Cheminformatics and Bioinformatics @ NIH...Cheminformatics-2017 7 • Researchers created a 3-D...

Cheminformatics and Bioinformatics @ NIH

Susan K. Gregurick, Ph.D. Division DirectorBiomedical Technology, Bioinformatics and Computational Biology

Cheminformatics-2017

“Science in pursuit of fundamental knowledge about the nature and behavior of living systemsand the application of that knowledge to extend healthy life and reduce illness and disability.”

...

The National Institutes of HealthThe Nation’s Steward of Medical & Behavioral Research

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Understanding the Dual Nature of NIH

NIH supports institutions & people(Extramural Research)

• >2,500 institutions• >400,000 scientists & research

personnel• Approx. 70,000 applications and 40,000

awards annually• Approx. 81% of the NIH budget

NIH is an institution(Intramural Research)

• Approx. 6,000 scientists• Approx. 11%

of NIH’s budget

Source: report.NIH.gov - awards by location, 10/5/2017

Alaska

Hawaii

Cheminformatics-2017 4

National Institutes of Health

National Instituteon Alcohol Abuseand Alcoholism

National Instituteof Arthritis andMusculoskeletal

and Skin Diseases

National CancerInstitute

National Instituteon Aging

National Instituteof Child Health

and HumanDevelopment

National Instituteof Allergy and

Infectious Diseases

National Instituteof Diabetes andDigestive and

Kidney Diseases

National Instituteof Dental andCraniofacial

Research

National Instituteon Drug Abuse

National Instituteof EnvironmentalHealth Sciences

National Institute onDeafness and Other

CommunicationDisorders

National EyeInstitute

National HumanGenome Research

Institute

National Heart,Lung, and Blood

Institute

National Instituteof Mental Health

National Instituteof NeurologicalDisorders and

Stroke

National Instituteof General

Medical SciencesNational Institute

of Nursing Research

National Libraryof Medicine

National Centerfor Complementary

and AlternativeMedicine

FogartyInternational

Center

National Centerfor AdvancingTranslational

Sciences

National Instituteof Biomedical Imaging and

Bioengineering

NIHClinical Center

Centerfor Information

Technology

Center for Scientific

Review

National Center on Minority Health

and Health Disparities

Office of the Director

No funding authority


NIH Mission

To seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.

To seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability

FY2018 Priorities:1. Fundamental Science Enhanced by Technological Advances

2. Treatments and Cures

3. Health Promotion and Disease Prevention

4. Enhancing Stewardship


Brain Research through Advancing Innovative Neurotechnologies

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Goal: Produce a clearer, dynamic picture of the brain that can show, for the first time, how individual cells and complex neural circuits interact in both time and space Leverages new computational algorithms and statistical methods to simulate the complexities of neural circuitry


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• Researchers created a 3-D model of the interactions between developing brain regions—in a dish.

• Using the model, the team looked at how mutations that cause Timothy syndrome affect brain development and discovered a defect in how neurons migrate between regions.

• The results suggest a way to study personalized brain development and disease.

NIH BRAIN Initiative Breakthroughs

After spheroids representing two different brain regions fuse in a dish, neurons from one spheroid (green) migrate into the other and forge connections with the neurons there.Pasca lab, Stanford University

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https://www.nih.gov/news-events/nih-research-matters/3-d-model-human-brain-development-disease Brain development is a complicated process. During mid-to-late gestation, neurons migrate from deep brain structures and organize themselves into the tissues that will become the human cerebral cortex—the outer layer of the brain and seat of higher-order mental functions. The brain is especially vulnerable during this building process. Glitches in this period are thought to set the stage for autism, schizophrenia, and other neurodevelopmental brain disorders. An autism-related disorder called Timothy syndrome is caused by mutations in the CACNA1C gene, which codes for the CaV1.2 calcium channel. The function of these channels is to transport calcium ions into cells. The altered channels stay open much longer than usual, which allows calcium ions to continue flowing into cells abnormally. Calcium ions are involved in many different functions during development, including cell-to-cell communication and migration. To study prenatal brain development and how such genetic mutations disrupt the process, a team led by Dr. Sergiu Pasca at Stanford University created a miniaturized brain model by directing human stem cells in a dish to become neurons and form 3-D brain organoids or brain-region “spheroids.” The studies were partially funded by NIH’s National Institute of Mental Health (NIMH). Results were published in the May 4, 2017, issue of Nature. The team coaxed 3-D cell cultures to acquire the characteristics of two specific regions of the forebrain (dorsal and ventral) during early development. The two types of spheroids fused together when placed near each other, simulating the stage of development when neurons begin migrating from deep regions of the forebrain toward the cerebral cortex. Using live-cell imaging, the team tracked neuronal migrations. Neurons from the spheroids resembling tissue in the deep forebrain region, which produced the neurotransmitter GABA (GABAergic neurons), migrated toward and formed connections with the neurons from the spheroids resembling tissue in the outer region, which produced glutamate (glutamatergic neurons). This miniature model mimicked the maturation of the human forebrain by creating neural circuits with both GABAergic and glutamatergic neurons. GABAergic neurons dampen neural activity, while glutamatergic neurons stimulate neural activity. In brain spheroids derived from skin cells of patients with Timothy syndrome, the researchers discovered a defect in the migration of the GABAergic neurons. The neurons moved more frequently but less efficiently. The scientists could experimentally correct this problem with drugs that reduce the activity of Cav1.2 channels.


