她和丈夫辞职读博，只为给自己研发绝症解药  --  一次与死神赛跑的改行.pdf

http://www.mittrchina.com/news/2535: 

https://www.technologyreview.com/s/611672/one-womans-race-to-defuse-the-genetic-time-bomb-in-her-genes/:  

2011 年，索尼娅•瓦拉巴（Sonia Vallabh）拿到一份基因检测报告，宣告了她的死刑，但同时也为她提供了生存指南。

瓦拉巴了解到，她的身体存在基因突变，在她的“朊蛋白”基因 DNA 序列上存在一个错误碱基对，最终将会使她患上一种罕见的叫做致命性家族失眠症的脑疾病。一年前，瓦拉巴的母亲就是因为这种病而去世，检测显示瓦拉巴也继承了这一缺陷。

瓦拉巴和她的丈夫埃里克•米尼克尔（Eric Minikel）决定努力阻止这种疾病出现，《纽约客》将他们的故事称之为“朊蛋白爱情故事”，现在他俩的故事可以说是家喻户晓。在诊断出这颗基因定时炸弹后，瓦拉巴和她的丈夫放弃了自己的律师和工程事业，转而成为致力于拆除这颗基因炸弹的科学家。他们预期在明年春天获得博士学位。

七年后的今天，他们认为自己发现了有效的治疗方法。这种药被称为反义药物，它是一种镜像分子，一旦该药物抵达脑部，可大大降低朊蛋白的数量。由此可能阻止错误折叠蛋白发生神秘的链式反应。折叠蛋白是朊蛋白类疾病的重要标志。

瓦拉巴分析道，朊蛋白越少，她患病的几率就越低。

两周前，在博客中瓦拉巴宣布她和米尼克尔正在与一位商业伙伴进行合作，这是一家位于加州名叫 Ionis 的生物科技公司，擅长生产反义化合物。“这是我第一次对某个治疗策略持乐观态度，”瓦拉巴写道。“在我们有生之年”反义药物治疗朊蛋白类疾病还是“有希望的”。

瓦拉巴与时间赛跑阻止自己患上朊病毒的过程向这个基因时代提出了一个有力的问题。给你一份自己遗传病的全面 DNA 蓝图，有生之年，你防止自己或者所爱之人病发的几率有多大？

还是有理由相信，这类医学尝试还是很有可能成功的。这不仅是因为基因测序可以轻松地揭示出分子水平的缺陷，还因为一系列有前景的技术——反义、基因疗法和 CRISPR 基因编辑——能够替代基因或者让基因沉默，从而从根源上有效解决基因问题。

而且这些治疗方法都运用了基因编码，实际上是由 DNA 或 RNA 组成的。这意味着本质上是分子水平的，可编程的。至少从理论上来说，还是有可能找到基因缺陷，然后迅速制出解药。

而在现实中，药物开发则是出了名地流程复杂。大多数药物都是无效的，要么是生理上出现意外，要么对人体有意外的毒副作用。但瓦拉巴称，在早期她探索困惑的阶段，她收到了来自博德研究所带头人艾瑞克•兰德（Eric Lander）的批评性意见。如今，瓦拉巴和米尼克尔也在博德研究所研究工作。兰德告诉瓦拉巴要关注遗传误差本身——遗传误差的蓝图就在她的诊断中。

“你需要看清自己手里已经攥着的东西，别再一味寻找，”瓦拉巴回忆到他说的话。

这意味着不再等着解答重要的科学未解之谜，像是朊蛋白在人体内会做什么，或者为什么会做某些事情，以及什么时候朊蛋白会错误折叠，什么时候会杀死脑细胞。今年 34 岁的瓦拉巴说道，“关于朊蛋白疾病实在是有太多有趣的问题了，而且即使在我们进行治疗时，这些问题还会一直存在。”

朊蛋白疾病是十分古怪的，因为这类疾病并不是由一种病毒引起，而是由一种受感染的蛋白质引起。这类疾病包括存在于绵羊中的痒病，库鲁病（通过同类相食传播），克雅氏病，人类版的疯牛病。

