從雙螺旋結構到設計型疫苗:與華生博士在冷泉港的邂逅

Share Button

News Released on 20100331

2010年3月諾貝爾醫學獎得主詹姆斯.華生博士(James D. Watson)訪台活動中,王長怡博士受清華大學邀請演講內容

From double helix to efficacious vaccines through molecular design:
A fellow Cold Spring Harbor villager’s report

Ladies and Gentlemen,
I want to thank National Tsin Hua University for inviting me to participate in this forum with the renowned Dr. James Watson. My personal experience with Dr. Watson began as a student at Taipei First Girl’s High School in 1966 when I became aware of the double helix structure of DNA. With a strong interest in science, I was fascinated by the huge potential of molecular biology.

Ever since my graduation from National Taiwan University, I have been on a pathway paved by “immunology” as being “the secret weapon of medicine” combined with a powerful motivation to develop medical interventions through the application of basic biomedical sciences.

Over the past 18 years, UBI and I personally have been buoyed by Dr. Watson’s encouragement, experience, and guidance.   This began just after he had retired from the Human Genome Project in 1992.  At that time the Chairman of Baxter International, asked him to provide guidance to UBI in our development of a preventative AIDS vaccine.  Encouraged by this, we asked Dr. Watson to join the UBI Board of Directors.  We were delighted when he accepted our invitation and began our longstanding association.

He has since provided us with guidance for our HIV vaccine, hepatitis C virus diagnostics, and foot-and-mouth disease vaccine and diagnostics programs.  He also encouraged us to work on SARS.  Now, he is helping us with our work on Alzheimer’s disease.

The development of a preventative AIDS vaccine was proceeding as expected until the discovery in the mid-90s of the vast differences between HIV lab strains from those that actually infect patients.  An AIDS vaccine has eluded us all for the past 26 years despite billions of dollars in research efforts.  For me personally, this was an obstacle I devoted 18 years of diligent research to get around.  At long last and armed with the latest findings on the structure of the virus, I believe that UBI is approaching that elusive goal.  We have what appears to be an effective vaccine for AIDS based on synthetic peptides mimicking key conserved pieces of the viral envelope protein gp120.  This experimental UBI vaccine elicits antibodies that interfere with the initial mechanism used by the virus to infect cells.  Most significantly, our assays have shown that this new vaccine blocks infection of human T cells by diverse HIV patient isolates.

Another journey into the field of the hepatitis C virus proved to be almost as difficult for us as HIV but for reasons other than science.  In 1993, after UBI’s success in the European market for its peptide antigen based HCV blood screening test. Chiron Corporation imposed on UBI a world class patent litigation over the issue of HCV diagnostic tests incorporating HCV epitopes.   Six Nobel laureates were involved as expert witnesses. Throughout this time, Dr. Watson patiently listened and supported us in this global patent battle which was waged under the reasonable argument that “lack of support for patent claims in the description of the invention can be used to limit the breadth of those claims, even after the patent is issued”.

Because of limited financial resources, we had to withdraw from the battle at the level of the House of Lords in UK and accept a less than satisfactory settlement with Chiron.  It took four more years of litigation involving more prosperous participants using our arguments to finally prevail in 2000.    This eventual result freed up the valuable information to be derived from detailed viral RNA or DNA sequences for the benefit of research, biomedical applications, and public health.  Such broad patent rights as Chiron had been awarded in return for their limited description of the HCV genome, can never again be granted in this world of advanced molecular biology.  By 2000, Chiron’s broad patents to all HCV peptide epitopes were knocked out in the European Union.  Consequently, UBI’s patent for diagnostic HCV peptide epitopes became the first such valid patent issued and is currently licensed by UBI to the largest diagnostic company in the world.

In 1997 when Taiwan experienced an economically destructive outbreak of foot-and-mouth disease, Dr. Watson’s encouragement was significant in having our team enter the field of FMD diagnostics and vaccine development.  We entered into a collaboration with his colleague from the UK, Dr. Fred Brown, a renowned virologist for his contributions to the FMD field.  After the Taiwan outbreak, and with Dr. Watson’s encouragement, I felt the task was upon us to visit the FMD issue with Dr. Brown, then at USDA Animal Disease Center off Long Island.

Over a two-month period of intensive effort, we developed a differential diagnostic test for FMD  by designing synthetic peptide epitopes for foot-and-mouth disease virus and testing them on Dr. Brown’s extensive FMDV sera panels representing almost all the serotypes of FMDV which he had collected over a 40 year period from infected and vaccinated pigs and cattle.    Our test scored 100% in detecting the antibody responses to those serotypically diverse viruses and vaccines.  Our innovative peptide-based diagnostic tests have high sensitivity and specificity and can distinguish infection from vaccination.  This work helped push forward the field of FMD diagnosis, which had stagnated for over a decade.

