The quest for the era of personalised medicine

In early 2017, a neurologist at Boston Children's Hospital called Timothy Yu began work on the most ambitious project of his life: to design and synthesise an experimental drug for a dying child, within a timeframe of just a few months.

Weeks earlier, Yu had been forwarded a desperate plea made on Facebook from a woman called Julia Vitarello. Her daughter Mila, then just five years old, had been diagnosed with Batten disease: a rare but devastating neurodegenerative disorder combining symptoms of Parkinson's disease, dementia, and epilepsy. Worse, Mila's form of Batten disease was driven by a unique gene mutation, meaning no existing experimental therapies would work.

Rather than accept her daughter's fate, Vitarello became an activist, setting up a foundation in her daughter's name. Through crowdfunding, she raised more than $3m (£2.4m) with the aim of funding a novel gene therapy. This ultimately led her to Yu.

After sequencing Mila's genome to identify the responsible mutation, Yu suggested developing a drug called an "antisense oligonucleotide". This relatively new treatment approach had recently been used to create a therapy for another rare disease called spinal muscular atrophy. Antisense oligonucleotides work by binding to the molecules produced by the mutated DNA, correcting their behaviour. But in this case, it would be different. Yu would create a personalised antisense oligonucleotide designed solely for Mila.

At the time it was the most audacious drug development timeline ever attempted: synthesising new medications typically takes years rather than months. But by the winter of 2017 the drug, named "milasen", was ready.

"I didn't set out for my daughter to be the first to receive a personalised medicine," says Vitarello, speaking to the BBC from her home in Colorado, US. "I was hoping we could find the mutation that was causing her disease, but then milasen, the drug Tim Yu developed for Mila, showed just what is possible. We have the ability to find the underlying genetic cause of a disease and then target a drug to it, even if it is unique to just one person. It was only after Mila started receiving the drug that I started to really understand what a big deal that was."

Over the next four years, the treatment helped to halt the progression of Mila's condition, and improved her quality of life. "Her legs got stronger so she could go up stairs with my help," says Vitarello. "She laughed and smiled at funny things in books and songs. She though people sneezing was hilarious."

Unfortunately, it came too late. The disease, already in an advanced stage, eventually returned. Mila died on 11 February 2021, aged just 10.

Her mother still wrestles with the loss. "What if she had started receiving the drug two months before when she still had her words and wasn't suffering seizures. What if she had got it two years earlier or from birth? I have days that are really hard. It just comes unexpectedly, in waves."

But two years on, Mila's story has begun to generate it's own legacy. Unknown to her mother at the time, the development of milasen was followed by geneticists around the world. They saw it as a landmark case of how genomic-driven personalised medicine could be used to tackle rare diseases. "This story is a really powerful example of what's possible," says Richard Scott, chief medical officer at Genomics England, which is run by the UK's department of health, and a consultant at Great Ormond Street Hospital in London.

Mila's story illustrates both the promise of personalised medicine, but also some of its frustrations. In theory, therapies targeted to a person's genetic makeup should be more effective and have fewer side effects. But in practice, personalised medicine is often erratic and expensive, and often there are simpler solutions. It also requires people to trust governments and companies with their genomic data, while the regulatory environment around medicines is ill-equipped to cope with therapies that are designed for just one person. Getting the safety and efficacy data needed for regulatory approval usually requires clinical trials involving hundreds, it not thousands of people.

Nevertheless, researchers are still trying – and it now seems there may be some genuine progress.

Newborn genetic screening programmes will look for 200 rare but treatable genetic diseases – a huge increase on the heel prick test that is currently used (Credit: Alamy)

Later this year, 100,000 healthy babies in the UK will have their entire DNA sequenced, as part of a landmark trial created by Genomics England called the Newborn Genomes Programme. The aim is to screen for 200 rare but treatable genetic diseases: a big advance on the heel prick blood test currently offered to newborn babies, which only checks for nine. It should enable affected families to receive a swift diagnosis. Treatments, which can range from drugs to special diets, could then begin quickly. In New York City, a similar project is already underway, screening babies for around 160-260 diseases depending on their parents' wishes.

