Category Archives: Molecular Medicine

What is Personalized Medicine?

Every individuals disease is different. Personalized medicine strives to provide the right medicine for the right patient with the lowest toxicity. Personalized cancer therapy using proteomics involves molecular profiling of the patients cancer cells to map the susceptible drug targets and thereby guide therapy. Research, like that being done by the Center for Applied Proteomics and Molecular Medicine, provides strategies for personalized treatment with the goal of providing physicians key missing molecular information about the disease in each of their patients and improving the quality of life for patients.

The Center for Applied Proteomics and Molecular Medicines mission is to: a) create new technologies and make basic science discoveries in the field of disease pathogenesis b) apply these discoveries and technologies to create and implement strategies for disease prevention, early diagnosis and individualized therapy. The primary emphasis of our disease research is cancer, but new technologies developed in the center are being applied to a number of important human diseases including cardiovascular disease, diabetes, and obesity, as well as liver, ocular, neurodegenerative and infectious diseases.

The 7th Global Reverse Phase Protein Array Workshop will be hosted in Dublin, Ireland on September 14-16, 2017. RPPA technology is a powerful multiplexed immunoassay that can quantitatively measure hundreds of proteins and post-translationally modified proteins from a limited number of cells or a fraction of a biopsy.In the last decade, RPPA has been extremely useful to:1) focus on the role of functional proteomics in the aetiology and pathogenesis of any disease.2) focus on translational-clinical biomarker research.3) design clinical trials of established and novel treatments to identify, validate and advance understanding of baseline and pharmacodynamic predictive biomarkers of drug effectiveness as well as of drug resistance mechanisms.This is only the start. Every day a growing number of basic research scientists, biomedical and pharmaceutical companies around the world find new applications for this constantly evolving technology. Regardless of whether you are a pioneer of the technology, an experienced user or a researcher interested in incorporating the technology into your portfolio, join us to discuss the next applications of this technology. These range from advances in personalized medicine to the identification of therapeutic targets and discovery and validation of biomarkers.This year in Dublin, we will continue to build on the knowledge exchanged at the previous meetings in Houston (USA) 2011, Edinburgh (UK) 2012, Kobe (Japan) 2013, Paris (France) 2014, Manassas (USA) 2015, and Tubingen (Germany) 2016.

The Side-Out Metastatic Breast cancer trial was announced at the annual meeting of the American Society of Clinical Oncology (ASCO) and is expected to expand into phase two this month.

ASCO Poster Presentation

The pilot study was the first of its kind to utilize novel protein activation mapping technology along with the genomic fingerprint of cancer as a way to find the most effective treatment. Results indicate that while prior standard chemotherapy failed the 25 women who participated in the 2.5 year pilot study, nearly half of the patients enrolled in the Side-Out trail had at least a 30 percent increase in progression-free survival.

This molecular approach creates opportunities for new therapies. For example, if a breast tumor shares the same protein pathway activation shared with lung cancer, then the drug developed to hit that target for lung cancer can be used now for breast cancer. The pilot study included only FDA-approved drugs currently on the market. Additional studies are expected to fold in new drugs as they become available with experimental drug.

Hear what patients and a treating physician has to say: Funded by Volleyball Tournaments, Breast Cancer Pilot Study Succeeds

Based on the results of this trial, CAPMM and the Side-Out Foundation are expanding this study to a new trial that is set to launch within the next month.

Read more here:
Center for Applied Proteomics and Molecular Medicine

Following is an outline describing the instructions for submission toMolecular Medicine. Submission types include: Research Article, Review Article, Commentary, and Letter to the Editor. Submitted manuscripts should conform to the requirements set forth in the Instructions for Authors here. Incomplete or non-conforming work will be sent back to the author to be corrected and may cause delays in the review process.

CriteriaMolecular Medicineis an open access journal that seeks to publish recent original findings that elucidate the pathogenesis of disease at the molecular or physiological level, which may lead to the design of specific tools for disease diagnosis, treatment, or prevention. Manuscripts containing original material relevant to the genetic, molecular, or cellular basis of key physiologic or disease processes are considered for publication if neither the article nor any part of its essential substance, tables, or figures has been or will be published or submitted elsewhere before appearing inMolecular Medicine. Manuscripts published inMolecular Medicineshould contain human or animalin vivoorex vivodata and describe the implications of the results for human disease and medicine, at a level approachable by our broad audience.

Pre-submission EnquiryIf authors are unsure as to whether or not their manuscript comes within the scope ofMolecular Medicine, they may request advice prior to full submission. An abstract or a summary highlighting the originality and significance of the study should be submitted to the Editorial Office via the online submission system:http://mc.manuscriptcentral.com/molmed. When asked for Manuscript type, be sure to select Pre-submission Enquiry.Pre-submission inquiries sent by email will not be considered.

The pre-submission enquiry service is a courtesy and is not required prior to full submission. Pre-submission enquiries can be difficult to assess reliably andMolecular MedicineEditors cannot make an absolute commitment to have a contribution refereed before seeing the entire paper. Entire papers should not be sent as pre-submission enquiries.

Submission TypesMolecular Medicineaccepts contributions in the following formats: Research Article, Review Article, Commentary, and Letter to the Editor.

Research Article reports comprehensive data from original experimental research. This type of paper demonstrates original concepts relating to the molecular or physiological basis of human disease. Because critical evaluation and replication of findings are essential to the scientific process, these types of articles include detailed descriptions of all processes and experimental techniques utilized in the study. In some cases, the Editors may commission Research Articles. Word count is approximately 7000 (including abstract [250 words], figures [count as 250 words each, 5-6 figures are typical], and references). The specific format includes the following sections in this order: Title, Running Head, Author Names, Keywords, Abstract, Introduction, Materials and Methods, Results, Discussion, Acknowledgements, Disclosure, Footnotes, References, Tables, Figure Legends, Figures, and Supplementary Data (if applicable).

Review Article brings together and analyzes available information in a specific field. These submissions include a summary of the topic/field, a description of gaps in knowledge of the topic/field, and synthesis of information to form a testable hypothesis. Reviews discuss recent developments in the topic/field and make projections about the future direction of a particular field. In some cases, the Editors may commission Review Articles. Word count is approximately 7000 (including abstract [250 words], figures [250 words each], and references).

Commentary commissioned by the Editors. However, in some cases the Editors may consider unsolicited works. Commentaries are professional opinion pieces covering cutting-edge research topics related to disease pathogenesis and the future of medicine. These may also address an issue of concern regarding work published outside ofMolecular Medicine. In this case the commentary may be sent to the original authors for a response. While this submission type does not require data, figures, or original research, they may be included to aid in the education of the interdisciplinary audience. Word count is approximately 1500-3000 (including abstract [250 words], figures [250 words each], and references).

Letter to the Editor addresses an issue of concern regarding work published by Molecular Medicineand may include data that enhances the dialogue surrounding the work. This may be viewed as an open post-publication review of a manuscript. Once received, comments will be reviewed by the Editors and may be sent to the original authors for a response. In some cases an independent reviewer may be asked to assess the comments. Word count is approximately 800 with up to 15 references and 2 figures.