关于药物的重要观点是根据设计缺失朊蛋白基因的老鼠从来都不会得朊蛋白类疾病，即使科学家将感染的朊蛋白注入老鼠的大脑。“从生物概念上来说，朊蛋白是一种可以改变形态的蛋白质，而且可以像模板一样复制。可以自构模板。这样才能够得以传播，”加州大学旧金山分校实验室的一位研究员库尔特•盖尔斯（Kurt Giles）说道。朊蛋白就是在这里首先被发现的。“由此就产生了要降低（朊蛋白）的想法。朊蛋白越少，模板复制得就越少。”

不过基因疗法有另外一个问题，就是如何进入人体抵达几十亿个脑细胞内。

去年，几十年前就出现的反义技术有了重大的突破，Ionis 公司研发的一种药物证明可以有效治疗一种儿童神经失调症，脊髓性肌萎缩，效果惊人。

那时，瓦拉巴和米尼克尔已经接触到 Ionis 公司，该公司已经同意给他们提供反义化合物，用于在老鼠身上测试朊蛋白基因。Ionis 公司神经科学负责人霍利•科塔西维希兹（Holly Kordasiewicz）回忆起 2014 年的见面。“我们前脚刚出门，就决定要不惜一切代价帮助这些人，”她这样说道。

该公司给瓦拉巴和米尼克尔一个待办事项列表，他们很快就完成了。病人注册？搞定。动物研究？搞定。显示药物是否有效的生物标记？在波士顿一家研究脊髓液朊蛋白水平的医院，该项研究正在进行中。

“索尼娅和艾瑞克做这项研究并没有真正的基金支持，只是想要完成它而已，”另一位介绍他们到 Ionis 公司的科学家杰夫•卡罗尔 (Jeff Carroll)（他已经找到了亨廷顿病的基因突变）说道。

一个没有那么容易解决的问题是，朊蛋白病真的很罕见，而且会迅速致死，很难提前诊断出来。这意味着治疗过程可能不会太引人注意。可能在美国仅有 200 人像瓦拉巴一样知道自己身体内有颗定时炸弹，卡罗尔说道，目前还没有哪一种药物在人体上进行过测试。一开始 Ionis 公司就告诉瓦拉巴夫妇此次合作是严格意义上的学术合作，并非出于商业目的。

通过从根源上清除朊蛋白，反义疗法或许可以帮助治疗一系列与此相关的罕见病症。像疯牛症一样，致死性失眠是十分罕见的，但把这些“超级罕见”的疾病集合在一起，作为一个群体，这些病就不是那么罕见了。

瓦拉巴和米尼克尔表示，现在他们已经有证据表明 Ionis 的反义分子可以在一定程度上保护老鼠不患上朊蛋白疾病。这些获得药物的老鼠寿命延长了约 70%。

如今，科塔西维希兹将该项目称作 Ionis 的“商业”项目，尽管该项目比较小，还处在初期，不适合出现在公司待研发药物的进度表上。“进展是，数据看上去挺好的，我们觉得可以在五年内研发出一种药来，”她这样说道。

瓦拉巴希望可以加快进度。致死性失眠症可能明天就会找上门，也可能是再过 30 年。一切都很难预测。她和米尼克尔刚刚有了第一个孩子，是一个试管婴儿，瓦拉巴说实验室用一种基因测试确保孩子不会携带突变基因。

为了自救，仅仅有药还不够。瓦拉巴需要在她生病之前就开发出药物。然而这么多年来，医生开出基因药物预防疾病的案例实在是太少了。

对瓦拉巴和她的丈夫来说，搞明白如何实施这种研究是他们接下来面临的另一个挑战。似乎他们希望美国食品及药物管理局可以批准在携带朊蛋白突变基因的病人身上进行预防试验。由于通常需要几十年该病才会发作（或许永远都不会），因此该项研究将主要依赖生物标记，如反义注射是否能够减少脊髓液中的朊蛋白水平。

瓦拉巴告诉我，她将自愿尝试该药物。“整体来说，我们的进展比外界预期的快很多，这一切都是因为我们拿到的这份十分清晰的基因蓝图。”

One woman’s race to defuse the genetic time bomb in her genes

How DNA sequencing and new genetic drugs raise the chance we can cure any inherited disease.

by Antonio Regalado, July 23, 2018

In 2011, Sonia Vallabh was handed a genetic report that contained a death sentence. But it also held a map for how to escape.

