方俊民教授 整理
I. Chemistry Plays a Key Role in the Science Division of Chemical Biology
With regard to “chemical biology”, a general question frequently asked is like this: whether “chemistry” or “biology” is the main body of this division? To answer this question, let’s take the more familiar terms of “microbiology” and “cell biology” as examples. You may agree that when one talks about microbiology, he/she actually emphasizes on microbes, but not animals or plants. The same understanding goes with cell biology, which focus on the study of cells. Apparently, chemistry is the main theme for the science division of chemical biology. We may coin “Chemical Biology: the chemistry of life science, bringing chemistry to life” from an internationally renowned Nature Chemical Biology journal.
II. The Editors of Nature Chemical Biology and Current Opinion in Chemical Biology are Chemists
There is no surprise that Professor Terry L. Sheppard, who has a strong chemistry background, serves as the Editor of Nature Chemical Biology journal. Professors Donald Hilvert and Steven V. Ley, who are chemistry professors at ETH (Federal Institute of Technology, Zurich, Switzerland) and University of Cambridge (UK), respectively, serve as the Editors of another internationally renowned journal of Current Opinion in Chemical Biology.
III. Aims and Scope of Chemical Biology
Nature Chemical Biology is a monthly multidisciplinary journal providing an international forum for the timely publication of significant new research at the interface between chemistry and biology. Topics covered by Nature Chemical Biology will include:
1. Chemical Synthesis
Diversity-oriented synthesis; Template-directed synthesis; Biomolecular modification and labelling chemistry; Solid-phase biomolecular synthesis: peptides, oligonucleotides, oligosaccharides; Synthesis of small biomolecules: lipids, carbohydrates, nucleosides, amino acids; Combinatorial chemistry; Natural products synthesis; Biomimetic synthesis; Asymmetric catalysis.
2. Expanding Chemistry through Biology
Enzymatic synthesis; Natural products isolation and characterization; Combinatorial biosynthesis; Biosynthetic engineering; Virus-based chemistry; Directed evolution and characterization of macromolecular catalysts and receptors; Chemical informatics.
3. Chemical Mechanisms in Biology
Enzyme inhibition and reaction mechanisms; Mechanisms of drug action in vivo; Small molecule-biological target interactions; Evolution and novel chemistry of catalytic nucleic acids; Pharmacological determination of protein function in vivo; Molecular probes of biological function; Mechanistic analyses of post-translational modification chemistry; Chemical insights into post-genomic approaches, including RNA interference and proteomics; Metal ions in biological systems; Chemical imaging agents; Single molecule chemistry of small molecules and biomolecules; Theoretical simulations and modelling of biomolecules; Molecular recognition; Small molecular model systems for metalloenzymes; Molecular machines; Pharmacologically active natural products; Biosynthetic pathway elucidation; Chemical approaches to protein interaction networks; Chemical ecology.
4. Expanding Biology through Chemistry
Chemical genetics and High Throughput Screening; Biomolecular and small molecular array fabrication and validation; Chemical insights into drug design and development; Synthetic biology; Unnatural biomolecular analogs in biological systems; Chemical genomics; Chemical regulation of biosynthetic pathways; Chemical methods for protein, carbohydrate and nucleic acid design; Chemical approaches to systems biology.
IV. Chemists Contribute Significantly in the Chemical Biology Journals
Taking two current issues of Nature Chemical Biology as the examples. The November issue (Nature Chemical Biology, 2005, Volume 1, Number 6, pp299-347) focuses on high yield of natural products. The December issue (Nature Chemical Biology, 2005, Volume 1, Number 7, pp349-397) demonstrates the utility of small molecules for modulating biological processes and offering leads for therapeutic applications. Chemists contribute soly or in parts to all six articles in this issue. It is noted that the first review article on “Chemistry in living systems” (Nature Chemical Biology, June 2005, Volume 1, Number 1, pp13-21) is contributed by Carolyn R Bertozzi in the Department of Chemistry, University of California, Berkeley.
