Dead bodies are revealing the secrets of how cancer kills: {Taj Pharmaceuticals}

Terminally ill cancer patients are giving scientists a precious resource to understand the disease: their own bodies, freshly supplied for autopsy

At the Francis Crick Institute in central London, Andrew Rowan is labelling test tubes filled with chunks of human brain. The pieces are brown and spongy-looking, as if they would be springy to the touch; the rest of the brain sits to his right, in a large, smoking polystyrene box of dry ice. On a shelf above him is a row of food blenders. There is a curious smell in the laboratory – not entirely unpleasant, but the kind one chooses not to ask about.

Rowan is excited. This particular brain is fresh from an autopsy conducted the previous week, and the donor – a man in his 60s – was found to have unforeseen tumours in his lower abdomen. “We were prompted that the case would be mainly brain disease, so we were surprised at the extent of it elsewhere,” Rowan says. “Hopefully it will give us some clues.”

As a senior research scientist at the institute’s Cancer Evolution and Genome Instability Laboratory, Rowan has handled his fair share of human tissue – to the extent that he can tell by eye which of his dissected samples are cancerous and which are not. (“They’re often different in colour, morphology, appearance.”) When he has finished organising these 100 samples of brain – some are set in liquid paraffin so they can be studied at room temperature, others kept frozen for longer-term study – he will select the best quality ones for genetic sequencing. As for the rest of the patient’s organs, that’s where the blenders come in.

“We’re making a slurry soup of matter,” he says. “We will then conduct something called ‘deep sequencing’ – we try and make sure we are picking up the total number of [genetic] mutations from that sample. All tumour tissue that is left over is collected for this, as we want to make sure nothing gets wasted.” Tools used for liquidising the tissue before it is sequenced can only be used once owing to the risk of contamination, so Rowan gets his “homogenisers” (standard food blenders) for cheap from Argos.

It sounds macabre, but it’s important research. Rowan is one of a team of experts working on a new study into the way tumours spread. The Posthumous Evaluation of Advanced Cancer Environment (PEACE) study is an ongoing project, funded by Cancer Research UK, that follows a simple premise: terminally ill cancer patients agree to donate their body to science after they die, allowing researchers to perform autopsies to collect their blood and tissue for testing.

Until recently, scientists working in labs such as this one have relied upon cancer tissue taken from surgically removed biopsies – a small section of disease taken from one site while the patient is alive. But the scope for experimentation with these samples is limited, and reveals very little about the wider ecosystem of the disease inside a patient’s body. Thanks to the volunteers signed up to PEACE, the team is now able to access entire, fresh organs from multiple sites in a patient’s body. It is the only study like it in the world, and the researchers believe the discoveries made from it could be revolutionary – both in furthering scientific understanding of cancer, and in the continuing quest to find a cure.

Some of the first recorded human autopsies are thought to have taken place in Egypt around 300 BCE, and throughout history medics, artists, philosophers and legal authorities have all taken inspiration or evidence from human and animal dissections. But while post-mortems remain relatively common, and are a legal requirement in many countries when a death is unexpected or suspicious, there has been a steep decline in hospital autopsies for research purposes over the past few decades. This is in part due to a misconception that, given the advances of modern technology, such apparently medieval practices are no longer useful. It is also a subject that makes many people squeamish – including, PEACE co-ordinators suggest, doctors and clinicians.

“When we were medical students, we used to go to the mortuary frequently to understand why patients died of that particular disease,” says Charles Swanton, one of the Crick’s leading cancer geneticists. “Now, I think there is a sort of view that we don’t need to know – that it’s not terribly important and it’s not going to tell us very much.”

As group leader of the Cancer Evolution and Genome Instability Lab, Swanton first broached the idea for PEACE during a conversation with his colleague, Mariam Jamal-Hanjani, in 2014. “I remember he walked into the lab late one night when I was still working and said ‘You should set up a patient autopsy’,” Jamal-Hanjani recalls. “I’d only just joined his lab and I thought ‘That’s a bit controversial’. But he’d planted the seed, and we just kept it going from there.”