Her body, she learned, harbored a gene mutation, a single wrong letter of DNA in her “prion” gene, that would eventually lead to a rare brain condition called fatal familial insomnia. Her mother had died of it the year before, and the test had revealed Vallabh had inherited the flaw too.

By now, the decision by Vallabh and her husband, Eric Minikel, to try to prevent her disease—“a prion love story,” the New Yorker called it—is well-known. After the diagnosis of the genetic time bomb, they dropped out of their careers in law and engineering and became scientists dedicated to defusing it. They expect to get PhDs next spring (see “Sonia Vallabh, 35 Innovators Under 35, 2016”.)

Now, after seven years, they think they have found a treatment that can do it. It’s called an antisense drug, a type of mirror-image molecule that, if it reaches the brain, could greatly reduce the amount of the prion protein. That could potentially forestall the mysterious chain reaction of misfolding proteins that characterize prion diseases.

Less of the protein, Vallabh reasons, and less chance she’ll get sick.

Two weeks ago, on their blog, Vallabh announced she and Minikel were working with a commercial partner, the California biotech company Ionis, which specializes in antisense compounds. “For the first time, I am optimistic about a specific therapeutic strategy,” she wrote. It’s “plausible” that antisense could treat the disease “in our lifetime.”

Vallabh’s race to prevent her own prion disease raises a question for the genetic age. Given a perfect DNA blueprint of your inherited disease, what’s your chance of stopping it in your lifetime, or that of someone you love?

There are reasons to think these types of medical long shots have become more likely to hit the mark. That is because gene sequencing can cheaply reveal molecular flaws, but also because a set of promising technologies—antisense, gene therapy, and CRISPR gene editing—are able to replace genes or silence them, in effect fixing genetic problems at their source. A close-up of up brain tissue affected by prions, misfolded protein that are toxic to neurons.

wikimedia commons

What’s more, these treatments employ the genetic code; they are actually made of DNA or RNA. That means that they’re fundamentally modular and programmable. At least on paper, it is now possible to take any genetic flaw and quickly sketch an antidote.

In reality, drug development is notoriously complicated. Most drugs fail, torn down by biological surprises and unexpected toxicity to the human body. But Vallabh says in the early, confusing days of her quest, she received critical advice from Eric Lander, the biologist who leads the Broad Institute, where she and Minikel now study and work. He told her to focus on the genetic error itself—the blueprint of which was in her diagnosis.

“You need to see what you have in your hand and stop looking,” she recalls him saying.

That meant not waiting to answer important scientific unknowns, like what the prion protein does in the body, or why, when it misfolds, it kills brain cells. “There are so many interesting questions about prion disease,” says Vallabh, who is 34. “And those questions will still be there when we are treating it.”

Prion diseases are profoundly strange because they’re caused not by a virus, but by an infectious protein. They include scrapie in sheep, Kuru (spread by cannibalism), Creutzfelt-Jakob disease, and the human version of mad cow disease.

The key drug insight was that mice engineered to lack the prion protein gene never get sick, even when scientists inject infectious prions into their brains. “The biological concept of a prion is a protein that changes it conformation, and that can template further copies. It’s self-templating. That allows it to spread,” says Kurt Giles, a researcher in the lab at the University of California, San Francisco, where prions were first discovered. “That leads to the idea of reducing the [protein]. The less of it there is, then you will get less templating.”

For genetic therapies, though, there’s a further problem, which is how to get them into the body so that they reach, for instance, billions of brain cells.

Antisense technology, conceived decades ago, had its big breakthrough last year when a drug developed by Ionis proved to be astoundingly effective in treating a childhood neurological disorder, spinal muscular atrophy.

