S4.E6. 叛逆、生病，傻傻分不清楚？ 

Randye Kaye 的兒子是思覺失調（paranoid schizophrenia）的患者。在確診前，她承受了生活中的各種煎熬，也明白確診之後與疾病共處必須經歷的困難。百靈佳殷格翰完全理解這一切有多麼不容易，也希望能夠用新的數位技術來解決許多家庭都正面臨的難題。

Randye Kaye 的故事通常是這樣開始的：「請想像一下，你有一個孩子；這個寶寶慢慢長大，慢慢成為一個大人；」停頓了一下後，她接著說：「現在，請想像你的孩子，好像因為青春期，開始有一點『怪怪的』，這個情況沒有因為時間而改善，彷彿成為了常態，甚至越來越糟；孩子在學校的表現每況愈下，並且開始被孤立、失去朋友。」

一般我們認為，在青春期的孩子，行為總是會有一點怪異，這並非特例；或許過幾年就會改善—也可能不會有任何改變。這些行為表現可能是精神疾病的最初病徵，而Kaye 親身經歷了這一段過程；Ben 被醫師判定為罹患思覺失調（paranoid schizophrenia）。Kaye 希望能透過自身的經驗，給予身處類似背景和經歷的家庭更多的支持，她完全能了解這些家庭的感受。「家中有罹患精神疾病的孩子，不只令人心碎，對家庭中的每一個人也都是無法逃避的巨大改變。對於像Ben這樣的孩子來說，在我們眼中稀鬆平常的日常瑣事，都可能是非常困難的挑戰。」

事實上，服用抗精神疾病藥物（antipsychotic drug）可以抑止這些症狀，令患者的生活作息趨於規律。在此前提下，越早開始治療，成功痊癒的機會也就越大。但這也產生了一個盲點：精神疾病所表現出來的症狀時常被誤判為只不過是青春期的叛逆行為，而讓我們錯失了治療的先機。百靈佳殷格翰以跳脫藥物治療的研究取向超前部署，試圖找出解決問題的方法，並希望能在初期診斷的過程中即成為醫師的助力。

「數位化」所帶來的革命性改變

百靈佳殷格翰中樞神經系統（Central Nervous System，簡稱CNS）疾病研究小組的Cornelia Dorner-Ciossek 博士是這項計畫中的關鍵角色，她發現神經研究領域能因為數位化技術的進步，產生前所未有的改變：「數位技術的運用讓我們對未來腦部研究的發展，充滿憧憬與期待。智慧型手機的進化日新月異，成為人們日常生活常態的手機也擁有更多複雜的功能。研究人員正在研究，如何有效率的運用數位化技術，提前判定是否罹患精神疾病，並且能協助人們面對這個改變。」

為優化早期精神疾病診斷的過程，百靈佳殷格翰正在推行的其中一項研究計畫稱之為「數位語音分析（digital speech analysis）」。調查發現，人們說話與表達自我的方式，與直覺思考的能力有關；而思覺失調、阿茲海默症以及許多的精神疾病，都會以不同的方式影響自我表達與思考能力；其晚期患者更是會明顯的表現出相當具代表性的變化。

百靈佳殷格翰研發了一個軟體，希望能透過分析人耳乍聽之下難以分辨的語句結構、說話節奏、聲調，藉此判斷是否處於早期症狀。Kaye 因為深知早期診斷的重要性，相當認同這項研究。他們當時看了非常多次醫生，也經歷了許多與精神科醫生之間令人不甚愉悅的交談，耗上許多年才確認Ben 患有思覺失調。回憶起當時，Kaye 說：「知道自己的孩子患有精神疾病，感覺像是世界末日。沒有人希望自己所愛的人得到這樣的結果。但對比這麼多年來的折磨以及不確定之後，確診對我們來說其實也是一種解脫。我們因此能開始著手尋找治療方案，這至少會帶來希望。」

提升患者生活品質

在未來，不只是早期確診，數位技術與智慧型裝置也可能成為幫助思覺失調患者控制疾病的一種選擇。CNS 疾病研究部主管Bernd Sommer 博士認為大數據（big data）可以帶來無限可能。研究團隊藉由智慧型手機取得在現實條件下難以蒐集的複雜數據。Sommer 說：「我們能用電子化的方式分析思覺失調患者的日常生活，這意味著，精神疾病實驗室會越來越不像一個實驗室，甚至不需要是一個實體空間。」

「我們知道在評估新藥的可能效益時，必須投入最大的努力；我們為了推動臨床研究設計，設定了兩個關鍵因素：『以技術實現精準的測量與準確性』，以及『以個人為單位，關心每一個參與者的心理健康狀況並聆聽他們的建議。』」CNS研究中心醫學部負責人Stephane Pollentier 博士說：「我們全心全力的釐清、瞭解影響患者的問題核心為何。」

