in urban environments, to climate change, which is having substantial impact on health … all contributing to the appearance of old pathogens in new places and new pathogens for which we have no immunity.
“We here must care about an Ebola outbreak 8,000 miles away in West Africa; we here must care about a cholera outbreak in Haiti; we wait for the consequences of the earthquake in Nepal. We live in a global village.”
This is your time to shape the future, Shapiro told the graduates.
“Step out of your comfort zone and follow your intuition,” she said. “Don’t be afraid of taking chances. Ask, ‘How can I change what’s wrong?’ ”
In closing remarks, Laurie Weisberg, MD, president of the Stanford Medicine Alumni Association and clinical professor of medicine at UC San Francisco, also encouraged students to step outside of their comfort zone.
“You may be the most brilliant, creative and productive scientist, clinician, writer or entrepreneur, but you’ll never know if you don’t embrace uncertainty, take on a new challenge, and give it a try,” she said. “To do what you love, and do it well, with all your heart — that’s what most important.
ByTRACIE WHITE
Tracie White is a science writer for the medical school’s Office of Communication & Public Affairs. Email her attracie.white@stanford.edu.
…Lucy Shapiro, Stanford University – National Medal of Science 2011 for the pioneering discovery that the bacterial cell is controlled by an …
Elaine Fuchs, Ph.D. Investigator, Howard Hughes Medical Institute
Rebecca C. Lancefield Professor
Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development
Skin harbors our largest reservoirs of stem cells. To maintain the body barrier, epidermis constantly self-renews and hair follicles undergo cyclical bouts of activity. Both stem cell compartments participate in repairing tissue damage after injury. Dr. Fuchs studies where adult stem cells come from, how they make tissues, how they repair wounds and how stem cells malfunction in cancers. Her group focuses on the mechanisms that impart skin stem cells with the ability to self-renew, develop and maintain tissues, and how these cells respond to external cues, and depart from their niche to accomplish these tasks.
The 2012 March of Dimes Prize in Developmental Biology has been jointly awarded to Elaine Fuchs, of the Rockefeller University and Howard Hughes Medical Institute, and to Howard Green, of Harvard Medical School, for their pioneering research on the molecular workings of skin stem cells and inherited skin disorders. The prize recognizes researchers whose work has contributed to our understanding of the science that underlies birth defects.
Elaine Fuchs was born in the United States and raised just outside Chicago. In 1972 she graduated with a B.S. and highest distinction in the Chemical Sciences from the University of Illinois. Her undergraduate thesis research in physical chemistry focused on the electrodiffusion of nickel through quartz. She moved from Illinois to Princeton University to study for her PhD in Biochemistry, investigating changes in bacterial cell walls during sporulation in Bacillus megaterium. In 1977, she joined Howard Green, then at Massachusetts Institute of Technology (MIT), for her postdoctoral studies. There, she focused on elucidating the mechanisms underlying the balance between growth and differentiation in epidermal keratinocytes, a system and research area that continues to fascinate her today. In 1980, she was recruited to the University of Chicago, where she moved up through the ranks to the position of Amgen Professor of Molecular Genetics and Cell Biology and Investigator of the Howard Hughes Medical Institute. She moved to The Rockefeller University in 2002, where she is now the Rebecca C. Lancefield Professor of Mammalian Cell Biology and Development.
Elaine’s research has encompassed identifying and characterizing the keratin genes expressed in human skin, understanding the transcriptional mechanisms underlying gene expression and differentiation in the epidermis and hair follicles, and revealing roles for Wnt and BMP signaling in skin. Currently, her lab’s focus is on understanding the niche for multipotent stem cells in skin. The thread that ties her research areas together is epithelial morphogenesis, understanding how external cues transmit their signals to elicit changes in transcription, cytoskeletal architecture and adhesion to establish the epidermis and hair follicles.
In the interview that follows, Fiona Watt, Editor-in-Chief of JCS, asks Elaine about her experiences as a woman in science.
FMW:How has your research career impacted on your personal life and vice versa?
EF: My father was a geochemist who specialized in meteorites at Argonne National Laboratories. My aunt, who lived in the house next door, was a biologist at Argonne, and an ardent feminist. My sister, four years my senior, is now a neuroscientist. My mother is a housewife, who loves gardening and cooking and used to play piano and paint in oils. Growing up in such a family, and with farm fields, creeks and ponds in the near vicinity, I developed a deep interest in science that has carried me through my professional life.
If I think back to the family influences that shaped my choice of career, I remember that my Dad strongly advocated my being an elementary school teacher. My aunt, his sister, was denied admission to medical school and she encouraged me to go into medicine. My mom told me that she thought I was a good cook and therefore I should become a chemist. My older sis was my idol, although I found her intelligence intimidating. She thought I should become an anthropologist. So, in contrast to my close friend and former colleague Susan Lindquist (now director of the Whitehead Institute at MIT), I was strongly encouraged by my family to go to college and do something with my life. I chose the University of Illinois at Urbana (my Dad told me that if there was a good reason why he should spend more than $2000 a year on my education, we should sit down and discuss the matter – otherwise, I should select either University of Illinois, our State school, or University of Chicago, where he got a tuition break. I vowed NOT to go to University of Chicago, because my sis, Dad and aunt went there, and I wanted to be different).
At the University of Illinois, I was one of three women in an undergraduate physics class of 200. My perception (shaped at least in part by the general aura of the scientific community at the time) was that, if I was to be accepted as a smart student, I probably needed to perform near or at the top of my class. I subsequently began studying very long hours, forgoing sleep and even studying while eating meals in the student cafeteria and while picketing classes during Vietnam War protests. Although my near perfect performances on tough physics and chemistry exams may have turned a few heads, I don’t feel that it served the deeper purpose of education, nor did it instill in me a long-standing love for these fields.⇓
By contrast, my participation in Vietnam War protests had a deeper impact on me, and I decided to apply to the Peace Corps. Having spent my electives taking Spanish and Latin American history, I was hoping to get accepted to go to Chile, which was headed by Allende, a liberal democratic Marxist. I was instead accepted to Uganda, which was headed by Idi Amin, a ruthless tyrant. It was then that I began in earnest contemplating graduate school, choosing Princeton’s Biochemistry Department, to move from physical sciences into the realm of more medically oriented science. I always suspected that my father was somehow behind the decision by the Peace Corps to send me to Uganda, but in the end going to graduate school was probably the right choice for me.
Not having taken biology since high school, I gravitated towards the most chemically oriented labs at Princeton. When I went to visit Bruce Alberts, he informed me that he only took the best students, which I was certain did not mean me. Marc Kirschner was no longer focused on physical biochemistry, but instead had begun working with disgusting-looking frogs. I settled on a Professor who had been quite open about his views that women should not be in science. Despite the fact that I was viewed by my mentor as a major disappointment relative to a fellow male graduate student who joined the same lab, I did learn from my mentor how to do well-controlled experiments, for which I’ve been forever grateful. Twenty years later, my mentor’s views regarding my relative lack of scientific skills even seemed to soften a bit.
Although I received my PhD in biochemistry, my education had not been very typical. I graduated without yet isolating protein, RNA or DNA. However, I had been frugal with my $3000/year graduate stipend, and had managed to travel (3rd class) through India, Nepal, Guatemala, Mexico, Peru, Bolivia, Ecuador, Turkey, Greece and Egypt (I’ve still never gotten to Chile or Uganda). In retrospect, I understand why my advisor had not taken me seriously!
Somehow, I managed to be accepted into the lab of Howard Green at MIT, and during my postdoctoral years, I limited my travel to Morocco, and began in earnest doing experiments. I chose Howard’s lab, because he was one of the pioneers in mammalian stem cell biology. He had developed methods to culture human epidermal stem cells under conditions where they could be maintained and propagated. I was yearning to switch model systems from bacteria to humans, hoping that my research might be more medically applicable, and I wanted to study the biochemical mechanisms underlying the balance between growth and differentiation in normal human cells. The system seemed ideal, and led me to become a skin biologist. Mouse genetics came later in my career after I was appointed to the HHMI at the University of Chicago, and had the resources to complement the culture system.