Cover LetterA cover letter should accompany each submission. The cover letter should:

To view a cover letter template, please see the freely available article: L Chipperfield, L Citrome, J Clark,et al.(2010) Authors' Submission Toolkit: A practical guide to getting your research published. Current Medical Research & Opinion. 26:8 p1968-1982.www.cmrojournal.com

Manuscripts should be submitted toMolecular Medicinevia our online submission system:http://mc.manuscriptcentral.com/molmed

Style ManualThe entire manuscript should be double-spaced and written in English with the format following the Council of Science Editors reference manual:Scientific Style and Format: The CSE Manual for Authors, Editors, and Publishers, Eighth Edition.Abbreviations may be used for genes, proteins, and other specialized names if spelled out in entirety at the first use. Any additional known names should also be included in the first use. Gene names must be italicized throughout the text.

File TypesThe following file types are NOT supported during submission: shs; exe; com; vbs; zip and docx. The maximum total size of files (in K) an author can submit is 60000. Five files may be uploaded at once. If you have difficulty submitting your file due to size restrictions please contact editor@molmed.org for assistance.

Non-Native English AuthorsThe European Association of Science Editors (EASE) has published multilingual guidelines for non-native English authors and translators. These guidelines are aimed at making scientific communication more efficient worldwide and preventing scientific misconduct. To view the multilingual guidelines please see this website:http://www.ease.org.uk/guidelines/index.shtml.

Format: Research ArticleThis specific format includes the following sections in this order: Title, Running Head, Author Names, Keywords, Abstract, Introduction, Materials and Methods, Results, Discussion, Acknowledgements, Disclosure, Footnotes, References, Tables, Figure Legends, Figures, and Supplementary Data (if applicable).

Title a title page must appear as the first page of the manuscript. The title page should include a title, running head, author list, keywords, and contact author information. The title of the paper should be 20 words or less. The title should not include acronyms or abbreviations.

Running Head this short version of the title should include a maximum of 45 letter spaces.

Author Names the author(s) list must include: the first name(s); the last/family name(s); the name of the department(s) and institution(s) in which the work was done; the institutional affiliation of each author; and the name, address, telephone number, fax number, and email address of the author responsible for correspondence. Any change in author list (additions/deletions) after paper acceptance must be justified in writing to the Editors. During online submission the full names and email addresses of all the authors are required. If the work is accepted, all authors are required to sign the Open Access Authorization andAcknowledgement of Authorship form. Molecular Medicine follows the authorship criteria put forth by the International Committee of Medical Journal Editors (ICMJE), which can be found here:http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-of-authors-and-contributors.html#two.

Keywords five MeSH-Medline keywords not included in the title must be included. For assistance visit:http://www.nlm.nih.gov/mesh/

Abstract (250 words) should include the rationale, objectives, results, and conclusions of the study. The Abstract should read as a single, continuous piece and not be written as a structured abstract (broken into separate sections).

Introduction should discuss appropriate, relevant sources that provide context for the study and help explain how the idea for the study came to be and why it is important. The objective and hypothesis of the study at hand should be explicitly stated in this section. The Introduction section should not include any mention of observed results.

Materials and Methods this section should include sufficient detail to allow another researcher to repeat the experiment. Descriptions may be 'in brief', followed by reference to a previous report using the same procedure, or by detailed description. One sentence referring a reader to a prior publication is insufficient.

General studies should include unambiguous identification of nonbiological materials used (chemicals) including the source of such materials, the types of apparatus used, including model number and manufacturer for specialized equipment, the experimental procedure, including potential hazards, if applicable; and the types of test performed, including statistical tests.

Biological studies should include unambiguous identification of genus, species, and strain; the source of any organisms (cell line, animal stock); and age, sex, weight, and condition of organisms as appropriate.

Protein molecular weights of DNA marker sizes should be indicated on figure panels showing gel electrophoresis. The quality of RNA should be proofed according to MIQE guidelines published in 2009 by S.A. Bustinet al. in Clinical Chemistry. Nucleic acid and protein sequences should be deposited in appropriate databanks in time for the accession numbers to be included in the paper. Please see theNCBI databases Web sitefor more information.

Microscopy should include the make and model of the microscope. Type, magnification, numerical aperture of the objective lenses and acquisition software are also needed. All micrographs must include an unlabelled scale bar in the image with a description included in the figure legend.

Research on animals should include a statement that the protocol was approved by the appropriate institutional committee and complied with theGuide for the Care and Use of Laboratory Animals.This statement is required for entry into peer-review.Descriptions should include information regarding:

the animal:n, age, sex, weight, and life stage, source (supplier), genetic nomenclature, microbial/pathogen status, and information related to preparation and assignment to treatment groups (including control groups);

the environment:micro and macroenvironments, diet, water, housing;

the method:include aspects of animal care that can affect research outcomes, experimental effects, administration of substances, use of infectious agents, sample acquisition, and euthanasia.

For details seeGuidance for the Description of Animal Research in Scientific Publications.Additional resources:ARRIVE Guidelines- Animal Research: Reporting In Vivo Studies,www.nc3rs.org.uk/ArriveEQUATOR Network Promoting transparent and accurate reporting of research studies,www.equator-network.orgAAALACwebsite -http://www.aaalac.org/International regulationson animal welfare are available at:http://www.aaalac.org/resources/internationalregs.cfm

Please properly site the use of any guides in the references and number the references accordingly. For example:

Committee for the Update of theGuide for the Care and Use of Laboratory Animals, Institute for Laboratory Animal Research, Division on Earth and Life Studies. (2011) Guide for the Care and Use of Laboratory Animals. 8th edition. Washington (DC): National Academies Press. [cited 20XX Month Day]. Available from: http://oacu.od.nih.gov/regs/

Institute of Laboratory Animal Resources; Commission on Life Sciences; National Research Council. (1996)Guide for the Care and Use of Laboratory Animals. Washington (DC): National Academy Press. [cited 20XX Month Day]. Available from: http://www.nap.edu/openbook.php?record_id=5140

Clinical studies should include pertinent details about human subjects, including methods of recruitment and relevant physical characteristics. Reports of human studies must include a statement that the protocol was approved by the appropriate institutional committee or that it complied with the HelsinkiDeclaration as revised in 1983 -http://www.wma.net/en/30publications/10policies/b3/index.html. Informed consent should be obtained for all subjects. When preparing reports of randomized clinical trials, authors should refer to the checklist published in the CONSORT Statement and should include a trial profile summarizing participant flow. For additional information, please see the NIH resource: Responsible Conduct of Research -http://bioethics.od.nih.gov/These statement arerequired for entry into peer-review.