The 200 diseases are individually rare, but collectively they impact as many as one in 200 children, says Scott. "While these are conditions which many people haven't heard of, the impact on those individual families is enormous."

This kind of genomic surveillance is happening hand-in-hand with strides in gene editing and other emerging treatment options, improving the prospects of managing or even curing all kinds of genetic diseases. Recently, the first gene therapy for hemophilia B was approved by the US Food and Drug Administration, while clinical trials are investigating the use of Crispr gene editing for sickle cell disease.

As these technologies advance, it will become increasingly possible to offer personalised treatments for children with rare diseases, as pioneered by Yu. There are at least 7,000 rare diseases caused by a single gene mutation, most of which develop in early childhood. Hence Scott predicts much more newborn screening. "With the pace of change and knowledge, I expect that over the next 10 years, the number of rare conditions where we can be really confident that there's a meaningful intervention will substantially shift," he says.

Mila's mother has also thrown herself into the fray in an attempt to speed up this transformation in medicine. Working from a computer in Mila's bedroom, Vitarello spends her time speaking to scientists, regulators, and drug companies around the world in the hope of driving forward the progress that was made with her daughter's treatment so it can help others with rare diseases.

"There are an estimated 400 million people with rare diseases around the world," she says. "Half of those are children and 60 million of those will die before they reach the age of five. That keeps me up at night. It's a silent pandemic. Many people thought milasen was a kind of one-off, but we are at the point where individualised, programmable medicines are now possible. The technology and the science is there and it is happening much faster than people expected."

Genomic sequencing, for example, is likely to become standard practice across the UK for all children diagnosed with cancer, says Matthew Murray, a paediatric oncologist and professor at the University of Cambridge in England. "Here in the East Genomics Laboratory Hub we are routinely offering this as standard of care," he says. "We anticipate that it will be more widely offered over the next few years, so that as many children as possible may benefit."

Vitarello and many of the scientists working in this area see a world where doctors will eventually have a toolbox of different treatments that can be programmed to an individual patient according to their specific genetic makeup.

This is the kind of future envisioned 20 years ago when the Human Genome Project was first completed. It was expected to usher in a new era of personalised medicine for all. This seemed within touching distance in 2003. But while some of it is now finally coming to fruition, it has not been as straightforward as genomics pioneers imagined.

Matching medication to DNA

One issue personalised medicine was meant to address was people's differing responses to drugs. For example, codeine is a commonly used painkiller, prescribed and sold to millions of people around the world each year. Due to genetic variations, the standard daily doses do not work at all in about 7-10% of the Caucasian population and 1-3% among other ethnic groups.

This is surprisingly common. Depending on our genome, we respond differently to many drugs. For example, some people absorb medications too quickly, meaning they need a higher dose to experience any benefit; others process them too slowly, leading to side effects. A study of 7,000 people published in February found they experienced significantly fewer side effects when the doses of certain drugs were tailored to their DNA, a process called pharmacogenetic testing.

According to the database PharmGKB, we currently have concrete evidence that our responses to 34 different drugs are influenced by genetics. Yet this information has made little difference to medical practice. There are just a handful of cases where pharmacogenetic testing is routinely offered, including the chemotherapy DPYD and the HIV drug Abacavir.

There are many reasons why pharmacogenetic testing has not been rolled out more widely, says Aroon Hingorani, professor of genetic epidemiology at University College London in the UK. Doctors and nurses need training on how to interpret test results. More studies must be done to obtain enough information on genetic variation between ethnic groups. Finally, it may not always be practical: an additional test takes time, and patients sometimes need immediate treatment.

Money is also a factor. With the health services around the world under financial strain, the onus is very much on scientists to prove beyond doubt that pharmacogenetic testing for a particular drug will benefit patients. "There are costs associated with any implementation of any new tests," says Hingorani. "So there's a difference between showing in a research setting that a particular genetic variant influences the level of a drug in the body, and showing that has an important effect on clinical outcome. It's a higher bar, and there have been very few randomised controlled trials looking at the utility of pharmacogenetic tests."