My experience at MIT had a powerful impact on my career. Howard Green was a quintessential cell biologist, which was something completely new to me. Nearly every lab at MIT was humming with brilliant postdocs, and I rapidly got hooked on the excitement of the science around me. I began to think that perhaps a scientific career might even be a possible goal for me – at least at some small teaching college or state university. After my first year at MIT, my advisor from Princeton nominated me for an Assistant Professorship at the University of Chicago, something that I assumed was to be a trial run for an academic job later down the road. I viewed the invitation to speak as a free trip home to visit my family, and was quite amazed when I subsequently received a job offer. It was only then when I began to realize that somebody must think more highly of my accomplishments than I did. My family’s pressure to accept the position was relentless and so I began an academic career as an independent scientist, feeling at the base of a totem pole of fantastic colleagues.
FMW:What changes for women in science have you observed during the course of your career?
EF: At Chicago, I was the first woman in a department of 15 biochemistry faculty members. But Janet Rowley, who already was a member of the National Academy of Sciences and a famous cytogeneticist, was in the Department of Medicine, and she sent hand-written notes congratulating me on every small success that would come my way. This inspired me, as did meeting Susan Lindquist in the Department of Biology, who became my long-standing close friend and colleague. In 1982, Sue also introduced me to David Hansen, to whom I have been happily married for 16 years!
Chicago reorganized their biological sciences departments in 1985, and Sue, Janet, several other women and I all chose to join the same Department, Molecular Genetics and Cell Biology. All of a sudden, women faculty members were in abundance and a force to be reckoned with. This and fantastic students became an endless source of enjoyment for me, and I remained at Chicago for over 20 years.
I feel that although there is still considerable work to be done to pave the way for women in science, the situation has improved considerably during the course of my career. Women are now routinely asked and elected to serve the scientific community in important ways. In this regard, I have served on the Advisory Council for the Director of the NIH, the Council of the National Academy of Sciences (NAS) and was President of the American Society of Cell Biology. In addition, major scientific organizations have cracked the door open wider for women, and I certainly feel fortunate to have been elected by my colleagues to the NAS, the Institute of Medicine and the American Academy of Arts and Sciences. I also feel honored to have received recognition from my colleagues through a number of scientific achievement awards, including the Richard Lounsbery Award from the NAS and an honorary doctorate degree from Mt Sinai and New York University Medical School. As women continue to make their way in the scientific community at all levels and in greater numbers, we will continue to see a rise in the creativity, reflection and breadth of thinking that is so necessary to move science forward.
FMW:Do you feel that being a woman is an inherent advantage/disadvantage for a career in science? Why?
EF: I can’t say that it is or isn’t, but for me the discrimination I have faced personally has served as an inspiration and a challenge to do better, not as an impediment to my career. The one thing I do feel now is that it is important for senior women to remember that the road for women scientists is not always an easy one. There is still substantial room for the scientific community to grow in the realization that, by opening the door to women, it is going to raise the level of scientific excellence. Senior women who are recognized by their peers as being successful have a responsibility to help educate those scientists who haven’t quite accepted this important message. And we have a responsibility to maintain the highest scientific and ethical standards and to serve as the best role models we can for the younger generation of outstanding scientists – both men and women – who are rising through the ranks. Leading by good example is still the best way to diffuse the now more subtle and less vocal, but nevertheless lingering, discrimination and dogmatism against women scientists within our scientific community.
No discussion of women and careers is complete without addressing the issue of children and motherhood. In my case, I’m afraid I don’t serve as a good role model because I don’t have children. However, I’d like to emphasize that this was a decision that my husband and I consciously made together. I’m married to the Director of Philosophy and Education at Teachers’ College, Columbia University, and for the past 20 years that we’ve known one another, we’ve enjoyed traveling the world, going to operas, symphony and chamber music concerts, eating leisurely dinners, dancing, swimming, quiet reflection, education and service to the broader community. We love our nieces and nephews, but children were not a high priority for our lives together. In another world, things might be different. However, I certainly don’t view this decision as a sacrifice that I had to make for my science.
FMW:What are your remaining career ambitions?
EF: I made the decision to move to Rockefeller in 2002 because it provided an exceptional constellation of world-renowned colleagues, generating a rich and stimulating new environment for the 17 postdocs and technicians who moved with me. Our research has progressively moved to the field of morphogenesis – understanding the molecular process that begins with a single stem cell and ends with a functional tissue, either epidermis or hair follicles. Characteristic of my checkered past, the research is a blend of biochemistry, molecular biology, cell and developmental biology, and the area enables us to combine our interests in signal transduction, transcriptional regulation, cytoskeletal dynamics and cell adhesion. The caliber of my students and postdocs keeps escalating, and the science continues to keep me in the lab nights and weekends, as it did when I was a postdoctoral fellow. Each day brings new challenges, and there is certainly no doubt now that the flame of excitement and interest in scientific discovery and education burns eternally within me. There is no `last’ objective – only new horizons and challenges. The revolution in biology that I have experienced in my own career tells me not to predict what my next objective will be.
I feel strongly that we make of our lives what we put into them. To succeed in a scientific career in academia takes motivation, commitment, effort, thought, creativity, intelligence, teaching skills, technical talent, organization, leadership, oral and writing skills, compassion and a strong sense of ethics. I know I’ve left out many other essential traits. Very few scientists have all these attributes, but we can each achieve a high degree of satisfaction if not success through honing the subset of attributes that we do have. I know that for me, the more I work on becoming a better scientist, mentor and participator in our scientific community, the richer all aspects of my life become.
Elaine Fuchs has collected many awards in her 30 years researching mammalian skin development, but it’s hard to beat the two prizes she received in late 2009. Shortly before winning the prestigious L’Oreál-UNESCO award for women in science, Fuchs was awarded the National Medal of Science—the US’s highest honor for outstanding scientific contributions.
After studying bacterial sporulation as a PhD student with Charles Gilvarg at Princeton, Fuchs joined Howard Green’s laboratory at MIT, where she investigated the expression of keratins in differentiating skin cells (1, 2). Fuchs then returned to her native Illinois to begin her own laboratory at the University of Chicago, and stayed for more than 20 years before moving to The Rockefeller University in New York in 2002. Fuchs’ research has touched on many aspects of skin differentiation and function. Asked to pick her favorite work, she chooses her pioneering use of mouse genetics to identify mutant keratins as the cause of several human skin diseases (3, 4). She also mentions the generation of super furry mice by expressing a stabilized version of the transcription factor β-catenin (5) as well as the identification and characterization of a multipotent stem cell population in the hair follicle (6, 7). In a recent interview, Fuchs discussed her latest awards, and explained why the skin continues to hold her interest.
Elaine Fuchs
Is it true that you refused to take the exam for graduate school entry?
Yes! [laughs] I was graduating near the top of my class from a very good university and I felt that the Graduate Record Examination wasn’t testing my real knowledge, but rather how I could perform in a written exam. So I decided that perhaps they’d appreciate some creative writing instead. I wrote three pages explaining the reasons why I was not going to be taking my GRE, and I sent it along with my applications.
I got accepted everywhere, but it’s quite unlikely that I would be admitted to any graduate program in the US today. I don’t think professors are as open-minded toward rebellious students as they were during the Vietnam War era.
How did you decide to go to Howard Green’s laboratory for your postdoc?
I had been working on bacterial sporulation and, in the course of that, I studied bacterial cell walls. Many antibiotics target the enzymes that synthesize cell walls, and that medical aspect was what I really liked about my science.