Mathematicspapers with mathematicsshould follow the guidelines suggested in the resources below:International Organization for Standardization: Quantities and Units - Part 2: Mathematical Signs andSymbols to be used in the Natural Sciences and TechnologyAmerican Mathematical Society: A Manual for Authors of Mathematical PapersHow to Report Statistics in Medicine: Annotated Guidelines for Authors, Editors and Reviewers

Statistics papers with statistical testing should state the hypothesis being tested/comparisons of interest, the name of the test, the n for each analysis, a justification for the use of that test, the alpha level for all tests, whether the tests were one- or two-tailed, and the actual P value for each test. Confidence intervals should be computed to complement the results of hypothesis tests. Discrepancies in any sample sizes due to exclusions, dropouts or missing data should be noted and explained. Data sets should be summarized with descriptive statistics, which should include the n for each data set, a clearly labeled measure of location (such as the mean or the median), and a clearly labeled measure of variability (such as the standard deviation, range, or interquartile range). Graphs should include clearly labeled error bars. Authors must state whether a number that follows the sign is a standard error of the mean (s.e.m.) or a standard deviation (s.d.).

Results original results should be presented clearly with appropriate subheadings. This section should not discuss implications or applications of the results.

Discussion should be an analytical examination of the study and results rather than a repetition of the information in the results section. It is relevant to compare the results of the study to the findings of similar studies and also to discuss the application of these results to the understanding of disease and the development of tools for disease diagnosis, treatment and prevention. The main findings should be placed in context to highlight the advance and describe how it moves the field forward. Avoid unqualified statements not supported by data.

Conclusion condenses work presented in the discussion and states the significance of the findings. Includes a statement of how the work may alter disease diagnosis, treatment, or prevention in the future.

Acknowledgments sources of financial support should be included along with any acknowledgements relevant to scientific advice or assistance.

Disclosure authors should include any necessary conflicts of interest. If none exist, the following text should be included: "The authors declare they have no competing interests as defined byMolecular Medicine, or other interests that might be perceived to influence the results and discussion reported in this paper."

Footnotes should be restricted to the title page (affiliations, corresponding author) and within tables. Footnotes on the title page are assigned consecutive superscript numbers (i.e., 1, 2, 3, etc.). Footnotes in tables are assigned consecutive, superscript capital letters (i.e., A, B, C, etc.).

References should be numbered consecutively as they are cited in the text and listed in parentheses. References first cited in tables or figure legends must be numbered so that they will be in sequence with references in the text. References should include full titles of the papers with inclusive page numbers. All authors should be listed when there are five or fewer; when there are six or more, the first author should be listed followed by "et al.'' Abbreviate the names of journals according to PubMed. Spell out names of unlisted journals. If essential, 'personal communication' may be incorporated in the appropriate place in the text. References to personal communications must be accompanied by a permission letter from the communicator authorizing publication of the comment. Manuscripts listed as in press should be numbered anda copy of the text should be submitted along with the manuscript under consideration. References to unpublished data or personal observation will not be accepted.Examples of reference styles can be found below.

Journal articles1. Gallowitsch-Puerta M, Tracey KJ. (2005) Immunologic role of the cholinergic anti-inflammatorypathway and the nicotinic acetylcholine alpha 7 receptor.Ann N Y Acad Sci.1062:209-19.

Complete books2. Tracey, KJ. (2005)Fatal Sequence:The Killer Within. New York: Dana Press. 184 pp.

Articles in books3. Forstner JF, Forstner GG. (1994) Gastrointestinal Mucus. In:Physiology of Gastrointestinal Tract.Johnson LR (ed.) Raven Press, New York, pp. 1255-1283.

Homepages4.Molecular Medicineonline [Internet]. c1994-2011. Manhasset (NY): The Feinstein Institute ofMedical Research; [cited 11 Apr 2008]. Available from http://www.molmed.org.

Tables should be included in the manuscript. Tables should be double-spaced each on its own page, portrait orientation, upright, with brief titles. Superscript capital letters should be used in consecutive order as footnotes as described above.

Figures: Instructions for FiguresFollowing is an outline describing the instructions for submission of figures to Molecular Medicine.

Acceptable File Typesinclude EPS, JPEG, and TIFF. Required resolution is 300-600 dpi. Required color mode is cyan, magenta, yellow, black (CMYK) which works best for commercial printers.

Font Should be a non-serif type, such as Arial (if you cannot use Arial, use Helvetica). Serif fonts are not acceptable. Font should be consistent within and across figures. Font size may vary, the minimum required font size is 6 points maximum font size is 12 points, the only exception being panel labels which may be 18 point, bold, all capitals. All fonts must be legible at actual print size (see column measurements below under Sizing). Line weights (.75pt 1.00 pt [2.00 pt for lines within flowcharts]; consistent within document. Symbol font may be used for special characters and Courier may be used for sequence alignments.

Capitalization Use sentence-style capitalization within figures. Capitalize the first word of each figure axis figure key label, figure title, etc.; subsequent words should be lowercase.Graph Style -Graphs should not include hatches or other patterns. Choose colors or shades of gray with enough contrast to stand out and make clear the meaning of the graph. Graph bars should be delineated with grays that differ by at least 20% in value. All controls (sham, untreated, vehicle) should be represented with white/open bars. Outline white, grey or colored bars with black. Graph lines should be .75-1.0 line weight. Please do not submit 3-D style graphs unless necessary.

Axis Labels Figures should be cited sequentially in the text using Arabic numerals. Figures should not contain more than one panel unless logically connected. Larger X and Y axis labels should be bold Arial. Axis number should be slightly smaller, using regular Arial. Use only X and Y axis lines, when appropriate. Avoid the use of complete boxes to enclose graphs. Use tick marks for only the major axis labels; smaller tick marks should be left off. Tick marks on graphs face outward and are used only for labeled quantities. Panel labels may be 18 point, bold, all capitals. Labels along the X-axis should be horizontal (if too long should be rotated 45 counter clockwise). Labels along the Y-axis should be rotated 90 counter clockwise. Labels along the Y-axis when on the right side (when there are two y-axes) should be rotated 90 clockwise. Numbers on axes are not bold. Initial symbols on axis labels should be spelled out, for example: Percent (%).

Figure Legends and Figure Keys Figure legends should include a short title and a brief explanation with sufficient detail to interpret the data presented. Do not exceed 350 words for each legend. Abbreviations should be defined at the end of the legend. Figure legends should be saved as part of the main text, not within the figures. Symbols should be in symbol font. Scale bars should be placed on images and defined in the legend. Text should not be placed over textured or shaded areas (light colored lettering on a dark background). Figure keys must be included within the legend and not in the figure itself.

Figure Layout Avoid unnecessary spacing within your figure layout. Avoid using unnecessary boxes to enclose graphs or images.

Panel Label Each panel of a multi-part figure must be labeled with a bold, capital, 18-point letter (A, B, C). Punctuation should not be included in the figure label. Labels should be placed in the upper left corner of each element and be no more than 12 mm away from the rest of the figure when viewed at 100%. Whenever possible, do not place this letter over other text or images.

Column Sizes Our journal columns are as follows: 1-column figure (2.3 inches/5.8 centimeters/166 points); 2-column figure (4.8 inches/12.3 centimeters/349 points); 3-column figure (7.3 inches/18.7 centimeters/532 points). Your figures should print at one of these sizes and still be readable and high quality.