It then took us a short  10 months to develop peptide-based prototype FMD vaccines .  This work involved fundamental discoveries in the field of FMDV and led us to file patent applications that now give us exclusive worldwide commercial rights for our line of FMD vaccines.  Equipped with the diagnostic and vaccine peptide technology against the FMDV, we established UBI-Asia in Taiwan.  We then set our sights on China to help solve its long term problem with FMD.   For this purpose, we established UBI-Shanghai which received first new biologics product approval in December 2004 from the Ministry of Agriculture.  The UBI-Shanghai facility was commercialized for vaccine production by 2008 and sold 180 million doses in its first year.  In the second year, that number nearly doubled to over 300 million doses.

I met with Dr. Watson again in the spring of 2003 before leaving for another trip to Taiwan, and told him about our initial success in the FMD field.  He said, “now you should work on SARS.”  I thought, wow, I just finished FMD and now you are giving me another assignment…SARS.  I am not ready yet.  However, the moment I stepped back onto Taiwan soil, I realized the severity of the situation and launched our efforts into SARS.  I  led our team to fully study the genome and protein structure and peptide sequences over a two week period.  Within one month of receiving the SARS patient sera from NTU  Hospital, UBI mapped the SARS genome epitopes and developed a blood screening test for antibodies to SARS virus.  We were awarded a major grant from the U.S. NIH to commercialize this test on behalf of U.S. public health and have published a classic paper on the development of our SARS antibody test in the U.S. CDC journal, Emerging Infectious Diseases.

UBI continues to develop multiple vaccines and immunotherapeutic products stemming from our designer vaccine technology platform.  We let Dr. Watson know of our progress on the HIV program including a monoclonal antibody directed against the HIV receptor complex capable of providing prophylaxis against HIV infection and an HIV RC vaccine that we have developed for the immunotherapy of AIDS patients.  This vaccine has a peptide epitope that mimics the site on the cell’s CD4 receptor which binds the viral gp120.  Among the continual reports in this field, UBI’s HIV RC immunotherapeutic vaccine was the first with a proven ability to generate high affinity antibodies that block the host cell CD4 from binding to the gp120 envelop glycoprotein of diverse HIV patient isolates.  This provides effective therapy for patients experiencing infections with rapidly mutating HIV strains.   We chose to make our antigenic construct from the cell site rather than from the viral gp120 site because a 3D structural model of gp120 with the necessary degree of precision for the CD4 recognition site was not available at the time.  Our early observations for the potential of the HIV RC vaccine enabled us to secure a major funding contract from NIH for the development of a therapeutic vaccine for AIDS .  The HIV RC immunotherapeutic vaccine is being readied for human trials, and we are simultaneously developing a preventative AIDS vaccine against all odds.

It appears we have now come full circle with Dr. Watson.  He began with us as a result of UBI’s involvement in developing a preventative AIDS vaccine, which has eluded the entire scientific field.

Dr. Watson once told me:  “Chang Yi, whatever amount of time you think it will take to accomplish a project, in my experience, it will take three times longer.”  In the case of a preventative AIDS vaccine, it has been more than 30 times longer than what Robert Gallo and Margaret Heckler, then Secretary of Health and Human Services, had hoped for in 1983: ” an AIDS vaccine to be developed in one year”.  I am hopeful that UBI is finally able to deliver the answer.

What impresses me the most about Dr. Watson, beyond his keen scientific mind and his accomplishment with the double helix, is his uncanny sense of timing. His apparently precognitive calls have rallied both the life sciences and the financial communities towards the advancement and support of progress on potentially ready areas of basic biology, genetics and biomedicine.  He has now led several generations towards goals on the molecular biology of genes, cells and cancers, and now on the molecular biology of the brain.

Dr. Watson was even more excited to learn of our Alzheimer’s disease vaccine, currently in human trial.  He offered to introduce us to a potential partner for collaboration.   So far our vaccine has shown a 100% response rate.  All patients given the vaccine have developed the desired antibodies with no vaccine-related adverse effects.

Without Dr. Watson’s support and guidance, we would not be on the same path towards these accomplishments.