To maintain my interest in biomedical research, I decided to switch to the growth and differentiation of human cells, but I knew I was going to need a good culture system. Howard was a cell culture guru—he developed the use of human epidermal cells as well as the 3T3L1 line for adipocyte differentiation. Almost everyone else was using transformed mammalian cells at the time and I thought these were great systems to study—I still do.
And you’ve worked on skin ever since—what has captivated you for so long?
Skin is such a complex organ. We focus on the epithelium, but epithelial–mesenchymal interactions are very important in dictating whether keratinocyte stem cells will stratify to make an epidermis or differentiate into a sebaceous gland or hair follicle. How does that happen? How do you start with a stem cell and build a tissue? There are lots of facets to the problem, ranging from transcription to cell–cell and cell–substratum interactions. There’s this endless array of signals from the environment that, in a sense, encompasses almost every aspect of biology.
So even though we still work on skin as a model system, we continue to ask different questions. We spent 10 years working on keratins, but if I’d stuck with that, I might have burned myself out. I learned early on in my career that it’s important to choose a problem you’re interested in, even if you don’t yet know the technology you need to address it. I think people get into ruts when they become very good at something and do it over and over again. What we’re doing now is very different to what we were doing several years ago, and we continue to try novel and original approaches.
One of those original approaches was using transgenic mice to link keratins with human genetic diseases…
After cloning and sequencing the first keratins, we’d begun to hone in on the key residues that were critical for the assembly of keratin intermediate filaments, but we couldn’t predict the disease we should be looking at from the disrupted keratin networks we saw in our cultured skin cells. We thought that engineering mice harboring our dominant-negative keratin gene might offer us better clues. We set up transgenic mouse technology, but when we got our mice expressing mutant keratin, they showed no phenotype at all. I thought, “We just wasted all this time learning this technology, and we’re getting nowhere.”
Then one day a technician said, “There’s this dead mouse that’s half eaten, and it looks like it’s got a severe problem with its skin.” We took a look and it was expressing whopping amounts of our transgene. We realized that the mom was eating every single phenotypic mutant while leaving behind all the nonphenotypic ones. I gave [laboratory members] Bob Vassar and Pierre Coulombe my office for the night, and they babysat until the moms delivered. After their preliminary analysis, we sat down with a dermatology textbook and it was pretty clear: the pathology matched perfectly with epidermolysis bullosa simplex, a blistering skin disorder in humans.
But not everyone believed you at first?
No. I don’t blame people because diagnosing mice as having a particular human disease was unconventional at the time. I presented the work at a large meeting, and the chair took the microphone and said, “I don’t know what you’ve got, but you certainly don’t have EBS.” It took a few moments for me to react—it was looking pretty bad. The audience listened to the chair, who continued to declare confidently that our findings were rubbish.“There’s this endless array of signals from the environment that encompasses almost every aspect of biology.”
But at that point Mina Bissell stood up and said, “I don’t know whether she’s going to be right or wrong, but I just heard an interesting story, and I think we should give her the chance to find out.” This broke the ice for UPenn’s chair of dermatology, John Stanley, to stand up and say, “Actually, I would also diagnose the pathology as EBS.” Eight months later, we published a paper documenting the human genetic basis of EBS, so it didn’t take long to prove our hypothesis.
You were one of very few female group leaders when you began in Chicago. How was that?
A technician from another laboratory came down as I was setting up my laboratory, and said, “Are you Dr. Fuchs’ new technician?” and I had to say, “I am Dr. Fuchs!” There were cases where I’d be introduced to the seminar speaker as the prettiest member of the department—things that would make me cringe. I didn’t know what to make of these comments, and I’m not sure the men knew what to make of having me there.
I didn’t care what my salary was—it was more than I’d got as a postdoc— until after I was a tenured faculty member, when I discovered that my salary was actually lower than what they were offering to starting assistant professors. It was only after I realized I’d been underpaid all those years that I got angry. So there were definitely gender issues that could’ve distracted me, but I was so thrilled to be able to do my science that nothing else seemed to matter so much.
You’ve been a strong advocate for women in science, which was recognized by your L’Oreál-UNESCO award. Do any significant challenges remain?
Things are enormously better, particularly in the US. In general, the door is open for women all the way up to being an associate professor but it’s still difficult at the upper end of the scale—there are very few women in leadership positions. And there are still women at some universities who feel they are underpaid, have less space, and receive fewer privileges than their male colleagues. Most major universities have gotten the message, but I’m not sure all the smaller universities have followed suit.
The other prize you won recently was the National Medal of Science. How was your trip to the White House?
Fuchs receives the National Medal of Science from President Obama.
SANDY SCHAEFFER/NSF
Having the President of the United States shake my hand and place a medal around my neck was a moving experience. It was also nice to have not only my husband, but also my mother (who’s close to 88 years old now), my sister, and eldest nephew present. It was particularly thrilling for me because President Obama recognizes the importance of basic research and science education to the future of our country.
Could scientists do a better job of communicating the importance of their work?
Yes—we need to educate politicians about the importance of basic research and increasing the budget for it. [Former congressman] John Porter, at a recent Howard Hughes meeting, asked us all, “When was the last time you contacted a politician and invited them to your laboratory? They need to see what scientists are doing.” If politicians don’t understand what we can learn from basic research and appreciate its importance, why should they support it?
How do you maintain your enthusiasm?
A professor’s role is a combination of research and education. I empathize with the pain students feel as they initially struggle with scientific research, yet there’s nothing more gratifying than watching a student’s first experiment work. You see them think, “Well, it’s really worth it after all. I can do it.” As long as I’m passionate about the scientific questions we tackle, I don’t think I’ll ever get tired of being a professor. It’s the best possible job in the world.
What can we expect next from the Fuchs laboratory?
New approaches, of course! We’ve identified lots of new genes that change their expression patterns as stem cells make epidermis and hair follicles. But we can’t use classical genetics to figure out what all these changes mean—a conditional knockout mouse takes a couple of years to make, and there’s a lot of redundancy in the genome. We’re developing new strategies to make functional analyses of mouse skin development a more tractable process. There are many signaling pathways that must converge to build and maintain tissues during normal development and wound repair, and a lot of pathways go awry to generate the myriad of human skin disorders, including cancers. We know a little bit here and there, yet we still have a lot of pieces to fill in. But I love the puzzle!
Miller started his education focusing on speech and language and published papers on these topics, focusing on mathematical, computational and psychological aspects of the field. He started his career at a time when the reigning theory in psychology was behaviorism, which eschewed any attempt to study mental processes and focused only on observable behavior. Working mostly at Harvard University, MIT and Princeton University, Miller introduced experimental techniques to study the psychology of mental processes, by linking the new field of cognitive psychology to the broader area of cognitive science, including computation theory and linguistics. He collaborated and co-authored work with other figures in cognitive science and psycholinguistics, such as Noam Chomsky. For moving psychology into the realm of mental processes and for aligning that move with information theory, computation theory, and linguistics, Miller is considered one of the great twentieth-century psychologists. A Review of General Psychology survey, published in 2002, ranked Miller as the 20th most cited psychologist of that era.[2]
Remembering George A. Miller
The human mind works a lot like a computer: It collects, saves, modifies, and retrieves information. George A. Miller, one of the founders of cognitive psychology, was a pioneer who recognized that the human mind can be understood using an information-processing model. His insights helped move psychological research beyond behaviorist methods that dominated the field through the 1950s. In 1991, he was awarded the National Medal of Science for his significant contributions to our understanding of the human mind.