By then, Vallabh and Minikel had been introduced to Ionis, and the company had agreed to provide them with antisense compounds targeted to the prion gene to test in mice. Holly Kordasiewicz, the head of neuroscience at Ionis, recalls the 2014 meeting. “We left the room saying we need to do everything that we can to help these people,” she says.

The company gave Vallabh and Minikel a to-do list, which they quickly worked through. Patient registry? Check. Animal studies? Check. Biomarker to show if a drug is working? That research, too, is under way at a Boston hospital studying prion protein levels in spinal fluid.

“Sonia and Eric are doing this with no real funding, just trying to make it happen,” says Jeff Carroll, another patient scientist (he’s got the mutation for Huntington’s disease), who introduced them to Ionis.

One problem not as easily addressed is that prion disease is astoundingly rare, quickly fatal, and rarely diagnosed in advance. That means there has been no great clamor for treatments. Maybe only 200 people in the U.S. know they have a time bomb like Vallabh, she says, and there’s not a single drug currently in human testing. Early on, Ionis let the pair know the collaboration was strictly academic and not a commercial prospect.

But by blotting out the prion protein at its source, an antisense treatment might help with a range of rare conditions linked to it. Fatal insomnia is vanishingly uncommon, as are cases of mad cow disease, but adding these “ultra-rare” diseases together makes them, as a group, slightly less rare.

Vallabh and Minikel say they now have proof that Ionis’s antisense molecules partly protect mice from prion disease. Those animals given the drug live about 70 percent longer.

Kordasiewicz now terms the program a “commercial” project at Ionis, though it remains too small and early-stage to appear on the company’s pipeline chart of drugs under development. “What changed is the data is looking good enough that we think we can have a drug in five years,” she says.

Vallabh hopes it can all go even faster. The fatal insomnia could begin to afflict her tomorrow, or in 30 years. There’s no way to predict it. She and Minikel just had their first child. The girl was conceived through IVF, and Vallabh says the lab employed a genetic test to assure them she wouldn’t carry the mutation.

To save herself, it’s not going to be enough to have a drug. She needs to get it before she ever falls ill. Yet doctors have little experience giving such a genetic drug over many years as a form of prevention.

Figuring out how to carry off such a study is the next challenge for Vallabh and her husband. It appears they hope the US Food and Drug Administration will permit a prevention trial in patients who carry the prion mutations. Since it can take decades for people to get sick (or not), such a study would instead rely on a biomarker, such as whether antisense injections can reduce prion protein levels in the spinal fluid.

Vallabh told me she would volunteer to take the drug. “The big picture,” she says, “is we are moving much more quickly than anyone could expect due to this beautifully clear genetic blueprint we were handed.”

PrP News:

https://www.technologyreview.com/s/424487/prion-disease-secret-of-immunity-revealed/:

Prion Disease: Secret of Immunity Revealed

Rabbits are immune to prion diseases. Now one molecular biologist thinks he knows why and says the secret could help in developing a treatment

• June 27, 2011

A prion is a misshapen protein that acts like an infectious agent (hence the name, which comes from the words protein and infection).

Prions cause a number of fatal diseases such as mad cow disease in cattle, scrapie in sheep and kuru and Creutzfeldt-Jakob disease (CJD) in humans. There is no cure and potential treatments are highly speculative.

In recent years, however, biologists have discovered several animals that are immune to prion diseases. These include horses, dogs and rabbits. Nobody knows why.

But a great deal of effort is being expended to find out. In the last couple of years, molecular biologists have identified the structure of the proteins in these immune species that in other animals cause prion disease. The obvious question is this: what’s the difference?

Today, we have an answer thanks to an impressive set of molecular simulations carried out by Jiapu Zhang at the The University of Ballarat in Australia.

Zhang has simulated how these proteins change shape as their temperature and pH changes.

His conclusion is that the immune proteins are more stable than the others because of a salt bridge that connects two parts of the immune proteins “like a taught bow string”. This prevents them from misfolding into an infectious form.

That’s an interesting result because it immediately provides a therapeutic target to aim at. “This salt bridge might be a potential drug target for prion diseases,” says Zhang.