Our design efforts and knowledge in the fields of immunology and biomedical sciences will pave the way to efficacious solutions.  Our goal in defending the public health remains as sharp as ever.  Dr. Watson opened the door with his discovery of the double helix structure of DNA.  Hopefully, we will be able to walk through those doors to solve some of the problems of infectious and chronic diseases.  Our colleagues are thankful to Dr. Watson for his encouragement and thoughtful insight. Dr. Watson stands alone among those in his field and of his stature to continually champion emerging and challenging fields of molecular biology and biomedicine.  As director and now emeritus chancellor of Cold Spring Harbor Laboratory for over 42 years, it will be exciting for Dr. Watson to host the first international Cold Spring Harbor Asia Conference on Emerging Infectious Disease this year.

On a more personal note, I have the good fortune to be associated with Dr. Watson as a fellow villager of Cold Spring Harbor as well.  The Cold Spring Harbor Laboratories and Watson School of Life Sciences, which he dedicated his life to build, have given tremendous pride to all citizens of the Cold Spring Harbor village.  His down-to-earth kindness and huge presence are felt by all villagers.  In all my associations with him he has always been selfless in sharing his knowledge and his great insights. His support and encouragement have had a great influence in my pursuit of this lifelong quest; to create out of amino acids, the building blocks of life, cost-effective and efficacious treatments for diseases which ravage the human spirit and body.


從雙螺旋結構到設計型疫苗:與華生博士在冷泉港的邂逅

各位先生女士們,首先我要感謝主辦單位邀請我參加這場有華生博士參與的論壇。我與華生博士的緣份開始於1966年我還在北一女中就讀的時候,當時的我已經體認到DNA『雙螺旋結構』的發現將帶領傳統生物學進入分子生物的世界。由於對科學充滿興趣,我開始深受潛能無限的分子生物學所吸引,因此選擇在這富於挑戰的領域開始我一生的旅程。

從台灣大學化學系畢業後,因著「免疫學為醫學之秘密武器」的信念以及「應用基礎生物來開發醫療方法」的強烈動機我踏入了這條疫苗研究之路。

在過去十八年來, UBI 與我個人都因華生博士的鼓勵、經驗與指導受益匪淺。就在 1992 年華生博士剛由『人類基因體計畫』中退休之際,Baxter 公司董事長向他請益關於UBI開發預防性 AIDS 疫苗的意見。受到這件事的鼓勵,我們因而邀請華生博士加入UBI 董事會,展開了我們與華生博士長期以來的合作關係。華生博士曾經提供我們在HIV、C型肝炎診斷試劑與口蹄疫診斷試劑與疫苗研究計畫的意見,他並且鼓勵我們致力於SARS病毒的研究,目前,他也正在協助我們於阿茲海默症疫苗clinical trial planning 上的研究。

預防性 AIDS 疫苗的開發計畫如預期中地一直進行著,直到90年代中期科學界發現:感染人類的 HIV 病毒品種與實驗室內培養的品種其實差異甚大。儘管26年來科學界投入了數十億美元的研究經費,AIDS 疫苗一直無法被開發出來;對我來說,18年辛勤努力的研究卻一無所獲是一大困境。 近年來,由於愛滋病毒和抗體結合的3D結構研究成果出爐,我們終於找到特殊胜肽設計組成及疫苗配方,可產生具防止病毒感染宿主細胞能力的中和性抗體,這個疫苗乃是根據模擬病毒套膜蛋白 gp120 上的關鍵保留區段所設計。更具意義的是,實驗結果顯示,我們的新疫苗能預防來自不同病人的病毒分離株感染。

我們在C型肝炎病毒診斷試劑開發領域中的研究之旅中亦遭遇如同HIV計畫般的困難,只是這些棘手難題並非科學層面。在1993年,由於目睹UBI HCV血液診斷試劑在歐洲市場的成功,美國 Chiron公司將財務資源吃緊的我們捲入一場在英國、有關使用 HCV 表位抗原 (epitope) 於 HCV 檢測試劑的國際專利訴訟。在這場訴訟中,有六位諾貝爾獎桂冠得主在英國專利法庭擔任專家證人。華生博士在 UBI 與 Chiron 公司進行訴訟的期間,於董事會上耐心聆聽事情的始末,並支持我們利用病毒胺基酸序列做各式創新的主張:『即使是已核發的專利,若在專利發明說明中未有足夠支持專利請求權項 (claim) 的內容,則專利請求權項之範圍可以被限制』。