From the days of William James, psychologists had the idea memory consisted of short-term and long-term memory. While short-term memory was expected to be limited, its exact limits were not known. In 1956, Miller would quantify its capacity limit in the paper “The magical number seven, plus or minus two”. He tested immediate memory via tasks such as asking a person to repeat a set of digits presented; absolute judgment by presenting a stimulus and a label, and asking them to recall the label later; and span of attention by asking them to count things in a group of more than a few items quickly. For all three cases, Miller found the average limit to be seven items. He had mixed feelings about the focus on his work on the exact number seven for quantifying short-term memory, and felt it had been misquoted often. He stated, introducing the paper on the research for the first time, that he was being persecuted by an integer.[1] Miller also found humans remembered chunks of information, interrelating bits using some scheme, and the limit applied to chunks. Miller himself saw no relationship among the disparate tasks of immediate memory and absolute judgment, but lumped them to fill a one-hour presentation. The results influenced the budding field of cognitive psychology.[15]
WordNet
For many years starting from 1986, Miller directed the development of WordNet, a large computer-readable electronic reference usable in applications such as search engines.[12] Wordnet is a dictionary of words showing their linkages by meaning. Its fundamental building block is a synset, which is a collection of synonyms representing a concept or idea. Words can be in multiple synsets. The entire class of synsets is grouped into nouns, verbs, adjectives and adverbs separately, with links existing only within these four major groups but not between them. Going beyond a thesaurus, WordNet also included inter-word relationships such as part/whole relationships and hierarchies of inclusion.[16] Miller and colleagues had planned the tool to test psycholinguistic theories on how humans use and understand words.[17] Miller also later worked closely with the developers at Simpli.com Inc., on a meaning-based keyword search engine based on WordNet.[18]
Language psychology and computation
Miller is considered one of the founders of psycholinguistics, which links language and cognition in psychology, to analyze how people use and create language.[1] His 1951 book Language and Communication is considered seminal in the field.[5] His later book, The Science of Words (1991) also focused on language psychology.[19] He published papers along with Noam Chomsky on the mathematics and computational aspects of language and its syntax, two new areas of study.[20][21][22] Miller also researched how people understood words and sentences, the same problem faced by artificial speech-recognition technology. The book Plans and the Structure of Behavior (1960), written with Eugene Galanter and Karl H. Pribram, explored how humans plan and act, trying to extrapolate this to how a robot could be programmed to plan and do things.[1] Miller is also known for coining Miller’s Law: “In order to understand what another person is saying, you must assume it is true and try to imagine what it could be true of”.[23]
Miller’s Language and Communication was one of the first significant texts in the study of language behavior. The book was a scientific study of language, emphasizing quantitative data, and was based on the mathematical model of Claude Shannon‘s information theory.[24] It used a probabilistic model imposed on a learning-by-association scheme borrowed from behaviorism, with Miller not yet attached to a pure cognitive perspective.[25] The first part of the book reviewed information theory, the physiology and acoustics of phonetics, speech recognition and comprehension, and statistical techniques to analyze language.[24]The focus was more on speech generation than recognition.[25] The second part had the psychology: idiosyncratic differences across people in language use; developmental linguistics; the structure of word associations in people; use of symbolism in language; and social aspects of language use.[24]
Reviewing the book, Charles E. Osgood classified the book as a graduate-level text based more on objective facts than on theoretical constructs. He thought the book was verbose on some topics and too brief on others not directly related to the author’s expertise area. He was also critical of Miller’s use of simple, Skinnerian single-stage stimulus-response learning to explain human language acquisition and use. This approach, per Osgood, made it impossible to analyze the concept of meaning, and the idea of language consisting of representational signs. He did find the book objective in its emphasis on facts over theory, and depicting clearly application of information theory to psychology.[24]
In Plans and the Structure of Behavior, Miller and his co-authors tried to explain through an artificial-intelligence computational perspective how animals plan and act.[26] This was a radical break from behaviorism which explained behavior as a set or sequence of stimulus-response actions. The authors introduced a planning element controlling such actions.[27] They saw all plans as being executed based on input using a stored or inherited information of the environment (called the image), and using a strategy called test-operate-test-exit (TOTE). The image was essentially a stored memory of all past context, akin to Tolman‘scognitive map. The TOTE strategy, in its initial test phase, compared the input against the image; if there was incongruity the operate function attempted to reduce it. This cycle would be repeated till the incongruity vanished, and then the exit function would be invoked, passing control to another TOTE unit in a hierarchically arranged scheme.[26]
Peter Milner, in a review in the Canadian Journal of Psychology, noted the book was short on concrete details on implementing the TOTE strategy. He also critically viewed the book as not being able to tie its model to details from neurophysiology at a molecular level. Per him, the book covered only the brain at the gross level of lesion studies, showing that some of its regions could possibly implement some TOTE strategies, without giving a reader an indication as to how the region could implement the strategy.[26]
Miller’s 1967 work, The Psychology of Communication, was a collection of seven previously published articles. The first “Information and Memory” dealt with chunking, presenting the idea of separating physical length (the number of items presented to be learned) and psychological length (the number of ideas the recipient manages to categorize and summarize the items with). Capacity of short-term memory was measured in units of psychological length, arguing against a pure behaviorist interpretation since meaning of items, beyond reinforcement and punishment, was central to psychological length.[28]
The second essay was the paper on magical number seven. The third, ‘The human link in communication systems,’ used information theory and its idea of channel capacity to analyze human perception bandwidth. The essay concluded how much of what impinges on us we can absorb as knowledge was limited, for each property of the stimulus, to a handful of items.[28] The paper on “Psycholinguists” described how effort in both speaking or understanding a sentence was related to how much of self-reference to similar-structures-present-inside was there when the sentence was broken down into clauses and phrases.[29] The book, in general, used the Chomskian view of seeing language rules of grammar as having a biological basis—disproving the simple behaviorist idea that language performance improved with reinforcement—and using the tools of information and computation to place hypotheses on a sound theoretical framework and to analyze data practically and efficiently. Miller specifically addressed experimental data refuting the behaviorist framework at concept level in the field of language and cognition. He noted this only qualified behaviorism at the level of cognition, and did not overthrow it in other spheres of psychology.[28]
Although the overall cure rate of acute lymphoblastic leukemia (ALL) in children is about 80 percent, affected adults fare less well. This review considers recent advances in the treatment of ALL, emphasizing issues that need to be addressed if treatment outcome is to improve further.
This comprehensive survey emphasizes how recent advances in the knowledge of molecular mechanisms involved in acute lymphoblastic leukemia have influenced diagnosis, prognosis, and treatment.
Gene-Expression Patterns in Drug-Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment
Amy Holleman, Meyling H. Cheok, Monique L. den Boer, et al.
N Engl J Med 2004; 351:533-42
Childhood acute lymphoblastic leukemia (ALL) is curable with chemotherapy in approximately 80 percent of patients. However, the cause of treatment failure in the remaining 20 percent of patients is largely unknown.
Methods We tested leukemia cells from 173 children for sensitivity in vitro to prednisolone, vincristine, asparaginase, and daunorubicin. The cells were then subjected to an assessment of gene expression with the use of 14,500 probe sets to identify differentially expressed genes in drug-sensitive and drug-resistant ALL. Gene-expression patterns that differed according to sensitivity or resistance to the four drugs were compared with treatment outcome in the original 173 patients and an independent cohort of 98 children treated with the same drugs at another institution.
Results We identified sets of differentially expressed genes in B-lineage ALL that were sensitive or resistant to prednisolone (33 genes), vincristine (40 genes), asparaginase (35 genes), or daunorubicin (20 genes). A combined gene-expression score of resistance to the four drugs, as compared with sensitivity to the four, was significantly and independently related to treatment outcome in a multivariate analysis (hazard ratio for relapse, 3.0; P=0.027). Results were confirmed in an independent population of patients treated with the same medications (hazard ratio for relapse, 11.85; P=0.019). Of the 124 genes identified, 121 have not previously been associated with resistance to the four drugs we tested.
Conclusions Differential expression of a relatively small number of genes is associated with drug resistance and treatment outcome in childhood ALL.
The treatment of leukemia is in constant flux, evolving and changing rapidly over the past few years. Most treatment protocols use systemic chemotherapy with or without radiotherapy. The basic strategy is to eliminate all detectable disease by using cytotoxic agents. To attain this goal, 3 phases are typically used, as follows: remission induction phase, consolidation phase, and maintenance therapy phase.