The idea is that it might be possible to stabilise prion proteins in cattle, sheep and humans using an artificial salt bridge, similar to the one in dogs, horses and rabbits.

A long shot but certainly worth pursuing.

Ref: arxiv.org/abs/1106.4628: The Nature Of The Infectious Agents: PrP Models Of Resistant Species To Prion Diseases (Dog, Rabbit And Horses)

https://www.visionair.nl/wetenschap/behandeling-ongeneeslijke-prionziekten-ontdekt/:

Behandeling ongeneeslijke prionziekten ontdekt?

door   Germen ·Gepubliceerd27 juni 2011· Bijgewerkt27 juni 2011

Prionen zijn besmettelijke eiwitten. Prionen veroorzaken ernstige hersenziekten als kuru en de ziekte van Creutzfeld-Jacob. Om een mysterieuze reden zijn honden en konijnen resistent tegen prionziektes. Onderzoekers hebben nu ontdekt waarom. Komt genezing nu dichterbij?

Wat zijn prionen?

Een zoutbrug beschermt konijnen tegen prionziekten.

Infectieziekten worden veroorzaakt door vier klassen ziekteverwekkers, leerden we vroeger op school. Bacteriën, virussen (pakketjes erfelijk materiaal in een eiwitmantel), eencellige eukaryoten (cellen met een celkern) en meercellige organismen, denk aan draad- en spoelwormen en schimmels. Toch traden er merkwaardige ziekten op die niemand kon verklaren. Zo is er de schapenziekte scrapies: schapen worden geteisterd door een gekmakende jeuk en sterven uiteindelijk. Ook bij mensen komen twee van dit soort ziekten voor: kuru bij kannibalen uit Papoea Nieuw Guinea en de Creutzfeld-Jakob ziekte, die vergelijkbare symptomen kent als kuru: de hersenen veranderen in een spons.

Hoe onderzoekers ook weefsel van zieke dieren en mensen afspeurden: de ziekteverwekker werd niet gevonden. Tot stralingsbioloog Tikvah Alper en wiskundige John Stanley Griffith in de jaren zestig met een hypothese kwamen die neerkwam op wetenschappelijke ketterij: deze ziekten werden veroorzaakt door besmettelijke eiwitten. Onmogelijk, oordeelde de gevestigde biologie. Tot moleculair bioloog Stanley Prusiner in 1982 aantoonde dat een besmettelijk eiwit, door hem prion gedoopt, andere “gezonde” eiwitten in de ziekmakende vorm kon wringen. Hier kreeg hij in 1997 de Nobelprijs voor geneeskunde voor – na de nodige controverse, zoals gebruikelijk in de wetenschap.

Prionen zijn chemisch gezien autokatalytische moleculen – moleculen dus die andere moleculen in zichzelf kunnen omzetten. Prionen krijgen alleen vat op PrP (prion protein), een normaal eiwit dat in de cellen van veel dieren en de mens voorkomt.

Prion-resistentie
Een raadsel was tot nu toe hoe het komt dat paarden, honden en konijnen, waar PrP ook in voorkomt, niet getroffen werden door prionziekten. We hebben nu een antwoord, dankzij een groot aantal conmputersimulaties van de vorm van prioneiwitten door Jiapu Zhang, een onderzoeker van de universiteit van Ballarat, Australië. Zhang bestudeerde in zijn model hoe deze eiwitten van vorm veranderen als de temperatuur en de pH veranderen. Zijn conclusie is dat de prion-resistente PrP-eiwitten stabieler zijn dan andere, omdat een zoutbrug twee delen van de immuunproteïne met elkaar verbindt, “zoals een strakgespannen boog”. Dit voorkomt dat ze zich in een infectueuze vorm kunnen buigen.

Dit resultaat is interessant; er komt nu namelijk een mogelijke therapie voor patiënten en ziek vee beschikbaar. “Deze zoutbrug kan een potentieel doel voor [medicijnen tegen] prionziekten vormen”, aldus Zhang.