Sometimes it is simpler to switch to a new drug with a "wider therapeutic window", meaning small fluctuations in its concentration in the blood have less of an impact on the body. "As an example, clinical trials found that people respond differently to an anticoagulant called warfarin, influencing its efficacy and safety," says Hingorani. "But then a new class of anticoagulants emerged which didn't vary so much, and the world moved on."

Entirely personalised medicines are probably not necessary for many diseases, either.

Instead, the medical world has largely focused on using genetics to develop what Hingorani dubs "impersonalised medicines". This entails using rogue gene variants to understand more about the biology of a disease, and develop drugs that help us all.

This approach has been adopted by the pharmaceutical industry, in a bid to improve the notoriously poor success rate of clinical trials. Already, better targets have been identified through large genomic studies: they include the protein lipoprotein(a), which elevates risk of heart disease when raised, and the gene PCSK9 which regulates cholesterol. They have yielded new drug candidates like Amgen's Olpasiran and Novartis' Inclisiran.

The common opioid painkiller codeine is not metabolised by some people due to a specific genetic variation (Credit: Alamy)

However, one area where personalised medicine may really find its niche is through screening for rare vulnerabilities like sudden heart failure. Sudden cardiac arrests accounts for up to 400,000 deaths in the US, often due to undiagnosed heart conditions. One of these is cardiomyopathy, the technical term for a heart muscle disease, which is particularly feared as it can cause sudden death during athletic activity.

We have clues to why some people are vulnerable. Cardiologists in South Africa have identified a mutation in a gene called CDH2, which causes the heart to develop with abnormal structure and function.

Dhavendra Kumar is a consultant clinical geneticist at St Bart's Hospital, London and runs a non-profit called the Genomic Medicine Foundation. He is pushing for more screening to detect those at risk, particularly in young people with a family history of heart disease.

"The people who experience these sudden cardiac events tend to be very active physically," says Kumar. "If we knew that there's a genetic abnormality in the family, we could test them, and potentially offer them genetic counselling."

It has been 20 years since the Human Genome Project was "completed", but this enormous effort to sequence and map the human "book of life" was only just the beginning. Far from closing the question of what makes our bodies tick and why they do so differently, research on the human genome has revealed a far more complex picture than anyone could have imagined. Beyond the Genome examines just how far our understanding of our genetics has come in the past two decades.

Another major hope for personalised medicine is that it can improve cancer treatment. Neil Ward, vice president and general manager at genomic sequencing company Pacific Biosciences, describes cancer as a "disease of malfunctioning genetics". That means the combinations of mutations within tumours hold the key to eradicating them.

Already, personalised medicines aimed at patients with a known genetic subtype have made a difference in some cancers. Women with advanced breast cancer who have a mutation in the PIK3CA gene are more resistant to chemotherapy. Doctors now prescribe specific drugs called PI3K inhibitors alongside hormone treatment: this has been shown to stabilise the disease, at least temporarily. Genetically targeted drugs are also used for non-small cell lung cancer, and ultimately gene therapy may help.

For Ward, this is just the beginning. "The reason why a lot of modern therapies extend life for only a matter of months, rather than cure the disease, is because they treat a big percentage of the tumour but not the whole thing," he says. "The way forward is trials based on the genetic architecture which use a combination of therapies, each tailored to different branches of the tumour's mutational family tree."

The promise of mRNA

Perhaps the most exciting genetically driven cancer medicines are the messenger RNA (mRNA) vaccines pioneered by companies like BioNTech, Moderna and CureVac. Clinical trials are currently testing mRNA vaccines against a range of cancer types including melanoma, ovarian, head and neck, colorectal, lung and pancreatic. These are the first cancer therapies entirely tailored to one patient's DNA.