All of Us

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Tailor treatments to individual patient’s characteristics. Toward this goal, NIH is establishing a group of one million or more volunteer participants that reflect the diversity of the United States to contribute health information over many years to: Link data to electronic health records Provide a foundation for research studies leading to prevention strategies, novel therapeutics, and medical devices Improve how drugs are prescribed (choice, dosage)


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Rheumatoid arthritis mechanisms may vary by joint

•An epigenomic analysis of rheumatoid arthritis in knee and hip joints revealed unique patterns that suggest disease mechanisms may differ from joint to joint.

•The findings could open the door to development of more effective, personalized therapies for rheumatoid arthritis.

A research team led by Drs. Gary S. Firestein and Wei Wang at the University of California, San Diego,

study fibroblast-like synoviocytes (FLS), a type of cell that lines joints and contributes to joint destruction

in rheumatoid arthritis

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The scientists used computer analyses to group the samples according to the thousands of methylation differences they found across the genome. As expected, methylation patterns differed between rheumatoid arthritis FLS and osteoarthritis FLS. The team found the patterns also differed between rheumatoid arthritis FLS isolated from knees and hips. The researchers next examined the biological pathways affected and identified several in FLS that were differentially methylated between rheumatoid arthritis knees and hips. Gene expression analysis confirmed that genes and pathways differ between the joint locations. Many of these pathways are related to immune function and inflammation. The team next examined drugs developed for use in rheumatoid arthritis. They compared the drugs’ targets to the joint-specific biological pathways they uncovered. This analysis suggested that several promising drugs might have been assessed differently if these pathways had been taken into account. This analytical method could form the basis for developing precision medicine approaches to rheumatoid arthritis. “We showed that the epigenetic marks vary from joint to joint in rheumatoid arthritis,” Firestein says. “Even more importantly, the differences involved key genes and pathways that are designed to be blocked by new rheumatoid arthritis treatments. This might provide an explanation as to why some joints improve while others do not, even though they are exposed to the same drug.”


Support for developing new cutting-edge techniques to advances treatment for sickle cell disease

Focus on Cancer Immunotherapy to discover new immune targets and evaluate new immune-based approaches

Treatments and Cures

Intervening in the Opioid Epidemic to:

• prevent opioid misuse and addiction• develop new and improved treatments for opioid addiction • improving the deployment of evidence based strategies for combatting overdose• preventing and treating addiction • develop more effective treatments for pain with reduced potential for addiction and

misuse


Designing more effective opioids

•Researchers used computer simulations to screen millions of molecules for opioid-like pain-relieving properties.

•The analyses allowed scientists to create a molecule that effectively alleviates pain in mice, but with fewer side effects than the opioid morphine.

A computer model of the synthesized pain relieving compound PZM21 (blue) docked with the

mu opioid receptor (grey).Dr. Bryan Roth, University of North Carolina

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To search for a potential pain reliever with fewer side effects than current opioids, a research team led by Dr. Bryan Roth at the University of North Carolina and Dr. Brian Shoichet at the University of California, San Francisco, screened more than 3 million compounds for those that may be able to turn on the Gi-mediated pathway, but not beta-arrestin. The study was funded by NIH’s National Institute of General Medical Sciences (NIGMS), National Institute on Drug Abuse (NIDA), and National Institute of Mental Health (NIMH). The findings were reported online in Nature on August 17, 2016. Using computer modeling, the scientists evaluated each compound in over 1 million structural configurations to determine how well the molecules can physically interact with the mu receptor. The team chose 23 molecules for further pharmacological testing. The researchers then focused on optimizing the structure of the most potent molecule, which strongly activated the Gi pathway but had little effect on beta-arrestin. The resulting compound, called PZM21, was assessed for its effects on pain in mice. Mice treated with PZM21 showed pain relief comparable to those treated with the opioid morphine, but the effects lasted longer. Unlike morphine, PZM21 did not slow the animals’ breathing, and it caused less constipation. Further, PZM21-treated mice didn’t display the drug-seeking behaviors of those given morphine, suggesting that the drug may have less addictive potential.