It took several more conversations for the pair to convince their colleagues, but by November 2016 they had managed to gather the resources and ethical approval required for the study. “For decades, science and medicine had been waiting to be invigorated with new technologies,” Swanton says. “Probably part of the reason why nobody’s been terribly interested in studying death is because, until recently, we’ve lacked the means to probe it.”

One in two people will develop cancer in their lifetime, according to figures from Cancer Research UK. And while research has advanced in leaps and bounds in terms of finding drugs and improving our understanding of the disease, doctors still don’t know the answer to one of the biggest questions: why do patients die? “There is some degree of complacency,” says Jamal-Hanjani. “If a patient’s got lung cancer or any type of cancer and then they die … clinicians will presume that they have died of their cancer. But that’s really a failure on our part.”

Mariam Jamal-Hanjani : A pioneering figure in cancer research

“In patients with cancer, there are some obvious reasons,” Swanton says. “Organ failure comes into it, [or] if you’ve got a brain metastasis patients can develop blood clots. But there are many other, much more subtle causes of death we know next to nothing about.”

One interesting finding to come out of the PEACE study already is that the degree of cancer cells found within patients at death can vary by several million, demonstrating how some people’s bodies can live much longer than others when faced with tumour spread. A lung cancer patient, for example, may have a tumour containing between 100 and 300 million tumour cells at the point of diagnosis. By the time they die, that figure may have reached one trillion.

“But what we are finding is that some patients really don’t have much of the disease in their body at all, and so we really don’t know how they die,” says Swanton. “There may be complex metabolic syndromes going on, it could be immune failure – we just don’t know. And we hope that PEACE can start to illuminate some of these questions.”

With so much money being pumped into cancer research (Cancer Research UK alone had an income exceeding £670 million in 2018-19), one common question researchers face is why we haven’t found a cure. While cancer drugs often work for months, and sometimes years, “drug resistance is the norm rather than the exception”, Swanton says. Although there are thousands of treatments in development, the prospect of a “one-stop” drug that could help all cancer patients is a particular challenge, he says, because of the way cancer cells evolve.

In many living organisms, evolution happens in a linear pattern. For instance, a mutation will form in a cell that becomes replicated several times until all the cells contain the same mutation. If that were the case with tumour cells, one could imagine it would be possible to wipe out the entire tumour with a single drug – because every cell in every tumour would essentially be the same. “But we now know that these tumours aren’t developing in a linear fashion at all – they are evolving in a branch manner,” Swanton says. While some cells contain mutations number one and two, others will have one, four and five; and others could have mutations one, six and seven – the evolution of the cells becomes increasingly unpredictable and complex. This, he says, is “a major reason why the drugs we use in the clinical setting fail”.

The PEACE project is trying a new approach, by looking at the wider human biology, beyond a specific tumour site – hence the need for access to the full human system. “In our diagnostic practice we tend to get a biopsy from one metastatic site [an area to which a tumour has spread] – it’s very rare that we ever get more,” says Swanton. “But if you could sample a lung and a brain and an adrenal gland and the liver … you could start to understand how the tumour cells start to react within the local environment. Because you cannot understand evolution unless you understand the species – in this case cancer – but also the environment in which it’s evolving.”

Through PEACE, Swanton and his team hope to develop their understanding of how and why tumours spread through the body, and attempt to find genetic patterns that might help explain cancer progression. A major purpose of the study is to collect enough material from autopsies to create a longstanding database of samples, which can hopefully be used in cancer research for decades to come.

The study is already producing results. In one paper, published in the journal Nature last year, the team looked at a patient with lung cancer. Analysing samples from different sites in the body to which the cancer had spread, they were able to identify genetic abnormalities. They then retrospectively analysed blood samples collected prior to the patient’s death, and detected the same genetic abnormalities. “This showed us that blood could be used as a predictor of genetic changes that may be involved in cancer progression and metastasis,” Jamal-Hanjani explains.