Supplementary Data to submit supplementary data, authors should upload it to the submission site with the rest of their files. On the dropdown list of file types, the author should choose "Supplementary." This supplementary data will not be published along with the manuscript in the print journal, but will be availableonline.

Format: Other Submission TypesWhile there are no strict headings for Review Articles, Commentaries, or Letters to the Editor, authors should familiarize themselves with these content types by reading the journal online at:www.molmed.org. Word limits for these submission types have been described above. Abstract, Acknowledgements, Disclosure, Footnotes, References, Tables, Figure Legends, and Figures should adhere to the style and requirements described under Research Article.

SubmissionManuscripts should be submitted to Molecular Medicine via our online submission system:http://mc.manuscriptcentral.com/molmed. Postal submissions will not be considered. If you do not already have an account, you will need to create one. Click on 'create account' in the upper right hand corner of the screen (or, for previousMolecular Medicineauthors or reviewers, check for an existing account). Once you have completed the profile information, click the Main Menu and icon for "Corresponding Author Center." Begin a manuscript submission, fill in the required fields and upload any necessary files. While online submission can accommodate a variety of file types, authors are urged to provide their manuscripts as original Microsoft Word documents and figures as original files (figures may also be submitted as Microsoft Powerpoint slides). Click herefor assistance with submission. Confirm your work has been successfully converted to both a PDF and an HTML file. Please confirm your images are readable in the PDF and HTML files. Unreadable figures may delay the review process. Click 'submit' to send your manuscript to the Editorial Office. Should you have difficulty with this process, please contact the Editorial Office at:editor@molmed.org.

The status of your manuscript can be viewed by logging back in to this submission system. A description of status updates are below.

Awaiting Admin Processing the manuscript is being considered for the peer-review process.Under Consideration the manuscript has been sent for peer-review.Awaiting AE Preliminary Decision peer-review reports have been received.Awaiting EDB Decision Approval the manuscript is in the queue for Editorial Board Review and decision.

For additional tips on manuscript preparation and submission, authors are encouraged to read the following free paper:

L Chipperfield, L Citrome, J Clark,et al. (2010) Authors' Submission Toolkit: A practical guide to getting your research published.Current Medical Research & Opinion.26:8 p1968-1982.www.cmrojournal.com

Scientific MisconductMolecular Medicinerecognizes the importance of ethical standards in the research community and is committed to promoting ethical practices in our publication. Below are examples of the journal's commitment.

Molecular Medicineis a member of the Council of Publication Ethics (COPE) and generally follows the Code of Conduct of Journal Editors.

Members ofMolecular Medicinebelong to the Council of Science Editors (CSE). See the following White Paper by the Council: CSE's White Paper onPromoting Integrity in Scientific Publications, 2009 Update.

Molecular Medicineis a member of CrossCheck by iThenticate. iThenticate is a text duplication screening service that verifies the originality of content submitted before publication. The iThenticate software checks submissions against millions of published research papers, documents on the web, and other relevant sources. Authors, researchers and freelancers can also use the iThenticate system to screen their work before submission by visitingresearch.ithenticate.com.

FeesUpon submission authors will be charged a manuscript processing fee of $100 USD, payable by credit card only. UPDATE: As of November 2015 based on user feedback, the submission fee will be eliminated beginning January 1, 2016. If the work is accepted, authors will be charged a flat publication fee of $1500 USD. UPDATE: As of November 2015 This fee will be increased to $1750 beginning January 1, 2016. There are no additional charges for color pages, excess pages or word count. Manuscripts will not be sent for processing until this fee has been received. To see if grant funds may be used for payment, click the following link: http://oad.simmons.edu/oadwiki/OA_journal_funds. Editors and reviewers do not have access to author payment information. Ability to pay does not inform Editor and reviewer decision-making. To request a fee waiver, please contact the Editorial Office at: editor@molemed.org.Please contactfinance@molmed.orgwith any questions.

Author Acknowledgement and DisclosureUpon acceptance, all authors are required to complete an Open Access Authorization form as well as a Conflict of Interest - Disclosure form. These must be submitted electronically. All forms from all authors must be completed and submitted prior to the release of a final typeset-author approved galley.

Contact InformationThe Feinstein Institute for Medical ResearchEditorial Offices ofMolecular Medicine350 Community DriveManhasset, NY 11030 USATelephone: (516) 562-2114Fax: (516) 562-1022Email

Updated 2.December.2015

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What happened to precision medicine? Phoenix Business Journal We have to get ahead of these things, she said. What I want to see is molecular medicine and precision medicine develop for diagnostics, for early detection and ultimately prevention. Barker isn't alone in believing in the future of precision medicine. and more »

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What happened to precision medicine? - Phoenix Business Journal

High magnification micrograph of hypertrophic decidual vasculopathy, as seen in pregnancy-induced hypertension. Credit: Wikipedia

A mother's risk of preeclampsia, a potentially life-threatening illness associated with pregnancy, can be linked in some cases to genes from her fetus. For the first time, a relationship has been found between fetal genes and the risk of preeclampsia in the mother. An international research collaborative has presented this finding in Nature Genetics, first published online earlier this summer.

Preeclampsia affects around 3 percent of births in Norway; worldwide, that number is estimated to be about 5 percent. In the vast majority of cases, the mother has mild symptoms, typically high blood pressure. Nevertheless, preeclampsia is one of the leading causes of death in both mothers and babies around the time of birth, and sometimes the only way to treat it is to deliver the baby, even prematurely.

Little studied

"For the first time ever, we have discovered a fetal gene that increases the risk of preeclampsia," says Ann-Charlotte Iversen at the Department of Clinical and Molecular Medicine at NTNU. She says there has not been much research on the role of fetal genes in triggering the illness.

Preeclampsia usually begins with a problem in the placenta, which is mainly composed of fetal cells. For that reason, it makes sense that fetal cells might have a hand in causing the illness, Iversen said, even though it is the mother's symptoms during the last part of the pregnancy that lead to the diagnosis.

The largest of its kind in the world

"Our findings are particularly solid for three reasons: We analysed a large number of individuals, we found several genetic variables that all point to the same gene associated with the risk, and two independent population studies confirmed that this gene is associated with the risk," Iversen said.

There are also a number of major studies that support the conclusions. CEMIR is one of 12 partners from six countries in an EU project called InterPregGen, which was created in 2011. "We are all working together to uncover the genetic risk factors for preeclampsia in the mother and fetus. We have linked a number of major European population studies to conduct the world's largest genetic study of preeclampsia," says Iversen. "Our contribution to the project has been information on a group of women from the HUNT study who have had problematic and healthy pregnancies, as well as information from the Preeclampsia Biobank, which has been collected independently."

The Nature Genetics article includes analyses of material from the Preeclampsia Biobank, including blood samples and tissue samples from placentas that have been collected at St. Olavs and Haukeland University Hospitals. The genetic variants identified by the researchers are associated with the FLT-1 gene, which encodes a protein that, in soluble form, is known as a biomarker for preeclampsia.