V. Chemists Provide Various Instrumental Methods to Advance the Research of Chemical Biology
Taking the recent issue of Current Opinion in Chemical Biology (October 2005, Volume 9, Issue 5, pp421-544) as an example, one can easily recognize from the article titles the important contributions of chemists.
1. Contemporary mass spectrometry for the direct detection of enzyme intermediates.
2. Surface enhanced Raman scattering for narcotic detection and applications to chemical biology
3. Optical fiber-based sensors: application to chemical biology
4. NMR analysis of protein interactions
5. Mass spectrometric analysis of protein interactions
6. Fluorophore-tagged GPCR ligands
7. Studying zinc biology with fluorescence: ain’t we got fun?
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附錄1：兩種化學生物學期刊主編之介紹
Nature Chemical Biology
Editor: Terry L. Sheppard
Before assuming the Editorship of Nature Chemical Biology, Terry spent 6 years at Northwestern University's Department of Chemistry, where he developed an independent program in nucleic acid chemical biology, which included investigations of oxidative DNA damage and repair, template-directed synthesis, and nucleoside therapeutics. This followed his appointment as a NASA postdoctoral fellow with Gerald F. Joyce at The Scripps Research Institute, where he discovered, using in vitro evolution, a "DNA enzyme" that catalyzed DNA depurination and strand cleavage. Terry completed his Ph.D. in organic chemistry with Ronald Breslow at Columbia University in 1995, where he synthesized 2',5'-linked DNA and evaluated its promise for antisense therapeutic applications.
Current Opinion in Chemical Biology
Editor: Donald Hilvert
Prof. Hilvert (b. 1956) received his B.A. (1978) and Ph.D. (1983) from Brown and Columbia Universities, respectively. Following postdoctoral work at Rockefeller University, he joined the faculty of the Scripps Research Institute (La Jolla, California), initially as an assistant professor (1986-1989), then as associate professor (1989-1993) and full professor (1994-1997). Since October 1997, he has been professor of chemistry at the ETH Zürich. He was an Alfred P. Sloan Research Fellow (1991-93) and received the Arthur C. Cope Scholar Award from the American Chemical Society (1992) and the Pfizer Award in Enzyme Chemistry (1994).
Editor: Steven V. Ley
Steve Ley is the BP (1702) Professor of Organic Chemistry at the University of Cambridge, and Fellow of Trinity College. He was President of the Royal Society of Chemistry (2000-2002) and was made a CBE in January 2002.
He was appointed to the staff at Imperial College in 1975 and became head of department in 1989. He was elected to the Royal Society (London) in 1990, and moved to Cambridge in 1992. Steve Ley's work of 575 papers has been recognized by 25 major prizes and awards, the most recent of which are the 2003 Ernest Guenther Award in the Chemistry of Natural Products (American Chemical Society), the 2005 Yamada-Koga Prize (Japan) and the 2006 Robert Robinson Award and Medal (Royal Society of Chemistry).
附錄2：這一期的所有論文皆有化學系教授為主要或共同作者
Nature Chemical Biology, December 2005, Volume 1, Number 7, pp349-397.
1. Photochemical tools for remote control of ion channels in excitable cells, by Richard H Kramer, James J Chambers and Dirk Trauner. (Dirk Trauner is in the Department of Chemistry, University of California, Berkeley).
2. Small molecules that delay S phase suppress a zebrafish bmyb mutant, by Howard M Stern, Ryan D Murphey, Jennifer L Shepard, James F Amatruda, Christian T Straub, Kathleen L Pfaff, Gerhard Weber, John A Tallarico, Randall W King and Leonard I Zon (John A Tallarico is in the Institute of Chemistry and Cell Biology, Harvard Medical School).