Chemotherapeutic agents are chosen that interfere with cell division. Tumor cells usually divide more rapidly than host cells, making them more vulnerable to the effects of chemotherapy. Primary treatment will be under the direction of a medical oncologist, radiation oncologist, and primary care physician. Although a general treatment plan will be outlined, the ophthalmologist does not prescribe or manage such treatment.
The initial treatment of ALL uses various combinations of vincristine, prednisone, and L-asparaginase until a complete remission is obtained.
Maintenance therapy with mercaptopurine is continued for 2-3 years following remission.
Use of intrathecal methotrexate with or without cranial irradiation to cover the CNS varies from facility to facility.
Daunorubicin, cytarabine, and thioguanine currently are used to obtain induction and remission of AML.
Maintenance therapy for 8 months may lengthen remission. Once relapse has occurred, AML generally is curable only by bone marrow transplantation.
Presently, treatment of CLL is palliative.
CML is characterized by a leukocytosis greater than 100,000 cells. Emergent treatment with leukopheresis sometimes is necessary when leukostastic complications are present. Otherwise, busulfan or hydroxyurea may control WBC counts. During the chronic phase, treatment is palliative.
When CML converts to the blastic phase, approximately one third of cases behave as ALL and respond to treatment with vincristine and prednisone. The remaining two thirds resemble AML but respond poorly to AML therapy.
Allogeneic bone marrow transplant is the only curative therapy for CML. However, it carries a high early mortality rate.
Leukemic retinopathy usually is not treated directly. As the hematological parameters normalize with systemic treatment, many of the ophthalmic signs resolve. There are reports that leukopheresis for hyperviscosity also may alleviate intraocular manifestations.
When definite intraocular leukemic infiltrates fail to respond to systemic chemotherapy, direct radiation therapy is recommended.
Relapse, manifested by anterior segment involvement, should be treated by radiation. In certain cases, subconjunctival chemotherapeutic agents have been injected.
Optic nerve head infiltration in patients with ALL is an emergency and requires prompt radiation therapy to try to salvage some vision.
Chemotherapy. Chemotherapy is the major form of treatment for leukemia. This drug treatment uses chemicals to kill leukemia cells.
Depending on the type of leukemia you have, you may receive a single drug or a combination of drugs. These drugs may come in a pill form, or they may be injected directly into a vein.
Biological therapy. Biological therapy works by using treatments that help your immune system recognize and attack leukemia cells.
Targeted therapy. Targeted therapy uses drugs that attack specific vulnerabilities within your cancer cells.
For example, the drug imatinib (Gleevec) stops the action of a protein within the leukemia cells of people with chronic myelogenous leukemia. This can help control the disease.
Radiation therapy. Radiation therapy uses X-rays or other high-energy beams to damage leukemia cells and stop their growth. During radiation therapy, you lie on a table while a large machine moves around you, directing the radiation to precise points on your body.
You may receive radiation in one specific area of your body where there is a collection of leukemia cells, or you may receive radiation over your whole body. Radiation therapy may be used to prepare for a stem cell transplant.
Stem cell transplant. A stem cell transplant is a procedure to replace your diseased bone marrow with healthy bone marrow.
Before a stem cell transplant, you receive high doses of chemotherapy or radiation therapy to destroy your diseased bone marrow. Then you receive an infusion of blood-forming stem cells that help to rebuild your bone marrow.
You may receive stem cells from a donor, or in some cases you may be able to use your own stem cells. A stem cell transplant is very similar to a bone marrow transplant.
2.4.4.2Acute Myeloid Leukemia
New treatment approaches in acute myeloid leukemia: review of recent clinical studies.
Standard chemotherapy can cure only a fraction (30-40%) of younger and very few older patients with acute myeloid leukemia (AML). While conventional allografting can extend the cure rates, its application remains limited mostly to younger patients and those in remission. Limited efficacy of current therapies and improved understanding of the disease biology provided a spur for clinical trials examining novel agents and therapeutic strategies in AML. Clinical studies with novel chemotherapeutics, antibodies, different signal transduction inhibitors, and epigenetic modulators demonstrated their clinical activity; however, it remains unclear how to successfully integrate novel agents either alone or in combination with chemotherapy into the overall therapeutic schema for AML. Further studies are needed to examine their role in relation to standard chemotherapy and their applicability to select patient populations based on recognition of unique disease and patient characteristics, including the development of predictive biomarkers of response. With increasing use of nonmyeloablative or reduced intensity conditioning and alternative graft sources such as haploidentical donors and cord blood transplants, the benefits of allografting may extend to a broader patient population, including older AML patients and those lacking a HLA-matched donor. We will review here recent clinical studies that examined novel pharmacologic and immunologic approaches to AML therapy.
Novel approaches to the treatment of acute myeloid leukemia.
Approximately 12 000 adults are diagnosed with acute myeloid leukemia (AML) in the United States annually, the majority of whom die from their disease. The mainstay of initial treatment, cytosine arabinoside (ara-C) combined with an anthracycline, was developed nearly 40 years ago and remains the worldwide standard of care. Advances in genomics technologies have identified AML as a genetically heterogeneous disease, and many patients can now be categorized into clinicopathologic subgroups on the basis of their underlying molecular genetic defects. It is hoped that enhanced specificity of diagnostic classification will result in more effective application of targeted agents and the ability to create individualized treatment strategies. This review describes the current treatment standards for induction, consolidation, and stem cell transplantation; special considerations in the management of older AML patients; novel agents; emerging data on the detection and management of minimal residual disease (MRD); and strategies to improve the design and implementation of AML clinical trials.
Age ≥ 60 years has consistently been identified as an independent adverse prognostic factor in AML, and there are very few long-term survivors in this age group.5 Poor outcomes in elderly AML patients have been attributed to both host- and disease-related factors, including medical comorbidities, physical frailty, increased incidence of antecedent myelodysplastic syndrome and myeloproliferative disorders, and higher frequency of adverse cytogenetics.28 Older patients with multiple poor-risk factors have a high probability of early death and little chance of long-term disease-free survival with standard chemotherapy. In a retrospective analysis of 998 older patients treated with intensive induction at the M.D. Anderson Cancer Center, multivariate analysis identified age ≥ 75 years, unfavorable karyotype, poor performance status, creatinine > 1.3 mg/dL, duration of antecedent hematologic disorder > 6 months, and treatment outside a laminar airflow room as adverse prognostic indicators.29 Patients with 3 or more of these factors had expected complete remission rates of < 20%, 8-week mortality > 50%, and 1-year survival < 10%. The Medical Research Council (MRC) identified cytogenetics, WBC count at diagnosis, age, and de novo versus secondary disease as critical factors influencing survival in > 2000 older patients with AML, but cautioned in their conclusions that less objective factors, such as clinical assessment of “fitness” for chemotherapy, may be equally important in making treatment decisions in this patient population.30 It is hoped that data from comprehensive geriatric assessments of functional status, cognition, mood, quality of life, and other measures obtained during ongoing cooperative group trials will improve our ability to predict how older patients will tolerate treatment.
The objectives of this review are to discuss standard and investigational nontransplant treatment strategies for acute myeloid leukemia (AML), excluding acute promyelocytic leukemia.
RECENT FINDINGS: Most adults with AML die from their disease. The standard treatment paradigm for AML is remission induction chemotherapy with an anthracycline/cytarabine combination, followed by either consolidation chemotherapy or allogeneic stem cell transplantation, depending on the patient’s ability to tolerate intensive treatment and the likelihood of cure with chemotherapy alone. Although this approach has changed little in the last three decades, increased understanding of the pathogenesis of AML and improvements in molecular genomic technologies are leading to novel drug targets and the development of personalized, risk-adapted treatment strategies. Recent findings related to prognostically relevant and potentially ‘druggable’ molecular targets are reviewed.