The protein contributes to damaging the mother's vascular system causing symptoms such as high blood pressure and an increased amount of protein in the urine. This happens as a result of problems with the placenta, essentially because fetal cells in the placenta produce the protein.

"We have shown here that the risk of disease may be because changes in the gene affect how the protein works and how it affects the mother. This is a fetal gene that gives the mother an increased risk of developing preeclampsia. This find clearly brings us closer to a better understanding of preeclampsia," Iversen said.

"The EU project has brought together geneticists, statisticians and clinicians. NTNU and CEMIR's expertise has been a complementary strength," says Iversen. Gabriela Silva, a PhD candidate, analysed the protein expression of FLT-1 in placental samples from sick and healthy pregnant women, while postdoctoral physician Liv Cecilie Vestrheim Thomsen was central in collecting the placentas.

"We have compared the result with the occurrence of the genes associated with the risk. This means that we have conducted a functional follow-up of the gene discovery, which has now been published," Iversen says.

Predicting which women will get sick

"CEMIR's Research Group for inflammation in pregnancy has a goal to figure out which disease mechanisms cause problems with the placenta and lead to the development of preeclampsia," says Iversen. The group is working to understand what goes wrong so they can detect problems early in a pregnancy. The goal is to predict which women will develop the disease.

"Our molecular analyses have identified specialized fetal cells in the placenta as the main actors in preeclampsia. These are the same fetal cells that have been identified with this new genetic discovery. This reinforces our conviction that fetal cells play an active role, and represents a big change in thinking, since research has previously focused most on the mother's immune system. If we want to prevent preeclampsia, we have to understand the foundation for the disease," says Iversen.

Explore further: Altered immune cells may both contribute to preeclampsia and offer new hope for treatment

More information: Ralph McGinnis et al, Variants in the fetal genome near FLT1 are associated with risk of preeclampsia, Nature Genetics (2017). DOI: 10.1038/ng.3895

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Fetal genes can increase the risk of illness during pregnancy - Medical Xpress

Donald and Barbara Zuckers foundation donated $61 million to the medical school founded by Hofstra University and Northwell Health, the organizations announced on Wednesday, leading to renaming the school for the couple.

Most of the donation or $50 million will go towards a permanent endowment to provide students need-based scholarship support in the Zucker School of Medicine.

Some $10 million meanwhile goes towards creating and endowing the Barbara Hrbek Zucker Emerging Scientists Program at the Feinstein Institute for Medical Research, which is headquartered in Manhasset.

The program is intended to prepare postdoctoral fellows for successful careers and support early career faculty in developing research programs.

More so than any other donors in our history, Don and Barbara Zucker have been extraordinary supporters of causes where we have historically struggled to get financial support, Michael J. Dowling, president and chief executive officer of Northwell Health, said in a statement.

Their latest gifts are a testament to the Zuckers leadership as philanthropists who recognize the vital role of medical education and research in transforming the future of medicine.

Donald Zucker, 86, a New York City real estate developer from Sands Point, and his wife Barbara, donated to Northwell in the past. The couple gave to organizations like the Zucker Hillside Hospital in Glen Oaks, Lenox Hill Hospital in Manhattan and the Elmezzi Graduate School of Molecular Medicine in Manhasset.

Lawrence Smith, the founding dean of the Zucker School of Medicine and physician-in-chief at Northwell Health, said that the couple recognized how important it is to support students financially.

Their generosity will ensure that our medical school will continue to be represented by a highly diverse, talented student body that reflects the communities we serve throughout the New York metropolitan area, Smith said.

Hofstra University and Northwell Health first launched the medical school in 2008. It currently has 400 students enrolled and had more than 7,000 applicants competing for 100 spaces in 2016.

Almost a decade ago, we set out to create a new model of medical education that would improve health care in our region and today we mark another milestone in that journey, said Stuart Rabinowitz, the president of Hofstra University. The Zuckers support solidifies and expands our commitment to train innovative physicians whose backgrounds and experiences are as diverse as the people they treat.

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Hofstra and Northwell rename medical school following $61 million donation - The Island Now

Neither substance is sufficient alone, said Dr. Chen-Yu Zhang, co-author of the study and a professor of biochemistry at Nanjing University in China. The royal jelly and plant microRNA work together to affect caste formation.

Were taking you on a journey to help you understand how bees, while hunting for pollen, use all of their senses taste, touch, smell and more to decide what to pick up and bring home.

Researchers raised honeybees in the lab to study the effects of the plant microRNA in bee bread. They found that larvae raised on diets supplemented with the plant material had smaller bodies and smaller ovaries than those raised without the supplement. Further experiments showed that one of the most common types of plant microRNA found in bee bread targets a gene in honeybees, TOR, which helps determine caste.

They did a nice job documenting the specific role of microRNA that has a very profound impact on this development, said Xiangdong Fu, a professor of cellular and molecular medicine at UC San Diego who was not involved with the study. Its fascinating. Depending on what you eat, you can end up a different way.

This information could provide new insight into the mysterious trend of rising honeybee deaths in the last decade, which could have a large impact on agriculture.

Xi Chen, a co-author of the paper and a professor of biochemistry at Nanjing University, said plant microRNA could play a role. We could check if changing microRNA in certain plants can cause the disappearance of the honeybee, he said.

The study also points to the interdependence of plants and honeybees. The plant substance that affects bee development is also important for the formation of certain flowers, Dr. Zhang said. The molecules can make a flower larger and more colorful, which attracts more bees and helps spread its seed, a sign of plant and insect co-evolution.

This is a large, emerging area of research, according to Dr. Philip Askenase, a professor of medicine and pathology at Yale University School of Medicine, who was not involved in the study. Here you have evolutionary dependence of the creature and the plants, he said. MicroRNA from plants can influence bee development and microRNA from bees can influence the pollen they spread, affecting the next generation of plants. They are mutually contributing microRNA to each other. Thats a big deal.

Learning more about how these molecules can affect species in different kingdoms like plants and insects or plants and humans could help identify therapeutic applications for cancer treatments or to suppress allergic reactions, Dr. Askenase said. Some important biological problems could now be addressed with this new knowledge of how nature works, he said.

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The Secret Ingredient That Stops Honeybees From Becoming Queens - New York Times

31 Aug 2017

Arriving at the same conclusion, essentially at the same time, three research groups have independently mapped the site where proteases snip off the extracellular portion of TREM2. Two papers in the August 30 issue of EMBO Molecular Medicine and one under review and posted on the BioRiv preprint server report that the site coincides exactly with a mutation in the microglial receptor, H157Y, that boosts AD risk by as much as 11-fold. Its incredible that all three results are essentially identical, said Christian Haass of Ludwig-Maximilians-Universitt, Munich, the senior author on one of the EMBO Molecular Medicine papers. Peter St. George-Hyslop of the University of Toronto, who co-led the second published study with Damian Crowther and Iain Chessell of AstraZeneca in Cambridge, U.K., presented their findings earlier this year at the 13th International Conference on Alzheimers and Parkinsons Diseases in Vienna (Apr 2017 news). Ulf Neumann at Novartis in Basel, Switzerland, led the thirdgroup.