• Coordinate access to and analysis of the many types of biological and behavioral ‘big data’ being generated by biomedical scientists

• Develop innovative and transformative computational approaches, tools, and infrastructures to make ‘big data’ and data science a prominent component of biomedical research

• Enable data sharing and utilization through the development of a new shared, interoperable cloud computing environment: the ‘Commons’

Data Science @ NIH


Making FAIR a Reality: NIH Data Commons Pilot Phase

1). Develop methods that support Global Unique Identifiers (GUID) for FAIR Biomedical Digital Objects2). Promote indexing metadata through FAIR compliant APIs.

1). Create Workspaces for Computations

2). Develop Scientific Use Cases

1). Develop cloud agnostic platforms

2). Develop open API standards

1). Develop FAIR guidelines and metrics2). Develop approaches to address data ethics, privacy and security


Data Commons Pilot Phase Consortium (DCPPC)

Compute Platform: Cloud

Services: APIs, Containers, GUIDs, Indexing, Search, Auth

Software: Services & Tools

Scientific analysis tools/workflows

Data

“Reference” Data SetsTOPMed, GTEx, MODs

FAIR

App store/User Interface/Portal/Workspace

Key Capabilities (KC)

1. Development and Implementation Plan for Community Supported FAIR Guidelines and Metrics

2. Global Unique Identifiers (GUID) for FAIR Biomedical Digital Objects

3. Open Standard APIs4. Cloud Agnostic Architecture and Frameworks 5. Workspaces for Computation6. Research Ethics, Privacy, and Security (AUTH)7. Indexing and Search 8. Scientific Use cases9. Training, Outreach, Coordination


Targeted Data Sets in Pilot Phase:

• TOPMed• Gtex• MODs

NIH Data Commons Pilot Phase

June July Aug

Awards finalized

Sept 12

Review of Applications

Aug 21-23

Invitation to Submit

Applications

Jul 12

Review of LOIs

Jul 7

LOIs DueJune 30

OTA Released

Jun 15

Kick off meeting

Review

Award Negotiations

Consortia Begins

Sept Mar 2018Oct

180 daysPlans and

prototypesSubmission of Applications

Jul 31


Cheminformatics and Medicinal Chemistry @ NIH

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• HTS for inhibitors• Virtual Screening and

Optimization• Medicinal and

Synthetic Chemistry• Computational

Synthetic Chemistry• Natural Products

inspired Therapeutics


NIH Funding in Cheminformatics

17

0

500000

1000000

1500000

2000000

2500000

3000000

3500000

4000000

4500000

NIGMS NIAID NINDS NCI NIMH NIAMS NIDA NIA NIEHS NHLBI NCATS NIDCD NICHD

Total Funding

Total Funding $21M

NIDA CENTER OF EXCELLENCE OF COMPUTATIONAL DRUG ABUSE RESEARCH (CDAR)

https://projectreporter.nih.gov/project_info_description.cfm?aid=9321115


Deep Learning and Cheminformatics

• Most scientists familiar with applications of deep learning to problems of image, speech, and text analysis.

• However, fewer are familiar with applying deep learning techniques to molecular data.

• Recently there has been an upswing in research andindustry interest in applying deep neural networks to predicting things like drug solubility, toxicity and maybe even synthetic routes.


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• PA-17-032

• This funding opportunity announcement encourages the use of existing and the development of novel computational approaches to identify drugs or drug combinations currently used for other conditions with potential to be efficacious in AD and AD-related dementias.

• POC: Suzana Petanceska, Ph.D. (NIA)

Translational Bioinformatics: Advanced Drug Repositioning for Therapy Development in Alzheimer’s (R01)


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• PA-17-330 (R01)

• Stimulate research to identify new and novel targets and mechanisms involved in tumor immune evasion

• A specific focus of this FOA is to encourage cross disciplinary collaborations between immunologists, cell biologists, medicinal chemists, pharmacologists, and molecular biologists

• POC: R. Allan Mufson, Ph.D (NCI)

Using Small Molecules and Molecular Genetics to Identify Novel Targets and Mechanisms Contributing to Tumor Immune Evasion


Chemistry Science Track Award for Rapid Transition (C/START)(R03)

• PAR-16-383

• The National Institute on Drug Abuse (NIDA) seeks to facilitate the entry of new/early stage investigators (ESIs) into substance use disorder (SUD) research.