Another study, published in Cell, looked at two patients with kidney cancer – one who died six months after diagnosis and another who died 17 years after diagnosis. Again, researchers analysed samples from different sites in the body. They identified distinct evolutionary patterns in each patient’s cancer progression, indicating that the genetic pattern in which a cancer evolves and spreads may offer clues to an individual’s clinical outcome.

This means scientists may one day be able to predict a patient’s experience with a particular type of cancer based on their genes. It could help doctors accurately prescribe drugs they know are more likely to benefit the patient, and stop wasting time on those that won’t – eventually tailoring each person’s treatment plan to their genetic make-up. “We know that the environment in which a cancer grows plays a crucial role in its behaviour and progression or regression,” Jamal-Hanjani says. “It’s by knowing how this genetic landscape changes in time, and how it leads to increasing disease burden, that we can understand better why drugs don’t work and why patients eventually die from their disease.”

The PEACE researchers’ work usually starts with a phone call. Sometimes this comes with forewarning: the patient is unwell, it won’t be long now. Other times, the death is more sudden: at home in the middle of the night, or in another hospital, and the team must make arrangements for autopsy as soon as possible.

As co-leader of the project, it is Jamal-Hanjani’s task to make this happen. “If I learn of a patient’s death, the next 24 hours are mayhem,” she says. “My team is communicating throughout the night. We’ll be sending emails even at midnight saying: ‘Where are we going to collect tissue from tomorrow? What did the last scan show? Have we got a slot with the mortuary? Have we found an undertaker?’”

For the autopsy to go ahead, the researchers must first secure copies of the patient’s consent form and death certificate. Jamal-Hanjani must also make sure there is no-one contesting the cause of death – if there is, it will complicate matters, although a coronary post-mortem can take place alongside the autopsy. She aims to strike a balance between practical concerns – booking a slot in the mortuary, bringing together the required staff – and a sense of duty to the patients and their family. “We try not to delay the process because families want it to happen fast,” she says. The study is not suitable for some people from Jewish or Muslim backgrounds, since their religion may require a rapid burial. “But sometimes we’ve been able to accommodate for that.”

Once permission has been secured, a team of clinicians, research assistants and mortuary technicians meets to gather the equipment needed: liquid nitrogen to freeze fresh tissue samples at -80°C, chemicals to preserve tissue into blocks, a dissection kit and medical packaging. The process itself can be brutally physical. Chests are cracked open to access lungs. Organs are removed in blocks, often the lungs and heart combined. A pathologist removes a kidney, slices it. The next person in line dissects it a little more. Another person puts it in the liquid nitrogen tank, and someone else labels it. The system is an exacting and precise conveyor belt, from the point of death to the moment the samples are brought back to the lab, with every piece barcoded and tracked.

Well-preserved tissue can last for many years – often for as long as a study has ethical approval – and so the researchers hope to build up a bank of good-quality samples to use in future work as well.

In the mortuary, the noise from the 24-hour flurry of emails, phone calls and planning comes to an abrupt stop. The mood is sombre, respectful. “There’s no laughter, there’s no discussion,” says Jamal-Hajani. “We just know that this is what our patient wanted, and we all get on with our business.” The researchers are looking for evidence of tumour spread, so major tumour sites will be collected, but, unlike any kind of surgery when the patient is alive, the team will also collect some healthy tissue from surrounding regions for the purposes of comparison.

Everything else is replaced as it was inside the body, and the patient is sewn back up. Attention to detail and duty of care take priority; even in cases where the donor’s skull must be opened for access to the brain, pathologists will make their incision at the back of the patient’s neck, so that once the procedure is over no scarring can be seen.