TREM2 binds anionic lipids released during neuronal and glial damage. It supports microglial metabolism and it promotes the migration, cytokine release, phagocytosis, proliferation, and survival of the cells (Aug 2017 news;Feb 2015 news). Evidence suggests that TREM2 spurs microglia to form a neuroprotective barrier around amyloid plaques and to clear A (May 2016 news; Jul 2016 news). Motivated by the discovery of roughly a dozen TREM2 genetic variants that increase the risk of frontotemporal dementia, AD, and possibly other neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinsons disease, researchers are searching for ways to bolster TREM2s protective function. Thinking that limiting ectodomain shedding might improve TREM2 signaling (see image below), the three research groups set out to find the cleavagesite.

Snip Site. ADAM10, or other proteases, may shed TREM2s extracellular ligand binding domain, abolishing TREM2-mediated signaling. (Courtesy of Yeh et al., 2017, Trends MolMed.)

In Haasss lab, first author Kai Schlepckow focused on the TREM2 C-terminal fragment (CTF) left over after shedding. Because -secretase quickly chews up the CTF in microglia, much as it does the C-terminal fragment of amyloid precursor protein in neurons, Schlepckow generated human embryonic kidney 293 (HEK293) cells expressing TREM2 and treated them with DAPT, a -secretase inhibitor. After immunoprecipitating the TREM2 CTF, he analyzed it by mass spectrometry. The result was crystal clear: a single major peak corresponding to a fragment with an N-terminus at serine 158. That amino acid lies in the extracellular domain of TREM2, 17 amino acids from the predicted transmembrane domain. Ive had experience mapping other cleavage sites and this one is super-precise. Ive never seen something like it, saidHaass.

Indeed, the result was so clean, Haass wondered if it was real. He had the researchers analyze the sequence on the other side of the break. Because sTREM2, the soluble extracellular domain, is too big to analyze by mass spectrometry, Schlepckow created a TREM2 construct with a tobacco etch virus protease cleavage site shortly before the proposed sheddase site. That way, the researchers could immunoprecipitate sTREM2 from the cell medium, shorten it with the TEV protease, and then determine its mass. Consistent with the CTF results, they obtained a single sharp peak corresponding to a peptide terminating at histidine 157. The researchers got the same results using human THP-1 cells, which are similar to monocytes, the cells that give rise tomicroglia.

Crowthers group also relied on mass spectrometry. First we used a library of peptide protease inhibitors to get a quick-and-dirty answer to where the site might be, said Crowther. First author Peter Thornton at AstraZeneca synthesized a set of D-amino acid polypeptides that overlapped TREM2 amino acids 140-176, where they thought metalloprotease likely cleaved. Then they used these peptides to compete with TREM2 for the protease in primary humanmacrophages.

All peptides that spanned TREM2 amino acids 158-160 reduced TREM2 ectodomain shedding, whereas peptides mapping to nearby regions did not. Interestingly, the most effective peptide worked equally well when its sequence was reversed, suggesting that the responsible metalloproteases recognize biophysical properties, such as charge, to target a specific sequence. To map that sequence more precisely, Thornton immunoprecipitated sTREM2 from the conditioned media of several cell types, isolated it by gel chromatography, digested it with trypsin and analyzed the fragments by mass spectrometry. From human macrophages, primary murine microglia, and HEK293 cells expressing human TREM2, H157 surfaced as the most likely sheddasesite.

Neumanns group tackled the question by generating a series of TREM2 constructs with deletions or amino acid replacements in the stalk region, located between the transmembrane and extracellular domains (see image above). They identified two regions, amino acids 169-172 and 156-164, in which mutations strongly reduced TREM2 cleavage induced by the protein kinase C activator PMA. To pinpoint the cleavage site, they designed a series of labeled peptides spanning the stalk region, incubated them with the metalloprotease ADAM17 in a test tube, and analyzed the resulting fragments using high-performance liquid chromatography and mass spectrometry. The researchers used ADAM17 because their prior data indicated it was a major TREM2sheddase.

Data from Dominik Feuerbach at Novartis also revealed the H157-S158 bond as the cleavage site. The researchers repeated the experiments using liquid chromatography and mass spec to analyze sTREM2 generated by HEK293 cells expressing human TREM2 and TYROBP, which forms a complex with the cytoplasmic portion of TREM2 (see image above). Feuerbach said they included TYROBP to mimic TREM2s physiological state as closely as possible. Again, they found cleavage occurred at the H157-S158site.

Researchers have reported that a histidine to tyrosine mutation at position 157 increases the risk for late-onset AD in Han Chinese and affects shedding (Ma et al., 2014). How might this change affect TREM2 processing? Haass and Crowthers groups compared shedding in cells expressing wild-type or the H157Y mutant. Crowther found that the extracellular domain of the wild-type protein has a half-life of less than one hour on the cells surface. Although the researchers didnt measure the mutant extracellular domain half-life directly, they found cells more rapidly pumped mutant sTREM2 into the conditioned medium. Shedding is fast in healthy cells, but it gets even faster with the variant, he said. Haass group obtained similar results. This was a surprise, said Haass, who was expecting the H157Y mutation to reduce sTREM2 production, just like other mutations that increase risk for neurodegeneration. The T66M and Y38C mutations associated with frontotemporal dementia, for example, preclude TREM2 from reaching the cell surface where shedding predominantly occurs, shutting down production of sTREM2. We got exactly the opposite of what we expected, saidHaass.

On further reflection, Haass and colleagues realized that increased shedding could have the same biological effect as reducing cell surface TREM2 because it reduced the amount of signaling-competent TREM2 on the cell surface. Indeed, Schlepckow found that monocytes expressing H157Y TREM2 phagocytosed a third less Escherichia coli than monocytes expressing the wild-type receptor. These findings support the idea that loss of function is key to the risk associated with H157Y TREM2, in line with most other TREM2 variants whose mechanisms have been dissected. Marco Colonna of Washington University in St. Louis noted that except for two TREM2 variants that increased ligand binding but were only weakly tied to AD risk, all other variants dampened TREM2 function, either by decreasing ligand binding, preventing TREM2 from reaching the cell surface, or, in this case, increasing TREM2 shedding. Feuerbach said the case for trying to therapeutically boost membrane-bound TREM2 is more compelling than ever. From a genetic point of view, this is one of the most attractive targets, said Feuerbach, first author of the BioRivpaper.

To identify the proteases responsible for wild-type and mutant TREM2 shedding, Thornton and colleagues used various protease inhibitors, as well as siRNA, to block or knock down the expression of ADAM17 or ADAM10,a.k.a. a-secretase, which process the A precursor protein (APP). Previous work implicated ADAM10 in TREM2 cleavage (Kleinberger et al., 2014). Lowering or blocking ADAM10, but not ADAM17, reduced TREM2 shedding. However, neither an inhibitor, nor ADAM10 siRNA, blocked shedding of the H157Y mutant as effectively as they blocked that of the wild-type. Crowther hypothesized the existence of a novel sheddase to account for the difference, but also acknowledged the mutant site might simply be more prone to ADAM10 cleavage and, thus, harder to fully block. It could just be that the H157Y conformation is so tasty, that ADAM10 just continues to nibble away, he said. Haass favors this latterpossibility.

