Grand Challenge seven is asking scientists to pull off the ultimate cell heist.

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The Hatton Garden jewel heist of 2015 has been described as “the biggest burglary in English legal history”.

Those responsible successfully entered an underground vault, emptying 72 safety deposit boxes and walking away with £14 million worth of jewels.

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

Dr Rick Klausner, former Director of the US National Cancer Institute and chair of our Grand Challenge Advisory Panel, describes macromolecules as “machines that have been produced through evolution”.

They are large molecules, pieced together from smaller building blocks. And there are four main types:

• Nucleic acids – like DNA
• Proteins – for example antibodies
• Carbohydrates – things like starch
• Lipids – things like fats and cholesterol

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 protein Beta-amyloid is found in patients with Alzheimer’s disease, while faults in DNA 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.

That’s why patients’ hair often falls out when they’re being given chemotherapy treatment. The drugs can’t tell a fast growing cancer cell from a fast growing healthy cell, like a hair cell.

We need to develop macromolecule drugs that can get inside cancer cells, where they can do a lot of damage

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Dr Rick Klausner

This is one reason why researchers are turning to macromolecules. They know that in some circumstances these molecules have the potential to target and kill only cancer cells.

Some macromolecule drugs – including antibodies like rituximab (Mabthera), which is used to treat Diffuse Large B Cell Lymphoma, and trastuzumab (Herceptin), used for HER2 positive breast cancer patients – have been a great success.

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:

1. 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.
2. Or, we have certain macromolecule drugs – like antibodies – that only work if there’s an ATM built into the bank’s walls that has cash hanging out of it.

“This isn’t enough,” says Klausner. “We need to develop macromolecule drugs that can get inside cancer 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?

“In the lab we have tools that allow us to develop macromolecules that can correct the fault that’s driving a cancer – by correcting this fault you force the cancer cell to die,” says Klausner.

Essentially, macromolecules have the ability to differentiate between banks with empty vaults and safety deposit boxes and ones containing all the jewels and money.

So far the promise of macromolecules has only been shown in the controlled environment of the lab. What about using these drugs in patients? Will they work in the same way?

Research so far suggests that we can develop 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.

We’re asking the research community to think about 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.

The ultimate cell heist

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.

“We know an enormous amount about cancer and about the differences between cancer cells and healthy cells,” says Klausner.

“And we have the lab tools to create macromolecules that are designed to fix a specific genetic fault – like a faulty RAS gene or BRCA gene that’s driving a cancer cell’s growth.”

“But they’re no use because we can’t get them into any type of cell – we can’t rob any bank, full or empty.”

“For a long time almost everyone working in this field has been trying to figure out how to only deliver macromolecules to cancer cells. But this Grand Challenge is saying ‘don’t worry about that; don’t worry about being cell specific’. If we can figure out how to get macromolecule inside all cells, the rest will take care of itself – the drug will distinguish a healthy cell from a cancer cell and leave it alone.”

Patient Perspective

– Terry, member of our Grand Challenge patient panel

Are we there yet?

So how are we going to get there? How are we going to pull off the ultimate heist and get these drugs into cells?

The honest answer is, we don’t know – that’s why this is such a big challenge.

Professor Duncan Graham, a nanoscientist from the University of Strathclyde and 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

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Professor Duncan Graham

“Equally, it could be something completely new and non-traditional. We just don’t know.”

But there is one thing he knows will help us answer the question – collaboration.

“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,” says Graham.

“Every time I speak to cancer researchers I find out a bit more about cancer. And they find out a bit more about nanoparticles – the science behind them and how they could be useful to them. It’s not an area they’re aware of because it’s such a different field from theirs.”

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.