A team of Indian scientists says it has achieved a stunning breakthrough in early cancer diagnosis with a discovery rooted in a contentious segment of cellular biology that, if validated by additional trials, holds vast market potential in a branch of therapeutic medicine worth tens of billions of dollars a year
A team of Indian scientists says it has achieved a stunning breakthrough in early cancer diagnosis with a discovery rooted in a contentious segment of cellular biology that, if validated by additional trials, holds vast market potential in a branch of therapeutic medicine worth tens of billions of dollars a year.
The discovery enables the detection of cancer and the stage the disease is in from a simple blood test with virtually 100% accuracy, according to the results of a 1,000-person clinical study described in a forthcoming paper in the peer-reviewed Stem Cell Reviews and Reports, a quarterly journal published by Berlin-based Springer Science + Business Media. The paper was published online on Thursday.
The technique was able to identify 25 different kinds of cancer. Most importantly, in some ways, it was able to detect cancer before the onset of tumour development. As cancer treatments have advanced, deaths from the illness in its early stages have dramatically declined, and a diagnostic tool that can flag cancers early could become a boon to millions who suffer from a deadly illness that also inflicts financial ruin on families.
The test, known as HrC, has been co-developed by Mumbai-based biotechnology firm Epigeneres Biotechnology Pvt. Ltd and Singapore-based Tzar Labs Pte Ltd. Mumbai-based nanotech scientist Vinay Kumar Tripathi and his family are majority shareholders in both companies.
“We can early-detect all types of cancer, even before tumour formation, from a simple blood test. It’s also the first prognostic test for cancer in the world," Tzar Labs chief executive officer (CEO) Ashish Tripathi said in a telephone interview. “Not only can we tell you you don’t have cancer, but we can also safely rule out the risk of cancer for the following year if your HrC marker falls in the safe zone. We envisage a world where one needs to do the HrC test once a year, and we will catch cancer either at stage 1 or prior."
Tripathi’s youngest son is the best-selling author Amish Tripathi, best known for the series Shiva Trilogy. His two other sons—Ashish and Anish, a former investment banker and consultant, respectively—are involved in the management of the two companies. The HrC test is so named after his son-in-law and former senior Mumbai police officer Himanshu Roy, who died by suicide in 2018 while ailing with cancer.
A global scourge
The company is now aiming to bring the test kits to the market in India by September-October this year, Ashish Tripathi said. It is working on securing regulatory approvals and also setting up a network of labs. The first such lab is coming up in Lower Parel in Mumbai. It is also in talks with investors to raise $200 million to fund large clinical trials, with 10,000-20,000 subjects, in Western markets.
The burden of cancer on the world is immense. The disease accounts for one in every six deaths worldwide, according to the American Cancer Society. It kills more people every year than HIV-AIDS, tuberculosis and malaria combined. In 2017, an estimated 17 million cases of cancer were diagnosed, and 9.5 million people died of the disease. By 2040, the figures are expected to reach 27.5 million new cases and 16.3 million cancer deaths.
The National Institute of Cancer Prevention and Research, based in Noida, estimates that India has 2.25 million cancer patients and adds 1.1 million new patients each year. Nearly 800,000 people die of the disease in the country annually.
The pharmaceutical and medical communities—as well as investors—will follow the outcome of the larger trials with great interest.
If validated, the results represent a major discovery, said Dr Ashish Kamat, professor of urologic oncology (surgery) and cancer research at MD Anderson Cancer Center in Houston, Texas.
“Any test that can reliably detect cancer very early is a game-changer. This would not only allow us to apply therapies while cancers are at highly curable stages but would also allow us to monitor the progress of treatment without exposing the patient to unnecessary toxicity of overtreatment," Kamat said. “If validated, this blood test, with high reported accuracy and reproducibility, that can diagnose all cancers, would represent a major breakthrough."