由於經費有限,我們當時不得不由上議院撤離這場專利戰役,並接受 Chiron 公司差強人意的和解條件。經過4年且涉及更多知名人士參與,我們的主張終於2000年獲得勝利,英國專利法第 44 條所定義的專利規則修正了。經由對抗壟斷HCV 表位的專利,我們成功捍衛了公共利益,而這也使得由病毒核酸序列所衍生的高價值資訊可自由釋放給學術研究、生物醫學與公共衛生研究使用。像Chiron公司這樣於C型肝炎病毒基因組專利中以有限的描述卻獲得涵蓋範圍寬廣的專利權的情況再也不會出現在高等分子生物學領域。截至 2000年,Chiron 公司所有關於 HCV 胜肽表位的專利權項在歐盟全部自行撤銷。 UBI 的診斷用 HCV 胜肽表位專利成了美國第一個有關診斷 HCV 的專利;而 UBI 目前已將該發明的美國專利授權給全球最大的診斷試劑公司。

1997年,台灣爆發口蹄疫大流行,華生博士的鼓勵對我決定讓研發團隊踏進口蹄疫診斷試劑與疫苗開發領域深具意義。經由他的引介,我們與華生博士的同事知名英國口蹄疫病毒學家 Fred Brown 博士開始進行合作。在台灣口蹄疫爆發後,並且在華生博士的鼓勵下,我們終於能與 Brown 博士造訪口蹄疫議題。

經過兩個月夙夜匪懈的努力,我們發展出一套具有鑑別能力的口蹄疫診斷方法:先設計口蹄疫病毒抗原表位的合成胜肽,然後以 Brown 博士所收集的豬、牛血清樣本進行測試。這些極珍貴的血清樣本乃是 Brown 博士40年來的收集,並且免費提供給我們在美國農業部動物疾病中心中使用。這些血清樣本涵蓋了所有口蹄疫病毒血清型,且包括被感染或是接受過疫苗注射的動物。測試結果顯示,我們開發的診斷試劑組合可以百分之百偵測到因病毒感染或施打疫苗而產生的抗體。這個創新的、以胜肽為基礎的檢測試劑具有高度靈敏度與專一性,且能夠區分由病毒感染或是施打疫苗的血清樣本,這項發明使停滯十年沒有進展的口蹄疫診斷研究往前推了一大步。

接著,我們僅花了短短10個月的時間即開發出口蹄疫胜肽雛型疫苗。疫苗的設計涉及口蹄疫病毒結構的基礎發現,我們也順利取得了相關的專利,保護此口蹄疫疫苗的全球、獨家商業化權利。帶著對抗口蹄疫的診斷試劑與胜肽疫苗開發技術,我們在台灣創立了聯亞生技公司,接續又在中國設立申聯生物醫藥公司 (UBI-Shanghai) 作為動物疫苗製造據點,以協助中國這個全球最大動物疫苗市場解決長久以來的口蹄疫問題。申聯於2004年12月取得中國農業部的第一份新獸藥證證書,2008 年正式將口蹄疫合成肽疫苗量產上市,首年即達到1億8千萬劑的銷售佳績;次年進而衝破3億劑,直達首年銷售量的兩倍之多。

2003年春天在我正要出發來台之前,碰巧在一個港灣飯店遇見華生博士,並告訴他口蹄疫疫苗初步成功的好消息。他對我說:「現在你該致力於 SARS 的研究了。」我心想,「哇~我才剛完成口蹄疫的研究計畫,你就指派我另一項任務……SARS。」我還沒準備好。然而,當飛機抵達台灣、我踏上土地的那一刻,我了解到情況的嚴重性。於是我立刻帶領團隊花了兩週時間全力研究 SARS 病毒的基因組、蛋白結構與胜肽序列以 SARS 病人的血清樣本來進行由 SARS 病毒蛋白上篩選出來之抗原表位的血清學驗證。從臺大醫院收到血清樣本起的二個月之內,UBI 即已找出 SARS 病毒的抗原表位 (epitope),並開發出一套偵測 SARS 抗體之血液篩選方法。此研究並且榮獲美國國家衛生研究院獎助,補助這項檢測試劑的商業化發展。這項SARS檢測試劑的研究成果後來被刊登在美國疾病管制局期刊-Emerging Infectious Diseases-中,成為經典文獻。