“People have asked me, ‘What kind of scars will I have, what colour stitching will you use?’” says Jamal-Hanjani. She tells them that the stitching is subcutaneous – under the skin – and uses flesh-coloured thread. “If it’s not a cremation, families sometimes haven’t had time to view the body, and they’ll do it after an autopsy, so we’ll try to minimise any incisions,” she explains. But beyond this, she takes such care because she believes the team is “so privileged. Some patients say, ‘When I’m dead, I’m dead … I don’t care what you do with my body.’ But for me, that respect and dignity that we try to maintain when patients are alive – that’s got to follow through even after death.”

The first person Jamal-Hanjani recruited to the PEACE study was 19 years old. A Cambridge University undergraduate studying politics, philosophy and economics, she was at the top of her class and had a bright future. But cancer is not one to discriminate, and, despite her youth, intelligence and ambitions, she died within 18 months.

“That first conversation really stayed with me,” Jamal-Hanjani remembers. “She was so bright, so interested in what we were doing. She asked real specific questions. She wanted to know what would happen to her eyes. Would her body be scarred, would there be bruising? She cared about the research, but also what her family would be left with.”

Approaching a patient about signing up to the study can be difficult. In the case of this young woman, “I told her that donating herself to medical science could help us to learn why some patients develop drug resistance and why, in her case, we didn’t have any treatment options that would work for her,” Jamal-Hanjani says. “I made it clear that she wouldn’t benefit from any of this herself.”

In the end, the team never did get to fulfil the student’s wish and go through with her autopsy. At that time, the project leader was heavily pregnant, and the study was in its early stages and had few resources. But the patient had also got married shortly before her death, and the sense was that her husband was not comfortable with the agreement. “It was bittersweet,” Jamal-Hanjani says. “I really do feel strongly that we must try to keep the patient’s living wish. I couldn’t do that for her, but I feel comfortable that I respected the wishes of her family whom she loved.”

More than this, Jamal-Hanjani says the student gave her the push she needed in those early stages of the project. “She taught me that there are patients out there who want to selflessly give like this – because they want to help research, because they know that’s how other patients might benefit in the future,” she says. “Before then, I had patients come to me and ask if there was anything they could do – for instance, donate their organs after death. With her, it was the first time I could say: ‘Here’s a study you could be involved in. I have something for you.’ We may not have collected samples from her, but at that point in my life she really motivated me to make it happen for others.”

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Usually, a patient is approached to join the study by Jamal-Hanjani or a fellow clinician, but sometimes individuals get in touch themselves after hearing about it through their doctor or online. To date, the project has recruited around 190 patients across the UK and completed more than 100 autopsies. Initially starting as a collaboration between the Francis Crick Institute and the nearby University College Hospital, the programme has expanded to include ten sites across Britain, including Glasgow, Sheffield, Southampton and Birmingham. The study is potentially open to anyone with tumours that have spread, but Jamal-Hanjani is cautious about who she recruits, and has turned people down if there is a chance their tissue would not be useful for the study.

On the flipside, there have been cases where patients are included who have not had the chance to personally consent while alive. “The study was set up with doctors and scientists, but also really heavy and ongoing input from patient advocacy groups,” she explains. “The feedback we had was that patients still want to be part of this study but maybe they’re physically not well enough to come and give consent.” At a certain point, a patient may have given power of attorney to a close relative – so a family might give consent on the patient’s behalf. Jamal-Hanjani admits it is difficult to that sort of patient down.

Every funded research project has targets. On paper, PEACE’s aim is to perform 500 research autopsies in five years. In reality, it is not on track. “It’s rather ambitious because, logistically, this study has been a nightmare,” says Jamal-Hanjani. “These patients can die anywhere. At home, in a hospice, in another hospital. They can be hours away from where we perform the autopsies. We don’t always know when a patient has died, simply that interaction with the family’s relatives after death can be incredibly difficult for us and for them.”

There’s also the issue of funding. PEACE was originally promised £5 million from Cancer Research UK spread over five years, but this was unexpectedly dropped to £4 million. According to Jamal-Hanjani, the amount is only enough to cover the basic infrastructure for the setup of the study – any analysis of samples relies on additional funding. The current round of financial backing ends in October 2021, and the team is desperately hoping to keep going for another five years beyond that. “It’s a horrible thought that we’ve got fixed funding for a certain number of autopsies,” says Swanton. “It’s a terribly cold measure.”

