The Hatton Garden jewel heist of 2015 has beendescribed as“英国法律史上最大的入室盗窃”。
那些负责任的人成功进入了地下保险库，清空了72个保险箱，并带着价值1400万英镑的珠宝走开。
But what does gaining access to a vault and emptying safety deposit boxes have to do with cancer? Surprisingly, more than you’d think.
Our final Grand Challenge is the ultimate cellular heist, attempting to sneak the latest ‘smart drugs’ – or macromolecules if we’re being technical – inside the body so they can take out cancer cells.
Big drugs, big potential
里克·克劳斯纳（Rick Klausner）博士，美国国家癌症研究所的前主任，我们的大挑战咨询小组主席将大分子描述为“通过进化生产的机器”。
They are large molecules, pieced together from smaller building blocks. And there are four main types:
- 核酸- 喜欢脱氧核糖核酸
- Proteins– for exampleantibodies
- Carbohydrates- 像淀粉
- 脂质- 像fatsandcholesterol
Each type of macromolecule carries out a wide range of jobs inside cells. They’re essential for growth and survival – without them, cells would die.
And if they become faulty or damaged, things can go wrong.
For example, abnormal build up of the proteinBeta-amyloid在患者中发现Alzheimer’s disease， 尽管DNA中的故障can lead to cancer.
But macromolecules can also be engineered to help combat diseases. And some have been used as treatments for cancer.
Is bigger better?
Most drugs used to treat cancer patients aren’t macromolecules – they’re much smaller, so they have no trouble getting inside cells.
And if those cells are cancer cells these drugs can do an effective job of killing the tumor cells.
But they have a downside – these drugs can also get inside healthy cells, damaging and killing them as well as cancer cells.
这就是为什么在接受化学疗法治疗时患者的头发经常掉下来的原因。这些药物无法从快速生长的健康细胞（例如毛细胞）中分辨出快速生长的癌细胞。
We need to develop macromolecule drugs that can get inside cancer cells, where they can do a lot of damage
里克·克劳斯纳（Rick Klausner）博士
这就是研究人员转向大分子的原因之一。他们知道，在某些情况下，这些分子有可能仅靶向和杀死癌细胞。
Some macromolecule drugs – including antibodies likerituximab (Mabthera), which is used to treat扩散的大B细胞淋巴瘤, and曲妥珠单抗（赫斯汀）， 用于HER2阳性乳腺癌cancer患者 - 取得了巨大的成功。
But these treatments have been successful because they don’t need to get inside the cancer cells. They work by targeting and killing cancer cells that have specific molecules on their cell surface.
“These drugs are good, but the problem is they don’t go inside cancer cells,” says Klausner. “They work on the cell surface, messing it up and killing the cell that way.”
So if a researcher wanted to target a faulty molecule inside cells, these macromolecule drugs wouldn’t be up to the job.
If we imagine all cells are like banks – and the cancer cells have their vaults full of faulty molecules we want to target – then the drugs we have work in one of two ways:
- Smaller drugs can get inside every bank, and while some will hit a full vault they may also hit some where there’s no cash inside.
- 或者，我们有某些大分子药物（例如抗体），只有在银行墙壁上内置有现金挂在其上的ATM时才起作用。
“This isn’t enough,” says Klausner. “We need to develop macromolecule drugs that can getinside癌症cells, where they can do a lot of damage.” But why – what’s the advantage of macromolecules that can get inside cells over the drugs and antibodies we already have?
克劳斯纳说：“在实验室中，我们有工具使我们能够开发可纠正驱动癌症的故障的大分子 - 通过纠正这种缺陷，您迫使癌细胞死亡。”
Essentially, macromolecules have the ability to differentiate between banks with empty vaults and safety deposit boxes and ones containing all the jewels and money.
到目前为止，大分子的承诺仅在实验室的受控环境中显示出来。在患者中使用这些药物呢？他们会以同样的方式工作吗？
到目前为止的研究表明我们candevelop and make macromolecules that could be used to kill cancer cells and leave healthy cells alone.
Only there’s one pretty big problem – we can’t get the drugs into any type of cell – cancerous or otherwise – in people.
That’s where our Grand Challenge comes in.
我们要研究社会思考how we can get potentially promising ‘smart drugs’ into all the patient’s cells, and not just cancer cells.
“The best bit is that the macromolecule is targeted to only kill a cell that has that specific fault” says Klausner.
“It doesn’t matter if the macromolecule gets into healthy cells as they don’t contain the fault the drug’s designed to fix and would be left unharmed.”
