What incentives do scientists have to study rare diseases? | Explained

One of science’s goals is to cure diseases and ease human suffering. Are advances in medical research going in this direction?

December 26, 2023 10:30 am | Updated December 28, 2023 10:50 am IST - Mangaluru

A colorised scanning electron micrograph of a T lymphocyte cell, obtained on March 16, 2015.

A colorised scanning electron micrograph of a T lymphocyte cell, obtained on March 16, 2015. | Photo Credit: NIAID

Founded by the millennial world’s most famous billionaires, the Breakthrough Prizes may not yet rival the Nobel Prizes in prestige, but the so-called “Oscars of Science” do offer three-times as much prize money. The 2024 prizes in the Life Sciences category recognised groundbreaking research set to change the lives of those suffering from three debilitating diseases: Parkinson’s disease, cystic fibrosis, and cancer.

These discoveries, along with the contexts and controversies surrounding them, exemplify the state of cutting-edge medical biology today.

“There are about 7,000 known rare diseases, affecting around 8% of the world’s population” and “75% of rare disease patients [are] children,” according to the Ministry of Health and Family Welfare. Despite these sobering numbers, there is little research underway on rare diseases.

Relatively few people are diagnosed with these diseases, so most drug-makers and pharmaceutical companies are unwilling to invest money in them. The result: many of these diseases continue to be poorly understood while treatment and cures remain elusive.

Despite the odds, some scientists doggedly pursue research into rare diseases. Ellen Sidransky, a clinical geneticist at the U.S. National Institutes of Science, is one of them. For more than 25 years, she has been studying Gaucher disease, an inherited metabolic disorder affecting 1 in 57,000 people worldwide. It has also been reported in India. Dr. Sidransky won the Breakthrough Prize for her work on Parkinson’s disease, however.

A ‘high profile’ condition

“Parkinson’s is a neurodegenerative disorder,” Krishna Deepak, a computational biologist at Azim Premji University, Bengaluru, said. “It happens when the neurons in the part of the brain that controls motor function and has impacts on cognition and other bodily functions start dying off.”

The reason for this neuronal cell death is a pile-up of protein aggregates that resist being cleared up. This is bad news because unlike other cells in the body, neurons aren’t replenished as readily. Before long, physiological symptoms turn up. “An affected individual’s arms will violently shake even while trying to do basic stuff like picking up a pen,” said Dr. Deepak, describing tremors, a characteristic symptom of Parkinson’s.

According to the World Health Organisation, more than 8.5 million individuals are currently living with Parkinson’s – meaning it’s not a rare disease. While it is most frequently diagnosed in a person after they turn 60, sometimes it develops earlier. Hollywood actor Michael J. Fox, who starred in hit films like Back to the Future, was diagnosed at just 29. He has since become the most recognisable face of advocacy and fundraising for Parkinson’s.

Being a high-profile disease means there is more research on it as well. For some time, we have known that Parkinson’s arises due to a combination of genetic and environmental factors. But there’s no cure or effective treatment for the affected, beyond symptomatic, and usually temporary, relief.

While studying patients with Gaucher disease, Dr. Sidransky discovered a mutation in a known gene, called GBA1, strongly indicated whether an individual would develop Parkinson’s. For this finding, she shared a Breakthrough Prize with Thomas Gasser and Andrew Singleton, who independently identified another risk gene, LRRK2. 

Dr. Sidransky frequently uses her own example to assert that research into rare disorders must be supported because it can lead to insights for the wider population. In a 2020 lecture, the former paediatrician reminded her audience that the discovery of the risk gene GBA1 was a serendipitous outcome of her research on Gaucher disease. “I want to be a cheerleader for research into rare diseases,” she said.

Knowing what to fix

Dr. Deepak confirmed that identifying risk genes of a disease can be tremendously meaningful. “Once you identify a correlation between a genetic mutation and a disease, you can – essentially – predict the likelihood of a person developing the disease.”

He pointed to the example of breast cancer and the BRCA1 genes to illustrate how this knowledge can empower those at risk. “Imagine if as soon as a child is delivered, the hospital has to do a genetic screening,” he said. “Or someone in the family has the disease so you test a child for the disease risk gene on their 10th birthday. If you find it, you know what to expect. You can check up regularly, and if an early diagnosis is made, then for diseases like breast cancer, there is a very good success rate with treatment. The person can have a good quality of life going forward”.

The benefits don’t end there. Identifying risk genes can also offer a wealth of information about a disease’s mechanism. For example, both GBA1 and LRRK2 are involved in preventing protein aggregate build-ups in the brain. “If you want to fix something, you need to know where to fix it,” he continued. “Now that we know some of the genes that are involved, we have a target. With gene-editing techniques like CRISPR becoming established, we can see therapeutics on the horizon maybe in 10 or 20 years.”

This prediction starts to look more realistic together with the second Breakthrough Prize in Life Sciences announced this year.

Cystic fibrosis is a life-threatening rare disease that affects around a lakh people worldwide. Dr. Deepak painted a visceral picture of its effects: “When you have a runny nose, the mucus is thin and watery, so it can flow, right? Now imagine the exact opposite. Thick mucus filling your lungs and digestive tract till you can’t breathe or function normally.”