Feuerbach, however, said his data points to ADAM17, rather than ADAM10, as the major TREM2 sheddase. In contrast to Crowthers group, which used HEK273 cells expressing human TREM2, but not TYROBP, Feuerbach used Chinese hamster ovary cells expressing both proteins, as well as human M2A macrophages, which are related to microglia and endogenously express TREM2 and TYROBP. To probe TREM2 cleavage, he used protease inhibitors, and ADAM10 or ADAM17 knockouts. His results indicate that TREM2 shedding depends much more on the activity of ADAM17. We would not exclude ADAM10 or other proteases from playing a role, but Id say ADAM17 probably accounts for 90 percent of the shedding, he said. Colonna and Thomas Brett, also at Washington University, thought that differences in cell types might account for the discrepancy. Different proteases might be more prevalent in different cellsprobably multiple proteases can do the job, said Colonna. Also, Feuerbach pointed out that TYROBP might affect the conformation of the cleavagesite.

From a therapeutic standpoint, researchers agreed the proteases matter less than the location of the TREM2 cleavage site. No one is interested in developing an ADAM10 inhibitor for AD, said Crowther, noting it would have too many undesirable secondary effects. Indeed, ADAM10s cutting of APP prevents the generation of A, noted Terrence Town, University of Southern California, Los Angeles. Hoping to more specifically target TREM2 clipping, Haass has begun generating antibodies against the TREM2 cleavage site. Not only could such antibodies help people with the rare H157Y mutation, but they might also help nearly anyone with AD, he believes. Antibodies against the TREM2 cleavage site could have a very potent effect, said Crowther. A boost in membrane-bound TREM2 that would rev up A phagocytosis would be beneficial. Indeed, evidence suggests people with sporadic and familial AD have increased levels of freewheeling sTREM2 in their spinal fluid, which may reflect an uptick in TREM2 shedding (Jan 2016 news;Suarez-Calvet et al., 2016). Nonetheless, Haass cautioned that it will be complicated to develop such a therapy because excessive TREM2 activity could beharmful.

Furthermore, any therapy that keeps TREM2 from casting off its extracellular domain will also cause a drop in sTREM2 levels. Brett wondered about the consequences, noting that, at least according to one study, sTREM2 causes inflammation, which is harmful, but also promotes microglial survival (Feb 2017 news). Colonna agreed. At the end of the day, we dont know if blocking sTREM2 production will have a positive, negative, or neutral effect, hesaid.

Regardless of whether regulating TREM2 processing has a future in the clinic, the new studies offer important basic insights, said Colonna. By looking at every single mutation, well understand TREM2 better.MarinaChicurel

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TREM2 Cleavage Site Pinpointed: A Gateway to New Therapies? - Alzforum

Newswise New York (August 31, 2017) Scientific innovator and physician Dr. Pawel Muranski has joined NewYork-Presbyterian and Columbia University Medical Center (CUMC) as director of cellular immunotherapy at the newly established Good Manufacturing Practices (GMP) cell production lab and assistant director of Transfusion Medicine and Cellular Therapy. He will also serve on the faculty of CUMC as Assistant Professor of Medicine, Pathology and Cell Biology, a principal investigator at Columbia Center for Translational Immunology (CCTI) and a member of Columbias Herbert Irving Comprehensive Cancer Center.

Were thrilled to have Dr. Muranski joining us to continue his innovative work, said Dr. Gary Schwartz, chief of the Division of Hematology/Oncology at NewYork-Presbyterian/CUMC and the Clyde 56 and Helen Wu Professor of Oncology (in medicine) at CUMC. His approach to T cell-based therapy holds so much potential and could revolutionize care for cancer patients, transplant patients and others.

Dr. Muranski is a hematologist who specializes in bone marrow transplantation and in developing adoptive T cell therapies, in which white blood cells called T lymphocytes are removed from a patient or a donor and then programmed to target viral infections, leukemic cells and solid tumors. Adoptive transfer of T cells, including Chimeric Antigen Receptor (CAR)-T therapy has shown great promise in early trials of patients with leukemia, lymphoma and several solid cancersin some cases leading to a complete remission.

Dr. Muranskis research will continue to focus on exploiting and enhancing the capability of engineered T cells to recognize and target cancerous cells or dangerous viruses. He has a particular interest in developing CD4+ T helper cellsthe master orchestrators of immune responseas a potentially powerful weapon against cancer. His T cells can also target viral infections in patients whose immune systems have been weakened by bone marrow or organ transplantation, cancer treatment, or autoimmune diseases.

Despite recent spectacular advances in the field of cancer immunotherapy, very few institutions have GMP laboratories with the capacity to grow and manipulate T cells, said Dr. Muranski. NewYork-Presbyterian and Columbia University Medical Center are now positioned to become leaders in cutting-edge cellular immunotherapies. Im excited to work with the team here on developing a comprehensive program that brings these innovative treatments to our patients.

In addition to his work in the GMP lab, Dr. Muranski will be working with Dr. Prakash Satwani, a pediatric hematologist and oncologist at NewYork-Presbyterian and associate professor of pediatrics at CUMC, on an upcoming major CAR-T cell initiative. He will also work closely with Dr. Markus Mapara, director of the Adult Blood and Marrow Transplantation Program at NewYork-Presbyterian/Columbia and professor of medicine at CUMC.

Dr. Muranski trained as a fellow at the Surgery Branch, National Cancer Institute (NCI), National Institutes of Health (NIH) in Bethesda, Maryland, where he performed innovative studies aimed at understanding of the role of CD4+ T cells as mediators of curative anti-tumor immunity. Most recently, he served in Hematology Branch, National Heart, Lung and Blood Institute (NHLBI) at the NIH, where his research focused on using T cell-based therapies to prevent viral infections in patients undergoing donor-based stem cell transplantation for blood cancers.

He earned his medical degree from the Medical University of Warsaw in Poland before completing a research fellowship at the Institute for Molecular Medicine and Genetics, Medical College of Georgia and a residency at St. Francis Hospital in Evanston, Illinois. He completed a clinical fellowship in hematology and oncology at the National Institutes of Health in Bethesda, Maryland.

NewYork-Presbyterian

NewYork-Presbyterian is one of the nations most comprehensive, integrated academic healthcare delivery systems, whose organizations are dedicated to providing the highest quality, most compassionate care and service to patients in the New York metropolitan area, nationally, and throughout the globe. In collaboration with two renowned medical schools, Weill Cornell Medicine and Columbia University Medical Center, NewYork-Presbyterian is consistently recognized as a leader in medical education, groundbreaking research and innovative, patient-centered clinical care.

NewYork-Presbyterian has four major divisions:

Columbia University Medical Center

Columbia University Medical Centerprovides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. The campus that Columbia University Medical Center shares with its hospital partner, NewYork-Presbyterian, is now called the Columbia University Irving Medical Center. For more information, visit cumc.columbia.eduorcolumbiadoctors.org.