SUMMARY: At the present time, AML remains a devastating and mostly incurable disease, but the combination of optimized chemotherapeutics and molecularly targeted agents holds significant promise for the future.
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
be discussed at a meeting,
be cited with text, or
replace or update an existing article that is already cited.
Treatment Option Overview for AML
Successful treatment of acute myeloid leukemia (AML) requires the control of bone marrow and systemic disease and specific treatment of central nervous system (CNS) disease, if present. The cornerstone of this strategy includes systemically administered combination chemotherapy. Because only 5% of patients with AML develop CNS disease, prophylactic treatment is not indicated.[1–3]
Treatment is divided into two phases: remission induction (to attain remission) and postremission (to maintain remission). Maintenance therapy for AML was previously administered for several years but is not included in most current treatment clinical trials in the United States, other than for acute promyelocytic leukemia. (Refer to the Adult Acute Myeloid Leukemia in Remission section of this summary for more information.) Other studies have used more intensive postremission therapy administered for a shorter duration of time after which treatment is discontinued.[4] Postremission therapy appears to be effective when given immediately after remission is achieved.[4]
Since myelosuppression is an anticipated consequence of both the leukemia and its treatment with chemotherapy, patients must be closely monitored during therapy. Facilities must be available for hematologic support with multiple blood fractions including platelet transfusions and for the treatment of related infectious complications.[5] Randomized trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000/mm3 rather than 20,000/mm3.[6] The incidence of platelet alloimmunization was similar among groups randomly assigned to receive pooled platelet concentrates from random donors; filtered, pooled platelet concentrates from random donors; ultraviolet B-irradiated, pooled platelet concentrates from random donors; or filtered platelets obtained by apheresis from single random donors.[7] Colony-stimulating factors, for example, granulocyte colony–stimulating factor (G-CSF) and granulocyte-macrophage colony–stimulating factor (GM-CSF), have been studied in an effort to shorten the period of granulocytopenia associated with leukemia treatment.[8] If used, these agents are administered after completion of induction therapy. GM-CSF was shown to improve survival in a randomized trial of AML in patients aged 55 to 70 years (median survival was 10.6 months vs. 4.8 months). In this Eastern Cooperative Oncology Group (ECOG) (EST-1490) trial, patients were randomly assigned to receive GM-CSF or placebo following demonstration of leukemic clearance of the bone marrow;[9] however, GM-CSF did not show benefit in a separate similar randomized trial in patients older than 60 years.[10] In the latter study, clearance of the marrow was not required before initiating cytokine therapy. In a Southwest Oncology Group (NCT00023777) randomized trial of G-CSF given following induction therapy to patients older than 65 years, complete response was higher in patients who received G-CSF because of a decreased incidence of primary leukemic resistance. Growth factor administration did not impact on mortality or on survival.[11,12] Because the majority of randomized clinical trials have not shown an impact of growth factors on survival, their use is not routinely recommended in the remission induction setting.
The administration of GM-CSF or other myeloid growth factors before and during induction therapy, to augment the effects of cytotoxic therapy through the recruitment of leukemic blasts into cell cycle (growth factor priming), has been an area of active clinical research. Evidence from randomized studies of GM-CSF priming have come to opposite conclusions. A randomized study of GM-CSF priming during conventional induction and postremission therapy showed no difference in outcomes between patients who received GM-CSF and those who did not receive growth factor priming.[13,14][Level of evidence: 1iiA] In contrast, a similar randomized placebo-controlled study of GM-CSF priming in patients with AML aged 55 to 75 years showed improved disease-free survival (DFS) in the group receiving GM-CSF (median DFS for patients who achieved complete remission was 23 months vs. 11 months; 2-year DFS was 48% vs. 21%), with a trend towards improvement in overall survival (2-year survival was 39% vs. 27%, P = .082) for patients aged 55 to 64 years.[15][Level of evidence: 1iiDii]
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Buchner T, Hiddemann W, Wormann B, et al.: GM-CSF multiple course priming and long-term administration in newly diagnosed AML: hematologic and therapeutic effects. [Abstract] Blood 84 (10 Suppl 1): A-95, 27a, 1994.
Löwenberg B, Boogaerts MA, Daenen SM, et al.: Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia. J Clin Oncol 15 (12): 3496-506, 1997. [PUBMED Abstract]
Witz F, Sadoun A, Perrin MC, et al.: A placebo-controlled study of recombinant human granulocyte-macrophage colony-stimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM). Blood 91 (8): 2722-30, 1998. [PUBMED Abstract]
There are different types of treatment for patients with chronic myelogenous leukemia.
Six types of standard treatment are used:
Targeted therapy
Chemotherapy
Biologic therapy
High-dose chemotherapy with stem cell transplant
Donor lymphocyte infusion (DLI)
Surgery
New types of treatment are being tested in clinical trials.
Patients may want to think about taking part in a clinical trial.
Patients can enter clinical trials before, during, or after starting their cancer treatment.
Follow-up tests may be needed.
There are different types of treatment for patients with chronic myelogenous leukemia.
Different types of treatment are available for patients with chronic myelogenous leukemia (CML). Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information about new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Six types of standard treatment are used:
Targeted therapy
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Tyrosine kinase inhibitors are targeted therapy drugs used to treat chronic myelogenous leukemia.
Imatinib mesylate, nilotinib, dasatinib, and ponatinib are tyrosine kinase inhibitors that are used to treat CML.
See Drugs Approved for Chronic Myelogenous Leukemia for more information.
Chemotherapy
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.
See Drugs Approved for Chronic Myelogenous Leukemia for more information.
Biologic therapy
Biologic therapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.
See Drugs Approved for Chronic Myelogenous Leukemia for more information.
High-dose chemotherapy with stem cell transplant
High-dose chemotherapy with stem cell transplant is a method of giving high doses of chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.
See Drugs Approved for Chronic Myelogenous Leukemia for more information.
Donor lymphocyte infusion (DLI)
Donor lymphocyte infusion (DLI) is a cancer treatment that may be used after stem cell transplant.Lymphocytes (a type of white blood cell) from the stem cell transplant donor are removed from the donor’s blood and may be frozen for storage. The donor’s lymphocytes are thawed if they were frozen and then given to the patient through one or more infusions. The lymphocytes see the patient’s cancer cells as not belonging to the body and attack them.
Combining the targeted drugs with other treatments
Imatinib and other drugs that target the BCR-ABL protein have proven to be very effective, but by themselves these drugs don’t help everyone. Studies are now in progress to see if combining these drugs with other treatments, such as chemotherapy, interferon, or cancer vaccines (see below) might be better than either one alone. One study showed that giving interferon with imatinib worked better than giving imatinib alone. The 2 drugs together had more side effects, though. It is also not clear if this combination is better than treatment with other tyrosine kinase inhibitors (TKIs), such as dasatinib and nilotinib. A study going on now is looking at combing interferon with nilotinib.
Other studies are looking at combining other drugs, such as cyclosporine or hydroxychloroquine, with a TKI.
New drugs for CML
Because researchers now know the main cause of CML (the BCR-ABL gene and its protein), they have been able to develop many new drugs that might work against it.
In some cases, CML cells develop a change in the BCR-ABL oncogene known as a T315I mutation, which makes them resistant to many of the current targeted therapies (imatinib, dasatinib, and nilotinib). Ponatinib is the only TKI that can work against T315I mutant cells. More drugs aimed at this mutation are now being tested.
Other drugs called farnesyl transferase inhibitors, such as lonafarnib and tipifarnib, seem to have some activity against CML and patients may respond when these drugs are combined with imatinib. These drugs are being studied further.
Other drugs being studied in CML include the histone deacetylase inhibitor panobinostat and the proteasome inhibitor bortezomib (Velcade).
Several vaccines are now being studied for use against CML.