以具體操作面向來說，這些新興研究可能會影響患者與病症共處的模式。思覺失調症可能會反覆發作，像是一個起伏的曲線；而以智慧型手機分析患者的活動模式與社交行為，或許能藉由演算，進而辨識病徵復發的跡象。Randye Kaye 親身經歷了這些挑戰；即便是親近的家人，也很難準確地安排時間以觀察患者的言行與生活。「數位技術可以為思覺失調患者與他們的家庭帶來極大的幫助。及早確認病徵的進程，能幫助我們更早進行治療。像我兒子一樣的人們，因此獲得了獨立生活的可能與希望。」

勇敢去做，堅持到底

腦部研究可謂是科學領域中最具挑戰性和最複雜的領域之一。腦部包含數十億個神經細胞與神經纖維，並由上兆個接點（connection）和突觸（synapse）連接在一起。也因為腦部的複雜程度，臨床研究與開發的失敗率相當高。挫折往往比突破更常見。治療方案以及服務項目的供給也因此匱乏。

負責多項臨床項目的Michael Sand 說：「我們有幸成為這塊領域的造浪者，雖然在工作上缺乏關注與資源的狀態難免令我們沮喪，但也能同時提醒我們，不能因為身為先驅、擁有優勢而自滿；瞭解這項計畫的重要性，知道我們所採取的研究取向與步驟確實具有發展的可能，令我們充滿動力！百靈佳殷格翰和我們一定會堅定的鑽研腦部領域。」這些研究發展帶給Randye Kaye 希望：「我發現，其實許多企業已經停止了神經領域的研究；看到百靈佳殷格翰如此堅持，努力為精神疾病患者群找醫療解決方案，帶給我很大的希望。」

具備創新意識的感知力（A SENSE FOR INNOVATION）

真正的造浪者，分分秒秒都在身體力行、實踐創新—百靈佳殷格翰「無邊界研究（Research Beyond Borders）」團隊中的造浪者們即是最佳典範，在未知的領域中探索就是他們的日常。全球無邊界研究團隊負責人Henri Doods博士表示：「我們將自己視為百靈佳殷格翰的『偵察部隊』，在世界各地的科學領域尋找富有發展性的創意與想法，並與外部研究機構、學術單位的研究人員進行串聯。」

Doods 所率領的團隊於2015年成立，陣容日漸壯大。Doods 以及德國比伯拉赫（Biberach）、美國康涅狄格州里奇菲爾德（Ridgefield, CT）的數位同事為開創元老，然後在美國波士頓、麻州、中國北京、上海、日本神戶、奧地利維也納增加駐點。這個約有20位成員的團隊持續探索各種能振奮人心、富有創新力的研究方法與技術，相信未來能吸引並凝聚更多製藥公司，齊心投入與努力。

齊心協力尋找創新的研究技術與方法

若發現具備發展性的計畫，Doods 團隊就會聯繫百靈佳殷格翰公司中能支援的科學家，透過溝通、確認研究需求，統整企業內部能提供的研究技術和資源，隨即啟動研究計畫。偵查團隊非常重視適應症（治療範圍，indication field），例如：針對抗生素耐藥性細菌（antibiotic-resistant germ）的新型治療方法，與中國清華大學成立虛擬研究中心，研究人員能系統性的研究百靈佳殷格翰用於多種傳染疾病的藥物成分。

From the eyes of a mother

Randye Kaye is mother of a son diagnosed with paranoid schizophrenia. She knows the difficulties in advance of a diagnosis and the trouble managing the disease. Boehringer Ingelheim knows these challenges too and uses the opportunity of digital technologies to break new ground.

Randye Kaye usually starts her key talks with these words: “Imagine you have a child. Think of how your little baby starts growing up, slowly becoming an adult.” After a short break she continues:“And now imagine your child is in puberty and slightly starts to act weird, it retreats, is getting worse in school and starts losing friends.”

In most cases, this is normal behavior, it is not unusual that children in puberty act a little bit strange. Usually this behavior changes after a few years – but sometimes it does not. Sometimes this behavior can be the first sign of a mental disease. Kaye experienced exactly that. She is the mother of Ben, who has been diagnosed with paranoid schizophrenia. Today she supports families with similar stories and experiences, because she knows how these families feel. “It is completely heartbreaking to see your child develop a mental illness. It’s a tremendous challenge for everyone in the family. Even day-to-day things we barely notice can be extremely difficult for Ben.”

Taking antipsychotic drugs can suppress the symptoms and enable a regulated everyday life. The earlier treatment begins in such cases, the better the chances of success. But exactly that can be a problem – the very first symptoms are non-specific. Patients seem apathetic or suffer from sleep disorders or listlessness. These symptoms are often misinterpreted as stemming from puberty. To tackle this issue, Boehringer Ingelheim follows a research approach that goes beyond the development of drugs. The goal is to offer support to physicians in the early-stage diagnosis of mental disorders.

USING THE MOMENTUM OF DIGITALIZATION

Dr. Cornelia Dorner-Ciossek from the Central Nervous System (CNS) Diseases research group at Boehringer Ingelheim plays a decisive role in this effort. She sees a huge opportunity in the field of neuro-research, especially by using digital technology: “The use of digital technology makes me feel optimistic about the future of brain research. Technological advancements have enabled smartphones to be commonplace and extremely sophisticated. Researchers are determining how we can best use this technology to both diagnose a mental illness and help people to manage it.”