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Dr. Pawel Muranski to Head New Cellular Immunotherapy Laboratory at NewYork-Presbyterian/Columbia University ... - Newswise (press release)

The virtual embryo offers predictions which cells express -- for example -- the genes even skipped (red) and twist (green). To appreciate the spatial distribution, researchers can look at the fly embryo from all angles. Credit: Drosophila Virtual Expression eXplorer, BIMSB at the MDC

After 13 rapid divisions a fertilized fly egg consists of about 6,000 cells. They all look alike under the microscope. However, each cell of a Drosophila melanogaster embryo already knows by then whether it is destined to become a neuron or a muscle cellor part of the gut, the head, or the tail. Now, Nikolaus Rajewsky's and Robert Zinzen's teams at the Berlin Institute of Medical Systems Biology (BIMSB) of the Max Delbrck Center for Molecular Medicine in the Helmholtz Association (MDC) have analyzed the unique gene expression profiles of thousands of single cells and reassembled the embryo from these data using a new spatial mapping algorithm. The result is a virtual fly embryo showing exactly which genes are active where at this point in time. "It is basically a transcriptomic blueprint of early development," says Robert Zinzen, head of the Systems Biology of Neural Tissue Differentiation Lab. Their paper appears as a First Release in the online issue of Science.

"Only recently has it become possible to analyze genome-wide gene expression of individual cells at a large scale. Nikolaus recognized the potential of this technology very early on and established it in his lab," says Zinzen. "He started to wonder whethergiven a complex organized tissueone would be able to compute genome-wide spatial gene expression patterns from single-cell transcriptome data alone." BIMSB combines laboratories with different backgrounds and expertise, emphasizing the need of bringing computing power to biological problems. It turns out the institute had not only the perfect model systemthe Drosophila embryoto address Rajewsky's question, but also the right people with the right expertise, from physics and mathematics to biochemistry and developmental biology.

"The virtual embryo is much more than merely a cell mapping exercise," says Nikolaus Rajewsky, head of the Systems Biology of Gene Regulatory Elements Lab, who enjoyed returning to fly development 15 years after studying gene regulatory elements in Drosophila embryos during his post-doctoral time at the Rockefeller University. Using the interactive Drosophila Virtual Expression eXplorer (DVEX) database, researchers can now look at any of about 8,000 expressed genes in each cell and ask, "Gene X, where are you expressed and at what level? What other genes are active at the same time and in the same cells?" It also works with the enigmatic long non-coding RNAs. "Instead of time-consuming imaging experiments, scientists can do virtual ones to identify new regulatory players and even get ideas for biological mechanisms," says Rajewsky. "What would normally take years using standard approaches can now be done in a couple of hours."

Breaking the synchronicity of the first cell divisions

In their paper, the MDC researchers describe a dozen new transcription factors and many more long non-coding RNAs that have never been studied before. Also, they propose an answer to a question that has puzzled scientists for 35 years: How does the embryo break synchronicity of cell divisions to develop more complex structures?

In a process called gastrulation, distinct germ layers form and cells become restricted with regard to which tissues and organs they may differentiate into. "We believe that the Hippo signaling pathway is at least partly responsible for setting up gastrulation," says Rajewsky. The pathway controls organ size, cell cycles and cell proliferation, but had never been implicated in the development of the early embryo. "We not only showed that Hippo is active in the fly, but we could even predict in which regions of the embryo this would lead to a different onset of mitosis and therefore break synchronicity. And that is just one example for how useful our tool is to understand mechanisms that have escaped traditional science."

Project underwent a tough gestation period

When the researchers started creating the virtual embryo, they did not know whether it would be possible. A key pillar of their eventual success is the Drop-Seq technology, a droplet-based, microfluidic method that allows the transcriptional profiling of thousands of individual cells at low cost. This technique had been newly set up in the Rajewsky lab by Jonathan Alles, a summer student.

However, the fly embryos needed to be selected precisely at the onset of gastrulation. Philipp Wahle, a PhD student in Robert Zinzen's lab, hand-picked about 5,000 of them before dissociating them into single cells. "I was convinced this would give us a large and completely unique data set. This was a great motivation for me," says Wahle. That laborious process created a new challenge. "You need to collect over several sessions to have enough material for a sequencing run," says Christine Kocks, who led the single-cell sequencing team. It was composed of Jonathan Alles, Salah Ayoub and Anastasiya Boltengagen, who jointly with computational scientist Nikos Karaiskos optimized the droplet-based sequencing. "So we had to find a way to stabilize the transcriptomes in the cells," added Kocks. "Finally, based on his earlier work with C. elegans embryos, Nikolaus suggested using methanol." The new single-cell fixation method was published in BMC Biology in May 2017.

As the data got better and better, Nikos Karaiskos, a theoretical physicist and computational expert in Rajewsky's lab, took on the challenge of spatially mapping such a large number of cells to their precise embryonic position. None of the existing approaches in the field of spatial transcriptomics was suitable to reconstruct the Drosophila embryo. "It was a reiterative process to filter the data, see what is inside and try to map it. It changed many times along the way," says Karaiskos. There was a lot of back and forth between members of the computer lab and wet labexchanges that are a defining characteristic of the BIMSB. "I had to question my work all the time, see where it was lacking and develop something better." He came up with a new algorithm called DistMap that can map transcriptomic data of cells back to their original position in the virtual embryo.

Navigating unchartered territory

The construction of the virtual embryo allowed Karaiskos to readily predict the expression of thousands of genes, an almost impossible task by traditional experimental means. Philipp Wahle, supported by Claudia Kipar, validated these predictions by visualizing the gene expression profiles at the bench with a traditional approach: In situ hybridization allows visualizing patterns of gene expression with colorful dyes that are visible under the microscope. "At this stage, a single layer of cells surrounds the entire fly embryo," says Wahle. "This makes it very accessible, thus enabling you to compare the computational data with imaging."

It is the first time that it has been possible to look at the about 6,000 cells of the embryo individually, assess their gene expression profilesand understand what determines their behavior in the embryo. "The most important technological advance of this study is that we don't lose the spatial information that is required to understand how embryonic cells act in concert," say the scientists. "This really is unchartered territory and requires new bioinformatics approaches to make sense of the collected data. This worked beautifully in our collaboration, not least because of the unique make-up of the Rajewsky lab, which integrates wet lab and computational approaches." One major advantage is that both groups are not only interested in technology but have specific biological questions that motivate them, says Rajewsky. "Robert has a deep understanding of early development. We can do single-cell sequencing runs and have the computational power to develop the tools that help us actually understand the underlying gene regulatory interactions."

The groups are already planning follow-up projects. One example would be to map the cells at different time points to see how they work together to form organs and tissues. Another would be to check whether the mapping approaches are applicable to more complex tissues.

Explore further: Lockdown genes to reduce IVF failure rates

More information: "The Drosophila Embryo at Single Cell Transcriptome Resolution" Science (2017). science.sciencemag.org/lookup/ 1126/science.aan3235

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Reconstructing life at its beginning, cell by cell - Phys.Org