3. Monocarboxylate transporter MCT1 is a target for immunosuppression, by Clare M Murray, Raymond Hutchinson, John R Bantick, Graham P Belfield, Amanda D Benjamin, Diana Brazma, Robert V Bundick, I David Cook, Robert I Craggs, Susan Edwards, Leslie R Evans, Richard Harrison, Elain Holness, Andrew P Jackson, Clive G Jackson, Lee P Kingston, Matthew W D Perry, Andrew R J Ross, Paul A Rugman, Sasvinder S Sidhu, Michael Sullivan, David A Taylor-Fishwick, P Craig Walker, Yvonne M Whitehead, David J Wilkinson, Andrew Wright and David K Donald (John R Bantick, Richard Harrison, Lee P Kingston, Matthew W D Perry, David J Wilkinson, and David K Donald are in the Department of Medicinal Chemistry, AstraZeneca R&D, UK).
4. C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L, by Sylvie Fournel, Sébastien Wieckowski, Weimin Sun, Nathalie Trouche, Hélène Dumortier, Alberto Bianco, Olivier Chaloin, Mohammed Habib, Jean-Christophe Peter, Pascal Schneider, Bernard Vray, René E Toes, Rienk Offringa, Cornelis J M Melief, Johan Hoebeke and Gilles Guichard (Pascal Schneider is in Department of Biochemistry, University of Lausanne)
5. Actin is the primary cellular receptor of bistramide A, by (Alexander V Statsuk and Sergey A Kozmin are in Department of Chemistry, University of Chicago; and Jeremy L Baryza, Vishal A Verma and Paul A Wender are in the Department of Chemistry and Department of Molecular Pharmacology).
6. Analysis of drug-induced effect patterns to link structure and side effects of medicines, by Anton F Fliri, William T Loging, Peter F Thadeio and Robert A Volkmann, Pfizer Global Research and Development, USA.
附錄3：彙整96學年度台灣大學化學研究所分設化學組、化學生物學組計畫書中對化學生物學的說明
化學生物學（Chemical Biology）的研究目標是在發展新化學和生物的策略去解決生命系統的問題。近年來化學的進展很大，基本上能夠合成、操控和研究任何複雜的分子。經由過去幾十年的突破性發現和創新之研究技術，化學基礎研究的成果得以轉移到產業上，也擴展其對我們社會實際層面的影響力。許多新材料、新醫藥、新工具和新元件不斷地被發明來改善人類的生活品質，而化學就在這研發過程中扮演一個關鍵的角色，因此化學廣被認為是科學的中心，在未來材料和生命科學繼續新的發展中亦是不可或缺的。然而隨著人類和許多物種的基因體序列完成解譯，生命科學的研究也進入一個新紀元，目前的挑戰是將基因資訊解密，去瞭解基因的功能，和利用這些知識去開發新儀器、新材料和新醫藥以解決生命系統中主要的問題。要達到這目標，化學家需要確定那些才是重要的生物問題，也才能據以研發新技術和新分子；另一方面，生物學家也需要這些新技術和新分子去探究複雜的生物系統。為了解決生命系統上複雜的問題，就需要新的研究策略，而「化學生物學」就應運而生了！