To understand the scientific foundation of the discovery, it’s necessary to understand a bit about stem cells and what they do. Stem cells are valued in medicine for their ability to create their own copies as well as to turn into other kinds of cells. Stem cells in the bone marrow, for instance, can give rise to red or white blood cells and platelets. These have found applications in a growing field known as regenerative medicine.
Among stem cells, the most valued are those with a property known as pluripotency—the ability to turn into any kind of cell in the body. It’s clear why these are sought after. If you have stem cells that can turn into any kind of cells, you could theoretically cure a range of ailments linked to tissue and organ damage. This potential has spawned a massive industry globally around stem cell banks and therapies, although treatments with regulatory approvals are few.
So far, two kinds of cells have been acknowledged to possess pluripotency. These are embryonic stem cells and induced pluripotent stem cells (IPSCs). The scientists who discovered IPSCs were awarded the Nobel Prize for medicine in 2012.
A third kind of cells has been claimed to possess pluripotency and has remained the subject of scientific controversy since 2006, when they were first isolated by Polish-American scientist Mariusz Ratajczak, a developmental biologist at the University of Louisville, Kentucky. These are called Very Small Embryonic Like stem cells, or VSELs.
The discovery by Tripathi and team are rooted in these cells, which have proved notoriously difficult to isolate and study. At a fundamental level, the discovery is akin to finding a signature for cancer in the blood, more specifically in peripheral blood, which is that portion of the blood that circulates in the body, as opposed to being sequestered within organs.
Tripathi and his team found two things. Firstly, in the peripheral blood of patients with cancer, a large number of VSELs were observed compared with those without the illness. Secondly, the expression of a transcription factor within the cell, known as Oct4a, varied, corresponding to the stages of cancer. A transcription factor is a protein that regulates the rate of transcription of genetic information from DNA to messenger RNA.
The team developed a scale based on the observations in a group of 104 cancer patients and then tested the scale in a registered double-blinded clinical trial with 1,000 people, half of whom were cancer patients. The trial correctly identified the cancer patients as well as the stage of cancer with 99% accuracy, the paper reports. The scale is also able to flag those at pre-cancer stages or at high risk of developing cancer.
All of this happens at a scale that’s hard to comprehend for the layperson. VSELs are difficult to isolate because they measure 3-5 microns, which makes them virtually indistinguishable from cellular debris. A micron, or micrometre, is one-millionth of a metre. In comparison, the thickness of a strand of human hair is about 70 microns. Anything below 40 microns is not visible to the human eye.
“The whole world had been looking for a marker for cancer cells. What Dr Tripathi’s team has achieved is a major breakthrough that India can be proud of. They have done excellent translational research," said Deepa Bhartiya, a co-author of the paper, who heads the stem cell biology department at the National Institute of Research in Reproductive Health, an arm of the Indian Council of Medical Research (ICMR).
If validated by larger clinical trials, the HrC test could emerge as a strong contender in a crowded and growing field where global biotech companies have been vying to develop accurate diagnostic tests for cancer from a draw of blood, which is referred to as liquid biopsy, with limited success.
Two techniques have been most favoured by such companies. One is to look for circulating tumour cells, and the other is to detect circulating cell-free tumour DNA (ctDNA) in the blood. But these have limitations—a small sample of blood might not capture a good sampling of such material and could result in a false negative reading. The other limitation is that their accuracy tends to be low at early stages, which is indeed when clinical intervention would be most effective.
Consequently, these have not yet developed into high-accuracy or commonly prescribed diagnostic tools.
Liquid biopsy is nonetheless a hot sector, and the space has seen some deal-making recently in the US. Last year, Illumina Inc., a US-based maker of machines used in genetic analysis, acquired Grail Inc., a top name in liquid biopsy, for $8 billion. Within weeks, Exact Sciences Corp. acquired Thrive Earlier Detection, a rival to Grail, for $2.5 billion.
Guardant Health Inc., the leader in the space with the first liquid biopsy test approved by the US Food and Drug Administration, has a market capitalization of $14 billion.