2.4.4.4. Chronic Lymphocytic Leukemia
Chronic Lymphocytic Leukemia Treatment (PDQ®)
General Information About Chronic Lymphocytic Leukemia
Key Points for This Section
Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).
Leukemia may affect red blood cells, white blood cells, and platelets.
Older age can affect the risk of developing chronic lymphocytic leukemia.
Signs and symptoms of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.
Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.
Certain factors affect treatment options and prognosis (chance of recovery).
Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).
Chronic lymphocytic leukemia (also called CLL) is a blood and bone marrow disease that usually gets worse slowly. CLL is one of the most common types of leukemia in adults. It often occurs during or after middle age; it rarely occurs in children.
Anatomy of the bone; drawing shows spongy bone, red marrow, and yellow marrow. A cross section of the bone shows compact bone and blood vessels in the bone marrow. Also shown are red blood cells, white blood cells, platelets, and a blood stem cell.
Anatomy of the bone. The bone is made up of compact bone, spongy bone, and bone marrow. Compact bone makes up the outer layer of the bone. Spongy bone is found mostly at the ends of bones and contains red marrow. Bone marrow is found in the center of most bones and has many blood vessels. There are two types of bone marrow: red and yellow. Red marrow contains blood stem cells that can become red blood cells, white blood cells, or platelets. Yellow marrow is made mostly of fat.
Leukemia may affect red blood cells, white blood cells, and platelets.
Normally, the body makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell.
A myeloid stem cell becomes one of three types of mature blood cells:
Red blood cells that carry oxygen and other substances to all tissues of the body.
White blood cells that fight infection and disease.
Platelets that form blood clots to stop bleeding.
A lymphoid stem cell becomes a lymphoblast cell and then one of three types of lymphocytes (white blood cells):
B lymphocytes that make antibodies to help fight infection.
T lymphocytes that help B lymphocytes make antibodies to fight infection.
Natural killer cells that attack cancer cells and viruses.
Blood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.
Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.
In CLL, too many blood stem cells become abnormal lymphocytes and do not become healthy white blood cells. The abnormal lymphocytes may also be called leukemia cells. The lymphocytes are not able to fight infection very well. Also, as the number of lymphocytes increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may cause infection, anemia, and easy bleeding.
This summary is about chronic lymphocytic leukemia. See the following PDQ summaries for more information about leukemia:
Older age can affect the risk of developing chronic lymphocytic leukemia.
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors for CLL include the following:
Being middle-aged or older, male, or white.
A family history of CLL or cancer of the lymph system.
Having relatives who are Russian Jews or Eastern European Jews.
Signs and symptoms of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.
Usually CLL does not cause any signs or symptoms and is found during a routine blood test. Signs and symptoms may be caused by CLL or by other conditions. Check with your doctor if you have any of the following:
Painless swelling of the lymph nodes in the neck, underarm, stomach, or groin.
Feeling very tired.
Pain or fullness below the ribs.
Fever and infection.
Weight loss for no known reason.
Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.
The following tests and procedures may be used:
Physical exam and history : An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
Complete blood count (CBC) with differential : A procedure in which a sample of blood is drawn and checked for the following:
The number of red blood cells and platelets.
The number and type of white blood cells.
The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
The portion of the blood sample made up of red blood cells.
Results from the Phase 3 Resonate™ Trial
Significantly improved progression free survival (PFS) vs ofatumumab in patients with previously treated CLL
Patients taking IMBRUVICA® had a 78% statistically significant reduction in the risk of disease progression or death compared with patients who received ofatumumab1
In patients with previously treated del 17p CLL, median PFS was not yet reached with IMBRUVICA® vs 5.8 months with ofatumumab (HR 0.25; 95% CI: 0.14, 0.45)1
Significantly prolonged overall survival (OS) with IMBRUVICA® vs ofatumumab in patients with previously treated CLL
In patients with previously treated CLL, those taking IMBRUVICA® had a 57% statistically significant reduction in the risk of death compared with those who received ofatumumab (HR 0.43; 95% CI: 0.24, 0.79; P<0.05)1
Treatment options for chronic lymphocytic leukemia (CLL) vary greatly, depending on the person’s age, the disease risk group, and the reason for treating (for example, which symptoms it is causing). Many people live a long time with CLL, but in general it is very difficult to cure, and early treatment hasn’t been shown to help people live longer. Because of this and because treatment can cause side effects, doctors often advise waiting until the disease is progressing or bothersome symptoms appear, before starting treatment.
If treatment is needed, factors that should be taken into account include the patient’s age, general health, and prognostic factors such as the presence of chromosome 17 or chromosome 11 deletions or high levels of ZAP-70 and CD38.
Initial treatment
Patients who might not be able to tolerate the side effects of strong chemotherapy (chemo), are often treated with chlorambucil alone or with a monoclonal antibody targeting CD20 like rituximab (Rituxan) or obinutuzumab (Gazyva). Other options include rituximab alone or a corticosteroid like prednisione.
In stronger and healthier patients, there are many options for treatment. Commonly used treatments include:
FCR: fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab
Bendamustine (sometimes with rituximab)
FR: fludarabine and rituximab
CVP: cyclophosphamide, vincristine, and prednisone (sometimes with rituximab)
CHOP: cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone
Chlorambucil combined with prednisone, rituximab, obinutuzumab, or ofatumumab
PCR: pentostatin (Nipent), cyclophosphamide, and rituximab
Alemtuzumab (Campath)
Fludarabine (alone)
Other drugs or combinations of drugs may also be also used.
If the only problem is an enlarged spleen or swollen lymph nodes in one region of the body, localized treatment with low-dose radiation therapy may be used. Splenectomy (surgery to remove the spleen) is another option if the enlarged spleen is causing symptoms.
Sometimes very high numbers of leukemia cells in the blood cause problems with normal circulation. This is calledleukostasis. Chemo may not lower the number of cells until a few days after the first dose, so before the chemo is given, some of the cells may be removed from the blood with a procedure called leukapheresis. This treatment lowers blood counts right away. The effect lasts only for a short time, but it may help until the chemo has a chance to work. Leukapheresis is also sometimes used before chemo if there are very high numbers of leukemia cells (even when they aren’t causing problems) to prevent tumor lysis syndrome (this was discussed in the chemotherapy section).
Some people who have very high-risk disease (based on prognostic factors) may be referred for possible stem cell transplant (SCT) early in treatment.
Second-line treatment of CLL
If the initial treatment is no longer working or the disease comes back, another type of treatment may help. If the initial response to the treatment lasted a long time (usually at least a few years), the same treatment can often be used again. If the initial response wasn’t long-lasting, using the same treatment again isn’t as likely to be helpful. The options will depend on what the first-line treatment was and how well it worked, as well as the person’s health.
Many of the drugs and combinations listed above may be options as second-line treatments. For many people who have already had fludarabine, alemtuzumab seems to be helpful as second-line treatment, but it carries an increased risk of infections. Other purine analog drugs, such as pentostatin or cladribine (2-CdA), may also be tried. Newer drugs such as ofatumumab, ibrutinib (Imbruvica), and idelalisib (Zydelig) may be other options.
If the leukemia responds, stem cell transplant may be an option for some patients.
Some people may have a good response to first-line treatment (such as fludarabine) but may still have some evidence of a small number of leukemia cells in the blood, bone marrow, or lymph nodes. This is known as minimal residual disease. CLL can’t be cured, so doctors aren’t sure if further treatment right away will be helpful. Some small studies have shown that alemtuzumab can sometimes help get rid of these remaining cells, but it’s not yet clear if this improves survival.
Treating complications of CLL
One of the most serious complications of CLL is a change (transformation) of the leukemia to a high-grade or aggressive type of non-Hodgkin lymphoma called diffuse large cell lymphoma. This happens in about 5% of CLL cases, and is known as Richter syndrome. Treatment is often the same as it would be for lymphoma (see our document called Non-Hodgkin Lymphoma for more information), and may include stem cell transplant, as these cases are often hard to treat.