We’re asking researchers to pull off the greatest cell heist ever.
终极牢房抢劫
Before the Hatton Garden thieves carried out their jewel heist they had to be prepared.
They had to bypass the security system and have tools to open the security deposit boxes once inside.
Most importantly, they needed equipment to get through the massive two meter thick concrete walls surrounding the vault.
This is the problem scientists are facing with macromolecules.
They haven’t yet got the tools they need to get macromolecule drugs inside any cell of the body, let alone cancer cells.
克劳斯纳说：“我们对癌症以及癌细胞和健康细胞之间的差异有很多了解。”
“And we have the lab tools to create macromolecules that are designed to fix a specific genetic fault – like a faultyRAS geneorBRCA genethat’s driving a cancer cell’s growth.”
“但是它们没有用，因为我们无法将它们纳入任何类型的单元格 - 我们无法抢劫任何银行，全部或空的。”
“很长一段时间以来，几乎每个在该领域工作的人一直在试图弄清楚如何仅向癌细胞提供大分子。但是这个宏伟的挑战是说‘不用担心。不必担心特定于细胞”。如果我们能弄清楚如何在所有细胞内获取大分子，其余的将自我照顾 - 该药物将使健康细胞与癌细胞区分开，并不用它。”
Patient Perspective
In the time since my diagnosis nearly 30 years ago I’ve seen what science can do and the huge advancements it can make. With the technology and knowledge we have now, and with funding schemes like The Grand Challenge, imagine how far we can go in the next 30 years.
这一巨大的挑战是鼓励科学家考虑甚至可能发展将大分子进入体内细胞的新方法。我们知道这可以在实验室中完成，但尚未在该环境之外完成。如果成功，这一挑战将使癌症研究达到另一个水平。这是一个艰难的挑战，但我欢迎它以及乐观的挑战，它为未来的癌症研究和癌症患者提供了乐观。
- Terry，我们的大挑战患者小组的成员
Are we there yet?
那么我们将如何到达那里呢？我们将如何推出最终的抢劫并将这些药物纳入细胞？
The honest answer is, we don’t know – that’s why this is such a big challenge.
Professor Duncan Graham，来自University of Strathclydeand an expert adviser to Cancer Research UK, says: “It’s impossible to predict exactly how this Grand Challenge will be answered. There are techniques available that we could perhaps use to disrupt cell membranes, make them leaky and increase their permeability to bigger drugs. We could use a physical force like ultrasound, or an energy force like localized heating. Or it could be something like low dose, localized radiation or magnetic fields”.
Answering this Grand Challenge will require bringing together the complementary expertise of different researchers from different areas of science to come up with a radically new proposal and solution to the problem
Professor Duncan Graham
“同样，这可能是全新的和非传统的东西。我们只是不知道。”
但是他知道的一件事将帮助我们回答这个问题 - 协作。
格雷厄姆说：“回答这一巨大的挑战将需要将来自不同科学领域的不同研究人员的补充专业知识汇集在一起，以提出一个新的新建议和解决问题的解决方案。”
“每次我与癌症研究人员交谈时，我都会发现更多有关癌症的信息。他们发现了更多有关纳米颗粒的信息 - 它们背后的科学以及它们如何对他们有用。他们不是他们知道的领域，因为这与他们的领域不同。”
Klausner agrees: “This problem is going to be solved by bringing together people who understand biology, physiology and cells with chemists, material scientists and people in the imaging field. We need to bring together people from very different areas to achieve this.”
There is one thing we can be sure of though.
If we overcome this Grand Challenge and work out a way to get macromolecules into cells, there is massive potential for offering new treatment options to patients.
That’s definitely something to aim for.
Recently I have been researching the possible role of beta amyloid protein oligomers in the protection of cancer? These otherwise toxic moieties involved in beta amyloid dependent Alzheimers Disease recently found to eliminate bacterial infections in nematode and mouse. There are probably novel anti microbial or anticancerous properties of abeta amyloid oligomeric proteins. I really liked regarding this article and I am constantly focussing on this area. A breakthrough might be present with abeta amyloid oligomers. They are recently reported to penetrate cell membrane by forming pore like structures. oligomers or larger protofilaments might present a key therauptic target for penetrating cancer cell and transferring anticancer drugs into the cells.
Please let me know if my idea could make any sense.
我是生物技术学家和结构生物化学家，在生物物理和生化蛋白研究方面具有专业知识，重点是NMR结构的蛋白质结构和功能的确定。
邮政研究员
TROSY NMR Lab
Prof K Pervushin Lab
南南技术大学
新加坡