Nearly all of them are based on the circulating cell-free tumour DNA methodology. The HrC test takes a different approach, trying to read a genetic signature it has found to correlate with cancer. Tripathi argues that the technology developed by his company is superior to existing liquid biopsy techniques for this reason.
The opportunity is vast. Investment bank Cowen Inc. has estimated the US market size for liquid biopsies across segments to be worth $30-130 billion annually.
The group controlled by the Tripathi family has filed for patents in the US, Japan, Europe, Singapore, South Korea, China and India. Ashish Tripathi says Epigeneres, the Mumbai-based firm, holds the exclusive license for the test in India and will price it “as low as possible".
Minority investors in Epigeneres include Edelweiss co-founder Venkat Ramaswamy, Justdial co-founder V. Krishnan, Vijay Karnani, former co-head of Goldman Sachs in India, HCG hospital group and Torrent Pharma.
The company owns an equity stake in the Singapore-based entity, Tzar Labs, which holds the IP for the invention.
The discovery is bound to wade into a festering controversy in the field of stem cells—do VSELs exist at all? It’s a subject that inflames deep passions in this rarefied field of research.
The best-known scientist who backs their existence and relevance is Ratajczak of the University of Louisville, who first reported isolating these cells from the bone marrow of mice in 2006. He is also the editor of the journal that has published the paper on the HrC test, although he wasn’t a reviewer.
Diane Krause, a professor of cell biology at Yale University, and Russell Taichman, a professor of dentistry at the University of Michigan, are among the notable scientists who have reported isolating VSELs. Krause’s group also reported being able to turn these cells into a group of specialized cells known as epithelial cells, which line the inner surfaces of internal organs. Bhartiya from ICMR has also been working on VSELs for more than 15 years and has also reported isolating these cells.
But multiple other groups have reported not being able to isolate such cells. Most notably, in 2013, a study led by Irving Weissman, an influential stem cell researcher and director of the Stanford Institute of Stem Cell Biology and Regenerative Medicine, failed to confirm the existence of VSELs. In a subsequent interview, Weissman termed them a “distraction".
The academic papers, as well as journalism on the subject, are thick with claims and counterclaims, with reputed scientists on both sides of the aisle.
In a conversation with Mint from Kentucky on a video call, Ratajczak said the debate was due to a combination of poor laboratory skills and vested interests.
“Forty independent groups on different continents have confirmed the presence of these cells. So the debate exists only because some groups have either not properly followed the protocols or lack the skills to do so. The other issue is that a new category of pluripotent stem cells threatens the business interests around the other two categories that have promised big but failed to deliver successful and safe therapies. There’s a lot of investor money, patents and other interests that would hate competition from a new category of stem cells. All of these play a role in the obfuscation around VSELs," he said.
On the HrC paper, Ratajczak said he’s not surprised at the findings. “It’s a great paper, and I’m not surprised that VSELs are increasing in blood with malignancy. We have known that the number of VSELs increase post-heart infarction, stroke or skin burns. Ten years ago, when we inoculated tumour in mice, we observed an increase in VSELs in peripheral blood."
He added that more research is needed on the findings, especially on the linkages between the genetic markers and different kinds of cancer.
Tzar Labs’ Tripathi says he is unfazed by the academic debate. The practical application of technology, based on these cells, such as the cancer test his company has developed, will eventually settle the debate, he hopes.
“Either way, what is important is that the company has been able to measure key genetic markers consistently from 1,000 + samples, including non-cancer patients. Hitherto it was understood that these markers were only found in tumour cells. The markers are well understood by scientists, and hence the company is not concerned about this debate."
The science around VSELs could remain unsettled for longer. But if larger clinical trials validate the HrC test, it would be a remarkable moment for Indian biotech.
Subscribe to Mint Newsletters
* Enter a valid email
* Thank you for subscribing to our newsletter.
Never miss a story! Stay connected and informed with Mint.
our App Now!!