Less often, CLL may transform to prolymphocytic leukemia. As with Richter syndrome, these cases can be hard to treat. Some studies have suggested that certain drugs such as cladribine (2-CdA) and alemtuzumab may be helpful.
In rare cases, patients with CLL may have their leukemia transform into acute lymphocytic leukemia (ALL). If this happens, treatment is likely to be similar to that used for patients with ALL (see our document called Leukemia: Acute Lymphocytic).
Acute myeloid leukemia (AML) is another rare complication in patients who have been treated for CLL. Drugs such as chlorambucil and cyclophosphamide can damage the DNA of blood-forming cells. These damaged cells may go on to become cancerous, leading to AML, which is very aggressive and often hard to treat (see our document calledLeukemia: Acute Myeloid).
The most widely used therapies are combinations of chemotherapy and radiation therapy.
Biological therapy, which targets key features of the lymphoma cells, is used in many cases nowadays.
The goal of medical therapy in lymphoma is complete remission. This means that all signs of the disease have disappeared after treatment. Remission is not the same as cure. In remission, one may still have lymphoma cells in the body, but they are undetectable and cause no symptoms.
When in remission, the lymphoma may come back. This is called recurrence.
The duration of remission depends on the type, stage, and grade of the lymphoma. A remission may last a few months, a few years, or may continue throughout one’s life.
Remission that lasts a long time is called durable remission, and this is the goal of therapy.
The duration of remission is a good indicator of the aggressiveness of the lymphoma and of the prognosis. A longer remission generally indicates a better prognosis.
Remission can also be partial. This means that the tumor shrinks after treatment to less than half its size before treatment.
The following terms are used to describe the lymphoma’s response to treatment:
Improvement: The lymphoma shrinks but is still greater than half its original size.
Stable disease: The lymphoma stays the same.
Progression: The lymphoma worsens during treatment.
Refractory disease: The lymphoma is resistant to treatment.
The following terms to refer to therapy:
Induction therapy is designed to induce a remission.
If this treatment does not induce a complete remission, new or different therapy will be initiated. This is usually referred to as salvage therapy.
Once in remission, one may be given yet another treatment to prevent recurrence. This is called maintenance therapy.
Chemotherapy
Many different types of chemotherapy may be used for Hodgkin lymphoma. The most commonly used combination of drugs in the United States is called ABVD. Another combination of drugs, known as BEACOPP, is now widely used in Europe and is being used more often in the United States. There are other combinations that are less commonly used and not listed here. The drugs that make up these two more common combinations of chemotherapy are listed below.
ABVD: Doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velban, Velsar), and dacarbazine (DTIC-Dome). ABVD chemotherapy is usually given every two weeks for two to eight months.
BEACOPP: Bleomycin, etoposide (Toposar, VePesid), doxorubicin, cyclophosphamide (Cytoxan, Neosar), vincristine (Vincasar PFS, Oncovin), procarbazine (Matulane), and prednisone (multiple brand names). There are several different treatment schedules, but different drugs are usually given every two weeks.
The type of chemotherapy, number of cycles of chemotherapy, and the additional use of radiation therapy are based on the stage of the Hodgkin lymphoma and the type and number of prognostic factors.
Adult non-Hodgkin Lymphoma is a disease in which malignant (cancer) cells form in the lymph system.
Because lymph tissue is found throughout the body, adult non-Hodgkin lymphoma can begin in almost any part of the body. Cancer can spread to the liver and many other organs and tissues.
Non-Hodgkin lymphoma in pregnant women is the same as the disease in nonpregnant women of childbearing age. However, treatment is different for pregnant women. This summary includes information on the treatment of non-Hodgkin lymphoma during pregnancy
Non-Hodgkin lymphoma can occur in both adults and children. Treatment for children, however, is different than treatment for adults. (See the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information.)
There are many different types of lymphoma.
Lymphomas are divided into two general types: Hodgkin lymphoma and non-Hodgkin lymphoma. This summary is about the treatment of adult non-Hodgkin lymphoma. For information about other types of lymphoma, see the following PDQ summaries:
Age, gender, and a weakened immune system can affect the risk of adult non-Hodgkin lymphoma.
If cancer is found, the following tests may be done to study the cancer cells:
Immunohistochemistry: A test that uses antibodies to check for certain antigens in a sample of tissue. The antibody is usually linked to a radioactive substance or a dye that causes the tissue to light up under a microscope. This type of test may be used to tell the difference between different types of cancer.
Cytogenetic analysis: A laboratory test in which cells in a sample of tissue are viewed under a microscope to look for certain changes in the chromosomes.
Immunophenotyping: A process used to identify cells, based on the types of antigens ormarkers on the surface of the cell. This process is used to diagnose specific types of leukemia and lymphoma by comparing the cancer cells to normal cells of the immune system.
Certain factors affect prognosis (chance of recovery) and treatment options.
The prognosis (chance of recovery) and treatment options depend on the following:
The stage of the cancer.
The type of non-Hodgkin lymphoma.
The amount of lactate dehydrogenase (LDH) in the blood.
The amount of beta-2-microglobulin in the blood (for Waldenström macroglobulinemia).
The patient’s age and general health.
Whether the lymphoma has just been diagnosed or has recurred (come back).
Stages of adult non-Hodgkin lymphoma may include E and S.
Adult non-Hodgkin lymphoma may be described as follows:
E: “E” stands for extranodal and means the cancer is found in an area or organ other than the lymph nodes or has spread to tissues beyond, but near, the major lymphatic areas.
S: “S” stands for spleen and means the cancer is found in the spleen.
Stage I adult non-Hodgkin lymphoma is divided into stage I and stage IE.
Stage I: Cancer is found in one lymphatic area (lymph node group, tonsils and nearby tissue, thymus, or spleen).
Stage IE: Cancer is found in one organ or area outside the lymph nodes.
Stage II adult non-Hodgkin lymphoma is divided into stage II and stage IIE.
Stage II: Cancer is found in two or more lymph node groups either above or below the diaphragm (the thin muscle below the lungs that helps breathing and separates the chest from the abdomen).
Stage IIE: Cancer is found in one or more lymph node groups either above or below the diaphragm. Cancer is also found outside the lymph nodes in one organ or area on the same side of the diaphragm as the affected lymph nodes.
Stage III adult non-Hodgkin lymphoma is divided into stage III, stage IIIE, stage IIIS, and stage IIIE+S.
Stage III: Cancer is found in lymph node groups above and below the diaphragm (the thin muscle below the lungs that helps breathing and separates the chest from the abdomen).
Stage IIIE: Cancer is found in lymph node groups above and below the diaphragm and outside the lymph nodes in a nearby organ or area.
Stage IIIS: Cancer is found in lymph node groups above and below the diaphragm, and in the spleen.
Stage IIIE+S: Cancer is found in lymph node groups above and below the diaphragm, outside the lymph nodes in a nearby organ or area, and in the spleen.
In stage IV adult non-Hodgkin lymphoma, the cancer:
is found throughout one or more organs that are not part of a lymphatic area (lymph node group, tonsils and nearby tissue, thymus, or spleen), and may be in lymph nodes near those organs; or
is found in one organ that is not part of a lymphatic area and has spread to organs or lymph nodes far away from that organ; or
is found in the liver, bone marrow, cerebrospinal fluid (CSF), or lungs (other than cancer that has spread to the lungs from nearby areas).
Adult non-Hodgkin lymphomas are also described based on how fast they grow and where the affected lymph nodes are in the body. Indolent & aggressive.
The treatment plan depends mainly on the following:
The type of non-Hodgkin’s lymphoma
Its stage (where the lymphoma is found)
How quickly the cancer is growing
The patient’s age
Whether the patient has other health problems
If there are symptoms present such as fever and night sweats (see above)
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