More than that, of course, the future of PEACE will depend on the continued willingness of volunteers to participate. “Patients have been our greatest advocate here, not doctors or lawyers,” says Swanton. “It’s been patients who have really wanted this to happen. And they’ve been incredible with their generosity in enabling us to do this. We really owe everything to them.”

The discoveries coming out of PEACE are too late to help Thomas Filson, but the decision to donate his body to the study was a no-brainer nonetheless. “Why? Well you’ve just seen two reasons why,” he says, indicating the two small boys scampering around him. It’s a warm day, and the 70-year-old is sitting in an armchair at the home he shares with his wife, Lynn, in Ashford, Surrey. The boys – two of his four grandchildren – are making a convincing case for ice-cream. Thomas is stoic, a straight-talking former carpenter with a star dangling unexpectedly from his left earlobe (his daughter’s belly button ring, he explains – “just because she didn’t think I’d dare”). On his wrists are piles of multicoloured woven bracelets and charity bands. He very much embraces life but doesn’t take it too seriously – certainly not since his diagnosis six years ago.

Thomas was just half a year from retirement when he was diagnosed with lung cancer. Then, as if to demonstrate how unfair life can be, Lynn’s breast cancer was identified. She has since made a full recovery, but spent the first few months of Thomas’s diagnosis sick from her own chemotherapy.

From a lifetime of smoking and working with wood, Thomas says his lungs “have had a fairly stressful time with dust and muck and everything. They told me at 50 I had to stop smoking because I’d kill myself. Then of course, years later, life comes and surprises you.”

Like several PEACE recruits, Thomas was already signed up to a different cancer research trial run through the Crick called TRACERx, which studies the biopsies of tumours surgically removed from living patients. Being part of active research appeals to him, so he was an ideal candidate for researchers to bring up the subject of autopsy. “I’ve been a carpenter all my life – dirt’s dirt, isn’t it?” he says. “I’ve got a fairly rounded view of life and death. I’m a Christian, don’t get me wrong, but I think of myself as just another ant, running over this planet destroying it. So I said ‘Yes, let’s go for it’ – because there is no cure for this type of cancer, what have I got to lose? Let’s give something back.”

Behind Thomas’s upbeat demeanour is a man whose body is increasingly weak. He can no longer walk very far, and his skin has suffered since his last round of immunotherapy drugs. But every morning, he takes out his deaf Staffordshire bull terrier out to the waterfront near his house. The two of them will sit, sometimes for a couple of hours, and give space to their thoughts. “I don’t get emotional because I think I’m going to die, but sometimes I get a bit frustrated because I can’t do what I want to do,” he says. “I very rarely get depressed, because I think my life has been good. But it’s easy to die; it’s harder for your family or your partner.”

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For Lynn, the road ahead will no doubt be difficult. But she agrees Thomas is making the right choice. “Tom and I – we’re at the stage now where if I woke up tomorrow and he was gone, I couldn’t grieve, because I’ve done my grieving,” she says. “People will probably look at me and think ‘What a hard woman’. But they haven’t lived with him with the knowledge that he’s going to die. And I think he’s absolutely doing the right thing.”

To spend time with both patients such as Thomas and the researchers behind the PEACE study, is to see the strong, mutual respect. Ultimately, it is this human level of understanding – and the shared experiences of how cancer affects a family – that drives the study.

“I’m not daft enough to think my body will be the breakthrough,” says Thomas. “It will take many more volunteers before that happens.” But both he and Lynn take courage from the hope that his death may ultimately help people. Lynn says she thinks taking part in the research has helped Thomas, too.

“I don’t get down,” Thomas nods. “Not really. I think what keeps me so buoyant is the fact that I have given myself to research and to PEACE, and to know that it’s not all in vain. I’m not dying in vain.”

Source: wired

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