Door een kunstmatige zoutbrug kunnen zo prioneiwitten in vee, schapen en mensen worden gestabiliseerd, vergelijkbaar met die in honden, paarden en konijnen.

Bron: 
Zhang, J., The Nature Of The Infectious Agents: PrP Models Of Resistant Species To Prion Diseases (Dog, Rabbit And Horses), arxiv.org

伊朗物理学会:

http://www.psi.ir/html/news/news/newsletter/90/psinews9007.pdf (pages 44-45)

http://psi.ir/farsi.asp?url=http://psi.ir/html/news/news/news2_f.asp?id=302

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سوالی که به ذھن می رسد این است که : تفاوت بین این حیوانات
چیست؟ اکنون جواب این سوال به لطف مجموعه ای از شبیه سازی ھای
ملکولی که به وسیله جیاپو زنگ 6 در دانشگاه بالارات 7 در استرالیا انجام
شده، آشکار شده است.
شبیه سازی ھای او نشان می دھد چگونه این پروتئین ھا، زمانی که دما و
تغییر می کند، تغییر شکل می دھند. نتیجه شبیه سازی او نشان pH
میدھد که وجود یک پل نمکی دو قسمت پروتئین ھای ایمن را به ھم وصل
می کند و آنھا را پایدارتر میسازد. این نتیجه بسیار جالب است چون امید
به درمان دارویی بیماری را افزایش میدھد. یعنی با ایجاد پل نمکی
مصنوعی پروتئین ھای پیرون را در موجودات غیر مصون در برار بیماری، پایدار
کرد. البته این کاری سخت است و امیدی نیست که در آینده خیلی نزدیک
به نتیجه برسد.

http://mti.edu.ru/blog/2011-07/18473-mostik-ustoichivosti-cekrety-krolikov:

Мостик устойчивости: cекреты кроликов

Опубликовано O_Shurigina в Пт, 07/01/2011 - 12:01              

Прионы — инфекционные агенты, вызывающие сложные и пока неизлечимые болезни коров, овец и человека. Однако кролики, собаки или лошади к ним удивительно устойчивы. Оказывается, все дело в «солевых мостиках».

Прионы — опасные и хитрые инфекционные агенты. Это не паразитические черви, не простейшие, не бактерии и не вирусы — их вообще не стоит считать живыми. В них нет нуклеиновых кислот: прионы представляют собой полипептидные цепочки белков аномальной пространственной конфигурации. И «размножаются» они крайне необычно. Взаимодействуя с нормальным белком организма, они меняют и его конформацию, превращая в новый опасный прион.

Обнаружены прионы были сравнительно недавно, известно о них довольно мало. Но считается, что они могут быть ответственны за развитие целого ряда заболеваний — не только у людей. Поклонникам сериала «Доктор Хаус» знакомы страшноватые названия прионных болезней — болезнь Крейцфельда-Якоба, болезнь Куру и т.д. Широкую известность получили случаи «коровьего бешенства» (губчатой энцефалопатии крупного рогатого скота), имеющего как раз прионную природу.

Действенных способов терапии до сих пор нет, зато обнаружен ряд животных, которые обладают неожиданной устойчивостью к прионным инфекциям. В их числе — и обыкновенные собаки, кролики, лошади. Природа такой устойчивости до сих пор оставалась абсолютной загадкой. Лишь теперь, благодаря работающему в Австралии биологу и математику Цзяпу Чзану (Jiapu Zhang) мы можем кое-что об этом рассказать.

Ученый проводил компьютерное моделирование изменений пространственной конформации прионов, выделенных из этих животных, при изменении температуры и рН. Он пришел к выводу, что прионы устойчивых видов обладают менее гибкой структурой, которую стабилизируют солевые мостики, дополнительные связи. Они фиксируют положение структурных доменов прионов, по выражению Чзана, «как туго натянутая тетива лука».

Этот вывод особенно интересен хотя бы тем, что сразу дает медикам направление, в котором можно вести создание терапевтических решений: стабилизация пространственной формы опасных для человека (и других видов) прионов путем создания в них дополнительных солевых мостиков.