One approach from Boehringer Ingelheim to improve the early diagnosis focuses on digital speech analysis. The way people speak and express themselves is determined by their ability to think straight. Diseases such as schizophrenia but also Alzheimer’s dementia and many other psychiatric diseases affect these, although in different ways. Especially people with advanced disease progression show many characteristic modifications in their speech. The software aims to analyze disease-typical telltale changes in sentence structure, rhythm, and intonation at an early stage when the changes are still imperceptible to the human ear. Kaye supports this, since she knows about the importance of an early diagnosis. It took several years, many visits to the physician and uncomfortable conversations with psychiatrists until her son got a diagnosis. Randye remembers the moment as follows: “Finding out that your child truly does have a mental illness is devastating, as nobody wants someone they love to come down with a diagnosis like that. However, after these years of uncertainty, learning what was going on was also a relief. We could now move forward to find treatment options and that was the hopeful part of it.”

IMPROVING A PATIENT'S LIFE

In the future, digital technologies and smart devices could also be an option to help patients with schizophrenia manage their disease. Dr. Bernd Sommer, Head of Department CNS Diseases Research, sees a great opportunity through the advancing of big data. Research teams now have access to complex patient data sets collected under real world conditions – possible through the smartphone. “We are able to analyze the daily problems of patients with schizophrenia electronically. That means the psychiatric lab is becoming less and less an actual physical lab and space,” explains Sommer.

“Knowing that we operate in a field that requires utmost diligence when assessing the potential effect of our new medications, we see two key elements to drive our clinical study design: we achieve precise measurement and accuracy through technology, but also include input from people personally involved in mental health situations and their insights,” says Dr. Stephane Pollentier, Head of Medicine CNS, “With that, we try to capture what really matters to patients.”

In concrete terms, the new possibilities could have an impact on how patients can tackle the symptoms of the disease. Because the symptoms of schizophrenia occur in recurrent attacks, the disease pattern is an interplay of ups and downs. By analyzing the mobility patterns and social behavior of patients via the smartphone, an algorithm could help to identify early signs of an upcoming relapse. Randye Kaye has been through these challenges herself. Managing the right timing can be difficult even for close family members. “These technologies could offer huge relief for the everyday life of people living with schizophrenia and the whole family. To know the course of the disease more precisely could help to intervene earlier. This gives people like my son the possibility to regain their independence,” notes Kaye on the potential impact.

STAYING STRONGLY COMMITTED

Brain research is one of the most challenging and complex fields of science. The brain contains billions of nerve cells and nerve fibers that are linked by trillions of connections or synapses. Due to the very complicated nature of the brain, failure rates in clinical development are high. Setbacks are more frequent than breakthroughs. The delivery of treatment and services remain inadequate.

“I am always humbled by the fact that we have the privilege to work in an area with so many unmet medical needs,” explains Dr. Michael Sand, who is responsible for several clinical programms. “Knowing of the importance of this work and seeing the promising steps we take keeps me motivated. At Boehringer Ingelheim, we stay strongly committed to the field of brain research.” This gives Randye Kaye hope: “I have noticed that many pharmaceutical companies have withdrawn from the neuro-research field altogether. It therefore gives me so much hope to see that Boehringer Ingelheim remains committed to finding solutions for people living with mental illness.”

A SENSE FOR INNOVATION

True pioneers stand out by blazing new trails and keeping their eyes open for innovation – just like the pioneers from the “Research Beyond Borders” team at Boehringer Ingelheim. Their daily work consists of research outside of the current therapy areas. “We like to think of ourselves as the ‘scouts’ of Boehringer Ingelheim,” says Dr. Henri Doods, Head of the global Research Beyond Borders Team. “We look for highly promising ideas across the global scientific community and get in contact with researchers at external research institutions and universities.”

Since its establishment in 2015, the team has grown considerably. Doods started with a handful of colleagues in Biberach, Germany, and Ridgefield, Connecticut, USA. Since then, additional sites have been opened in Boston, Massachusetts, USA; Beijing and Shanghai, China; Kobe, Japan; and Vienna, Austria. Here, about 20 employees are permanently searching for exciting and innovative academic approaches and technologies that could see increased interest from pharmaceutical companies in the future.

ABOUT 20 EMPLOYEES ARE PERMANENTLY SEARCHING FOR INNOVATIVE ACADEMIC APPROACH ES AND TECHNOLOGIES

Should a project turn out to be particularly promising, Doods and his team connect the scientists in charge with the right project partner within Boehringer Ingelheim. The project partner will then be in constant communication with the scientists, identify needs and drive forward the research project with the help of skill sets and resources available in-house. The scouts always focus on indication fields with a high medical need. One example are new therapeutic concepts for antibiotic-resistant germs, such as tuberculosis pathogens. Together with the Tsinghua University, a leading university institution in China, a virtual center was established for this purpose. There, researchers systematically investigate Boehringer Ingelheim’s active ingredients for their use in various infectious diseases.