professional development presented to acs student group oct 16, 2013
DESCRIPTION
Lessons learned in a scientific career presented to undergraduate students mostly majoring in chemistry at UCSD on October 16, 2013TRANSCRIPT
From B Student to Associate Vice Chancellor & Professor
Philip E. Bourne [email protected]
10/16/13 ACSSA 1
urp.ucsd.edu
Lesson 1 Change is Good
• My high school teacher Mr. Wilson said I would be a failure at chemistry
• My PhD is in chemistry
• The opportunity to live in different places shaped my life
• Good friends are forever
Lesson 2 Nurture Friends & Colleagues
50 Years Later
PhD – The Molecular Basis of Cancer Treatment
• I thought I was at the center of the scientific universe
• I later discovered I was actually in deep space
Lesson 3 See things for what they are
Lesson 4: Follow Your Heart
Circa 1974
• Your head will tell you stuff• Your heart will tell you something different
• Follow your heart
Postdoctoral Work – The Molecular Basis of How the Body
Works
• Regrets: never learnt another language
Lesson 5 Learn to live with regret
How I Got Excited
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Some Things Stay with You Your Whole Life
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Senior Scientist – Columbia University New York
• Driven not by career but wanting to live in New York City
The Authoring Years
Lesson 6Make the most of
every day
Got Involved with the The Human Genome – Was Only Possible by Applying Computers to
Problems in Biology
• Took at least 10 years and ~$1Bn
• Biology’s equivalent of landing on the moon
• We now have thousands of genomes
• $50 genome is upon us
Came to UCSD to Apply Computers to Big Biological Problems
• Possibly the best place in the world to do computational biology
Fell in Love with the Data Problem
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Num
ber
of r
elea
sed
entr
ies
Year
Proteomics DataIts Not Just About Numbers its About Complexity
The Omics Revolution Courtesy of the RCSB Protein Data Bank10/16/13 ACSSA 15
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2005 - Started a New Journal to Support My Field – Led to a Passion for
Open Access
Josh Sommer and Chordoma Disease
http://fora.tv/2010/04/23/Sage_Commons_Josh_Sommer_Chordoma_Foundation#fullprogram
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Josh Sommer – A Remarkable Young ManCo-founder & Executive Director the Chordoma Foundation
http://sagecongress.org/Presentations/Sommer.pdf
Motivation10/16/13 ACSSA 19
Chordoma
• A rare form of brain cancer
• No known drugs• Treatment – surgical
resection followed by intense radiation therapy
http://upload.wikimedia.org/wikipedia/commons/2/2b/Chordoma.JPG
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http://sagecongress.org/Presentations/Sommer.pdf
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http://sagecongress.org/Presentations/Sommer.pdf
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http://sagecongress.org/Presentations/Sommer.pdf
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http://sagecongress.org/Presentations/Sommer.pdf
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http://sagecongress.org/Presentations/Sommer.pdf
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http://fora.tv/2010/04/23/Sage_Commons_Josh_Sommer_Chordoma_Foundation
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Lesson 7 – Go After the Big Problems
1. Can we improve how science is disseminated and comprehended?
2. What is the ancestry of the protein structure universe and what can we learn from it?
3. Are there alternative ways to represent proteins from which we can learn something new?
4. What really happens when we take a drug?
5. Can we contribute to the treatment of neglected {tropical} diseases?
August 14, 2009
2. Drug Discovery
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The Worst of Times
Source: http://www.pharmafocusasia.com/strategy/drug_discovery_india_force_to_reckon.htm
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Here is One Reason Why• Tykerb – Breast cancer
• Gleevac – Leukemia, GI cancers
• Nexavar – Kidney and liver cancer
• Staurosporine – natural product – alkaloid – uses many e.g., antifungal antihypertensive
Collins and Workman 2006 Nature Chemical Biology 2 689-70010/16/13 ACSSA 30
Bioinformatics – Reverse Engineering Drug Discovery
Characterize ligand binding site of primary target (Geometric Potential)
Identify off-targets by ligand binding site similarity(Sequence order independent profile-profile alignment)
Extract known drugs or inhibitors of the primary and/or off-targets
Search for similar small molecules
Dock molecules to both primary and off-targets
Statistics analysis of docking score correlations
…
Xie and Bourne 2009 Bioinformatics 25(12) 305-312
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The Problem with Tuberculosis
• One third of global population infected• 1.7 million deaths per year• 95% of deaths in developing countries• Anti-TB drugs hardly changed in 40 years• MDR-TB and XDR-TB pose a threat to
human health worldwide• Development of novel, effective and
inexpensive drugs is an urgent priority
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Map 2 onto 1 – The TB-Drugomehttp://funsite.sdsc.edu/drugome/TB/
Similarities between the binding sites of M.tb proteins (blue), and binding sites containing approved drugs (red). 10/16/13 ACSSA 33
From a Drug Repositioning Perspective
• Similarities between drug binding sites and TB proteins are found for 61/268 drugs
• 41 of these drugs could potentially inhibit more than one TB protein
No. of potential TB targets
raloxifenealitretinoin
conjugated estrogens &methotrexate
ritonavir
testosteronelevothyroxine
chenodiol
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Top 5 Most Highly Connected Drugs
Drug Intended targets Indications No. of connections TB proteins
levothyroxine transthyretin, thyroid hormone receptor α & β-1, thyroxine-binding globulin, mu-crystallin homolog, serum albumin
hypothyroidism, goiter, chronic lymphocytic thyroiditis, myxedema coma, stupor
14
adenylyl cyclase, argR, bioD, CRP/FNR trans. reg., ethR, glbN, glbO, kasB, lrpA, nusA, prrA, secA1, thyX, trans. reg. protein
alitretinoin retinoic acid receptor RXR-α, β & γ, retinoic acid receptor α, β & γ-1&2, cellular retinoic acid-binding protein 1&2
cutaneous lesions in patients with Kaposi's sarcoma 13
adenylyl cyclase, aroG, bioD, bpoC, CRP/FNR trans. reg., cyp125, embR, glbN, inhA, lppX, nusA, pknE, purN
conjugated estrogens estrogen receptor
menopausal vasomotor symptoms, osteoporosis, hypoestrogenism, primary ovarian failure
10
acetylglutamate kinase, adenylyl cyclase, bphD, CRP/FNR trans. reg., cyp121, cysM, inhA, mscL, pknB, sigC
methotrexatedihydrofolate reductase, serum albumin
gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole, severe psoriasis, rheumatoid arthritis
10
acetylglutamate kinase, aroF, cmaA2, CRP/FNR trans. reg., cyp121, cyp51, lpd, mmaA4, panC, usp
raloxifeneestrogen receptor, estrogen receptor β
osteoporosis in post-menopausal women 9
adenylyl cyclase, CRP/FNR trans. reg., deoD, inhA, pknB, pknE, Rv1347c, secA1, sigC
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Rule 8 – Give Back
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What Would I Work On If Starting Today?
• Neuroinformatics• Translational research – interdisciplinary, lab
to market• Science advocacy• Anything big data
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