• ESIs are invited to submit applications for small scale, innovative chemical/pharmacological pilot research projects

• Enable an ESI the opportunity to gather preliminary data in support of subsequent research grants

• POC: Kristopher Bough, PhD (NIDA)


Initiatives that Support Computational and Mathematical Sciences

• Biomedical Information Science and Technology Initiative (BISTI)Promote the optimal use of computer science and technology to address problems in biology and medicine by fostering collaborations and interdisciplinary initiatives (bisti.nih.gov)

• Big Data to Knowledge Initiative (BD2K)Develop new approaches, standards, methods, tools, software and competencies that will enhance the use of biomedical data & support initial efforts toward making data sets “FAIR” Findable, Accessible, Interoperable, and Reusable(datascience.nih.gov/bd2k)

• Interagency Modeling and Analysis Group (IMAG)Provide an open forum for communication among government representatives for trans-agency activities that have a broad impact in science (imagwiki.nibib.nih.gov)

• NSF/NIH Joint program in Mathematical Biology

Bring mathematics and statistics into the core of biological and biomedical research and to broaden the use of innovative mathematics in understanding life processes.


• Supports basic research that increases understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment and prevention

• Funds scientists to investigate how living systems work at a range of levels, from molecules and cells to tissues, whole organisms and populations

• Supports research in certain clinical areas, primarily those that affect multiple organ systems

• Provides leadership in o Training the next generation of scientistso Enhancing the diversity of the scientific workforceo Developing research capacities throughout the country

NIGMS Mission

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6-day-old zebrafish larva. What look like eyes will become nostrils, and the bulges on either side will become eyes. Oscar Ruiz and George Eisenhoffer, University of Texas MD Anderson Cancer Center, Houston nucleosome, Karolin Luger, Colorado State Universit


• Division of Biomedical Technology, Bioinformatics, and Computational Biology

• Division of Cell Biology and Biophysics

• Division of Genetics and Developmental Biology

• Division of Pharmacology, Physiology,

and Biological Chemistry

• Division of Training, Workforce

Development, and Diversity

• Center for Research Capacity Building

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NIGMS Scientific Components

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DNA of 485 people; genetic types tinted in different colors. The map shows genetic variation decreases with increasing distance from Africa; Noah Rosenberg and Martin Soave, University of Michigan


Investigator Initiated Research @ NIGMS

Maximizing Investigators' Research Award (MIRA) PAR-17-094

Provide a single grant for sustained research support to investigators to:

o Enhance ability to take on ambitious projects

o Increase flexibility in research directions

o Increase research time and productivity

o Enable mentoring in a stable environment

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Application deadline: May 17, 2017; January 17, 2018; May 17, 2018; January 17, 2019; May 17, 2019, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates. Eligibility is restricted to PDs/PIs with at least one NIGMS R01 equivalent award (defined here as R01, R37, DP2, and SC1 awards) that was awarded funding in the fiscal year prior to the fiscal year of the MIRA application submission and whose project end date is in the same or subsequent fiscal year of the MIRA application submission


Collaborative Research @ NIGMS

A mechanism to support research that cannot be accomplished by individual researchers PAR-17-094

o Budget $500K - $1.5M D.C. for research activities

o Address research questions of significant complexity, scope, and biomedical impact

o Foster highly integrated and collaborative research teams

o Strengthen scientific communities and advance scientific problems through coordinated research effort

o Increase ESI exposure to team-based research, through pilot studies

Presenter

Presentation Notes

Application deadline: May 17, 2017; January 17, 2018; May 17, 2018; January 17, 2019; May 17, 2019, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates. Eligibility is restricted to PDs/PIs with at least one NIGMS R01 equivalent award (defined here as R01, R37, DP2, and SC1 awards) that was awarded funding in the fiscal year prior to the fiscal year of the MIRA application submission and whose project end date is in the same or subsequent fiscal year of the MIRA application submission


NIGMS Research Funding

https://www.nigms.nih.gov/research


Initiates grant application

NIHGrant Proposal

Researcher

Assess programsSecond level of review

InstituteNational Advisory

Councils

Evaluates scientific merit of grant proposal

Scientific Review Panel

Institute Director

Makes final decisionAllocates funds

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Understanding the Funding Process


NIGMS Research Support

• More than 3,000 investigators and 4,500 research grants

• Over 11% of the grants funded by NIH

• Emphasis is on investigator-initiated research

Success Rates

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computer model of the cell membrane, where the plasma membrane is red, endoplasmic reticulum is yellow, and mitochondria are blue, Bridget Wilson, University of New Mexico


Keep in Touch!

https://loop.nigms.nih.gov

@NIGMS

@NIGMSgenes

Thank You!


Initiatives that Support Bioinformatics and Computational Biology

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• Biomedical Information Science and Technology Initiative (BISTI)Promote the optimal use of computer science and technology to address problems in biology and medicine by fostering collaborations and interdisciplinary initiatives

• Big Data to Knowledge Initiative (BD2K)Develop new approaches, standards, methods, tools, software and competencies that will enhance the use of biomedical Big Data by supporting research, implementation and training in the data sciences

• Interagency Modeling and Analysis Group (IMAG)Provide an open forum for communication among government representatives for trans-agency activities that have a broad impact in science

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