Cystic fibrosis is an inherited condition caused by mutations in a single gene, CFTR, that regulates just how thick or fluid the mucus is. This vital information about the disease mechanism and the gene responsible became a shot in the arm for researchers working on therapeutic options. Still, being a rare disease, progress was slow. Since the discovery of the CFTR gene in 1989, patients of the disease – many of them children – have been waiting with bated breath for a cure.

A miracle, but not quite

To be fair, there were a few options, but it took 30 years for something truly promising – when a drug called Trikafta was approved for use in the U.S. in 2019. The development of this drug won Sabine Hadida, Paul Negulescu, and Fredrick Van Goor, researchers at Vertex Pharmaceuticals, a Breakthrough Prize this year.

“In cystic fibrosis, the CFTR protein misfolds and becomes unable to function,” Dr. Deepak explained. Trikafta, he added, is a combination of three drugs that together ensure the protein can fold into its proper conformation, travel to the cell surface, and function as it should.”

Effective in 90% of patients, Trikafta has been called a “blockbuster combination drug” and “the biggest lifeboat for cystic fibrosis yet”. “[T]his level of success in treating a disease is a fantastic achievement,” Dr. Deepak, who comes from a drug discovery background himself, said.

He recalled being taught that cystic fibrosis was fatal. “To see that it has been cured in my lifetime is quite incredible.”

So a happy ending for the 1.6 lakh people estimated to be living with the disease? Not yet. There is a tragic catch: Vertex has priced the drug at $326,000 (Rs 2.71 crore) a year and is also blocking low-cost versions, rendering it virtually impossible for people in developing countries like India from accessing Trikafta.

This led to the ‘Right to Breathe’ campaign led by a global community of cystic fibrosis-affected families based in, among other countries, India, South Africa, Ukraine, and Brazil. The vast majority of cystic fibrosis patients “are being left to suffer and die without treatment, simply because a  company cares about nothing other than profit,” they protest on their website.

A tug of war

Vertex isn’t the first big pharma company to have faced such a charge. In 2019, regulators approved a cure for spinal muscular atrophy called Zolgensma, made by Novartis. It’s a single injection that can spare infants a painful, and often shortened, life. The problem: Zolgensma is only available for Rs 18 crore.

‘Right to Breathe’ campaigners believe they have a strong case because the company benefited from significant funding from a cystic fibrosis patient advocacy group in its early days. They contend that Vertex thus has no excuse to restrict patients from accessing the drug.

Big pharma’s justification for exorbitant pricing is that this is the only way to recoup the billions they’ve invested in developing the drug. “Traditional drug discovery processes take anywhere between seven to 20 years, and sometimes you put in all that and nothing comes out of it,” Dr. Deepak said. “So for the process to work, a company has to stay in the market, not go bankrupt, and keep on investing in research and development for all this time.”

This is something that bothers me – this tug-of-war between doing what is right and business interests.”

Some therapies have had more success with this tug-of-war. In October 2023, CAR-T cell therapy, a cutting-edge treatment for cancer first approved in the U.S. in 2017, was approved for use in India. The American version cost Rs 3.3 crore whereas an indigenous version developed by ImmunoACT, a company incubated at IIT Bombay, costs one-tenth as much.

A cure for cancer?

CAR-T cell therapy is a novel way of fighting cancer. “You take a T cell from a person, engineer it to target the cancer specific signal, and put it back in the system,” Dr. Deepak explained. “It will proliferate and the engineered T-cells will destroy every cancer cell it encounters.” The therapy has been shown to be effective even a decade after treatment, “so it’s like a living drug that continues to offer protection, as long as it’s still there.”

For developing CAR-T, American scientists Carl June and Michel Sadelain received the third Breakthrough Prize in Life Sciences this year.

While it’s indeed a breakthrough, Dr. Deepak cautioned that the therapy is still primarily for “liquid cancers” such as blood cancers. “A vast majority of cancers are actually solid tumours. We still need a way of targeting those, and research is ongoing in that direction.”

And again, a single regimen of CAR-T cell therapy costs Rs 30-40 lakh, and out of reach of most Indians. It does, however, demonstrate how much we stand to gain by promoting indigenous research.

Dr. Deepak rued that most South Asian countries rely on the U.S. or European countries for fundamental discoveries and to unearth drug candidates, even though Western priorities are usually aligned with those of Caucasian populations. “I think governments, even in developing nations, can do more,” he said. “Even if we put in a little more money into basic research, we can have a better understanding of most diseases.”

The 2024 Breakthrough Prizes laureates demonstrate the cutting-edge ways scientists are making use of basic science to improve the quality of human lives. But they also highlight systemic, non-scientific factors that influence what scientists choose to study and who gets to access the fruits of their labour. “I wish scientists could just go in with an open mind and explore diseases for the sake of humanity, rather than being driven by market dynamics,” Dr. Deepak said with a sigh. “But maybe that’s too much to expect.”

Yet he remains optimistic: “The breakthroughs may inspire other researchers to look closely at systems they are working on through new lenses, or take up the cause of neglected and understudied disease targets.”

Nandita Jayaraj is a Mangaluru-based science writer and co-author of Lab Hopping (2023).

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