從90年代中期起,UBI 持續應用此胜肽疫苗設計技術平台陸續研究開發各種疫苗與免疫治療產品。當時我們拜訪華生博士並告訴他我們 HIV RC 愛滋病治療性疫苗的開發進度。HIV RC 疫苗包含模擬 CD4 分子上與 HIV 病毒 gp120 結合的胜肽表位,在眾多研究報告中,UBI 的 HIV RC 疫苗乃是第一個被證實具有產生高親和力抗體能力的 HIV 疫苗,而其所誘發產生的抗體可阻斷宿主細胞CD4分子與不同病人的 HIV 分離株上之 gp120 結合,進而淨化免疫系統。我們選擇由寄主細胞端而非 HIV 病毒端進行疫苗抗原設計乃是由於當時尚無法獲得 gp120 蛋白的3D立體結構資訊。HIV RC 疫苗在初期的開發成果讓我們獲得了美國國家衛生研究院相當可觀的研發資金補助,目前 HIV RC 疫苗已即將進入人體臨床試驗。憑藉著 UBI 豐富的疫苗設計經驗與特有平台技術,加上高度精確的3D分子模型資訊,我們現在相當有信心能夠發展出有效的預防性愛滋病疫苗。我們已經確認我們所設計的疫苗能夠誘發廣效中和性抗體可對抗高度變異的不同 HIV 病毒株。華生博士開始與 UBI 結緣是由於我們的預防性 AIDS 疫苗開發計畫,過了18年到如今疫苗的組成及配方才正式解出,彷彿我們與華生博士一起繞了一大圈又回到原處。

華生博士曾告訴我:「長怡,不論你認為需要花多久時間可以完成一項計畫,在我的經驗裡,完成的時間往往是當初預估的三倍以上。」以預防性 AIDS 疫苗為例,這個答案已經躲避了整個愛滋病研究領域26年之久;他是對的。自1983年Robert Gallo、及當時衛生及公共服務部 (Secretary of Health and Human Services) 部長Margaret Heckler 期盼一年內開發出 AIDS 疫苗以來,至今已超過30倍長的時間;我盼望,UBI 最終能夠從一個全新的科技角度提供預防性AIDS 疫苗的解答。

除了敏銳的科學頭腦與在解開DNA雙螺旋結構的成就之外,華生博士最令我印象深刻的事就是他對於時間點不可思議的判斷力。由於他總是在早於當代呼召之前即預知下一個時代的科學研究趨勢,因此得以整合生命科學與財務團體並促成基礎生物學、遺傳學與生物醫學研究的顯著進展。現在他已經領導許多世代朝向包括基因分子生物學、細胞與癌症分子生物學,以及大腦分子生物學等不同領域的重要目標邁進。

當華生博士對於我們在開發阿茲海默症疫苗上的成果更加興奮。UBI 的阿茲海默症疫苗目前正在進行第一期臨床試驗,目前結果顯示接種疫苗所產生的免疫反應率達到百分之百,所有接種疫苗的病人均能在沒有因疫苗引起之不良副作用反應的情況下產生抗b- amyloid蛋白的抗體。華生博士更大力推薦在分子遺傳領域的大師與我們合作,以最佳化此阿茲海默症疫苗後續臨床二期、三期試驗內容的設計,進而提高療效評估與分析的準確度。

所以,華生博士應該會相當以我們的成就為榮。我們在免疫學與生物醫學領域的疫苗設計經驗與知識將為有效的醫療解決方案開創一條新道路。我們捍衛公共衛生的目標一如既往明確,華生博士在 DNA 雙螺旋結構上的發現開啟了分子生物及醫學的新境界,希望我們也能夠協助解決感染與慢性疾病問題而關上一部份門。我的 UBI 同事們都非常感謝華生博士的鼓勵與深刻洞見。華生博士在他的專業領域中傲視群倫,並且以他的地位持續奮戰於新興且極有挑戰性的分子生物學與生物醫學領域,做為冷泉港實驗室的負責人與榮譽退職校長長達42年,將由華生博士在2010年主辦的第一屆新興感染疾病國際冷泉港亞洲研討會令人感到興奮。

就我個人而言,我很幸運地因恰好也是冷泉港居民而認識華生博士;冷泉港實驗室與華生生命科學學院是華生博士投注一生心力所創辦的學術殿堂,為冷泉港帶來極大的榮耀,所有的冷泉港居民都可以感受到他的親切與大師風範。在我與他的接觸過程中,包括擔任 UBI 董事與資深顧問,他總是無私的分享他的知識以及深知灼見。華生博士的支持與鼓勵深切影響我對畢生職志之追求,亦即由生命之沙-胺基酸-創造經濟有效、可以治療摧殘人類身心靈的疾病之方法。

本篇發表於 佳文共賞, 王長怡博士演講。將永久鏈結加入書籤。

發表迴響

你的電子郵件位址並不會被公開。

你可以使用這些 HTML 標籤與屬性: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>