From B Student to Associate Vice Chancellor & Professor

Philip E. Bourne pbourne@ucsd.edu

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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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Questions?

pbourne@ucsd.edu

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