化學生物學的意義是從原子和分子的層次，去瞭解並研究複雜的生命現象和生物化學反應，提供以有機、無機、物理和分析化學為基礎，進而發展出新的化學研究策略，去診斷、預防和治療人類的疾病。傳統的生物化學（Biochemistry）注重生物大分子的結構和其新陳代謝的過程，如蛋白質、核酸、醣類及脂肪質的構造、分解和生合成。而新興的化學生物學除了對生物大分子的結構和其新陳代謝的瞭解外，更注重化學和生物學互相的作用，如「結構與功能的關係」以及「化學小分子與生物大分子的相互作用」，從瞭解基因和蛋白質開始，終極則是開發新技術和新分子去探究生命現象和解決問題。進行化學生物學的研究，基本上需要有化學系的研究專長，譬如：
1. 合成新化合物的技術，包括設計並合成化學小分子和生物大分子。
2. 解析結構的關鍵技術，包括發展新的測量技術，如光譜、質譜和影像等儀器，以及利用奈米技術和高速篩選分析的方法。
3. 開發新的化學反應，包括使用化學和生物的方法，以及對生物化學反應機構的探討。
傳統的生化技術能大致辨別生物分子的功能，如某一蛋白催化特定的反應，由此得以建立分子結構與生物功能的連結。然而許多生物分子仰賴動態分子構形的調整來達成其功能，只有靜態的結構知識無法完整了解分子如何工作。單分子影像或光譜技術近年蓬勃發展，將把生物系統研究的精準度往上提升到新的層面：如訊號反應單一分子事件，能追蹤單分子時間演化，單分子事件發生的空間位置得以精準定位。要能進一步研究生物分子如何執行其預設的功能時，單分子的動態研究工具能提供許多珍貴的動力學訊息，增進我們瞭解分子結構、動態分子構形、與生物功能三者之間的密切關係。此外對分子操控技術的掌握也是近年生物物理進步的另一個動力。生物系統變因太多，個體差異大，同一生物個體不同的空間位置也代表不同的環境。要能進一步掌控實驗條件，微操控技術是一類關鍵技術。微操控技術與單分子影像或光譜技術的配合應用，需要前緣物理化學家的訓練，這是化學家發揮專長的重要研究方向。
符合時代之教學和研究潮流：
隨著人類基因體定序的完成，以及許多動物、微生物和植物的基因的序列解譯，生物科技已進入一個新紀元，接下來所面臨的挑戰是如何瞭解基因功能，並藉此發展新的技術及醫療產品，在這跨領域的研究中，化學將扮演更重要的角色。台大化學所化學生物學組的學程計畫，是提供化學和生物的學習介面，這是符合時代的教學和研究潮流。譬如，世界一流的哈佛大學就設立「化學暨化學生物學系」（Department of Chemistry and Chemical Biology），還有其他世界一流的化學系，如耶魯大學、麻省理工學院、司克利普斯研究院（The Scripps Research Institute）、加州大學柏克萊校區等，數目不勝枚舉，這些學校都很強調結合化學生物學的教學和研究體系的重要性，同時也可證明台大化學所設立化學生物學組，是符合時代之教學和研究潮流，是培養在這跨領域的領導人才所必需的作為。
邁向國際一流大學頂尖系所
台大化學系在歷經相當時間的籌備下，規劃出未來發展之中長程目標，期冀於十年之內擠身國際一流大學頂尖系所。本系近年來在研究上的傑出表現，以及拓展尖端領域的深度及廣度，為國內外有目共睹，因此我們有充分的理由相信可以達成這個目標。其中化學生物學領域的建立已列為本系規劃發展中最重要的ㄧ環。
台大化學所目前有多名教授從事化學生物學相關領域的研究，成績斐然。系上多位教授在生物分子探針設計、生物單分子動力學、葉綠體ATP合成酶動力學、DNA與蛋白質檢測方法、含醣多肽分子結構、奈米生物技術、生物羥基磷灰石奈米結構、藥物開發等重要領域都有豐碩的研究成果，過去三年所完成的相關碩、博士論文逾五十篇。其中方俊民教授主持的有關SARS病毒蛋白酶抑制劑之設計與合成研究，更在國際上處於前沿領導地位。此外，國科會九四年度跨領域整合型研究計劃中，「以尖端物理／化學方法探索生物系統」之研究主題，本系共有兩項整合型計劃獲得補助，分別為陳逸聰教授總主持的「以奈米線場效電晶體及光學感測器探討神經網路功能」，以及陳振中教授總主持的「類澱粉質纖維分子結構之固態核磁共振研究」。兩位皆為本系相對年輕的教授，預期他們在未來數年間將令本系的化學生物學研究往前再推進一大步。可見本系投入化學生物學研究的人力與資源，已達增設新學組的臨界點。