"Every patient has different tumour antigens," explains Uğur Şahin, a German oncologist who co-founded BioNTech with his wife Özlem Türeci. "The way cancer vaccines work is you take the patient's tumour, identify the mutations, select the ones which can induce an immune response, and then make a vaccine designed for that patient only. It's a different concept to most vaccines, it's a treatment rather than a preventative option."

Such is the hope that mRNA vaccines are the next frontier of cancer treatments, particularly for advanced forms of the disease, the UK's National Health Service (NHS) has agreed a groundbreaking partnership with BioNTech to fast-track their development over the next seven years. If mRNA vaccines turn out to be consistently more effective than standard cancer treatments, it could be a watershed moment for personalised medicine.

However, they will also be extremely expensive. Some cancer experts question whether mRNA vaccines are worth the money across all forms of the disease, as genomic targets have not always proven useful.

"We have already put a lot of money into doing genomic sequencing of cancer patients, and it has been shown to be very important in lung cancer," says Johan Hartman, a professor of breast cancer pathology at the Karolinska Institute in Stockholm. "But we have yet to see in clinical trials that the large proportion of patients across other solid cancers have any benefit from broad genomic profiling."

In some cases, Hartman suggests, it might not be the genome driving the tumour. Instead we should consider other forms of personalisation like advanced image analysis, driven by artificial intelligence (AI). He has co-founded a spin-off company called Stratipath, which uses a deep learning model to find patterns in scans of breast tumours and predict the best treatments.

The rapid development of mRNA vaccines against Covid-19 have raised hopes that they can be used to target cancers by tailoring them to individual patients (Credit: Getty Images)

Using AI to personalise therapy may also be more cost-effective for stretched healthcare systems. While genomic sequencing is getting cheaper, there are other costs. Screening for a disease involves accumulating the genomes of many healthy individuals to benefit a small minority. This is expensive.

To fund it, Ward predicts public healthcare systems will strike partnerships with pharmaceutical companies keen to amass more data to aid their drug development pipelines. "The pharmaceutical industry will be willing to subsidise the generation of that data," he says. "As long as there's some reciprocal access to the medical records of those individuals over time, it will allow their drug development processes to become twice as efficient as they are currently."

This leads us to the last and biggest issue with personalised medicine: ethics. A person's DNA is extremely personal information, whether it is used in screening for sudden heart attacks or rare childhood diseases, or even analysing a tumour. There is a balance to be struck between protecting a patient's health and their right to privacy.

The arguments are more straightforward in the case of cancer patients. Nevertheless, many might feel uncomfortable about major corporations being given access to anonymised versions of their personal data, especially in the case of newborn babies where the consent must be given by their parents.

That's why one of the major aims of the Newborn Genomes Programme is to monitor public acceptance. Are most families happy to have their child's DNA stored in health service databases for years, in case it could improve their medical treatment? Such a system could in theory help oncologists to identify children born with mutations that put them at a higher risk of leukemia, and then use that data to give them targeted therapies. But only if parents agree.

"A lot of the work we'll do through the programme is about understanding people's attitudes to how we might store and hold data, what the expectations are, and how you might empower people to be part of decisions about how their data is used," says Scott, "For example, if a child falls ill two or three years down the line, whether it's useful to hold the data so you can access it more rapidly to make a diagnosis, or whether it might help predict the right doses of a particular medicine later in life. Is that the sort of thing we should offer people, and how do they feel about that?"

Vitarello believes there needs to be some major changes in the way medical professionals, patients and health regulators see these kinds of treatments. It is going to potentially require a different approach to the way drugs are tested, and some willingness to embrace risk.

In the meantime, those scientists who watched Mila's story unfold are continuing to develop the technologies needed to make more personalised treatments possible. How does Vitarello feel about this legacy for her daughter?

"I've had 60-year-old, 70-year-old scientists with tears in their eyes saying they couldn't believe this sort of precision medicine was happening in their lifetime," she says. "After Mila died, so many people got in touch to say they had changed what their lab was working on or started a company or moved to another country to work with someone. There have been medical students who said they have gone into their career because of Mila's story.

"As a mom, I always thought she would go on to do something so big in her life. I never thought it would be this."

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