A simple ten-minute universal cancer test that can be detected by the human eye or an electronic device - published in Nature Communications (Dec 2018) by the Trau lab at the University of Queensland. Red indicates the presence of cancerous cells and blue doesn't.
Matt Trau, a professor of chemistry at the University of Queensland, stunned the science world back in December when the prestigious journal Nature Communications published his lab's discovery about a unique property of cancer DNA that could lead to a simple, cheap, and accurate test to detect any type of cancer in under 10 minutes.
No one believed it. I didn't believe it. I thought, "Gosh, okay, maybe it's a fluke."
Trau granted very few interviews in the wake of the news, but he recently opened up to leapsmag about the significance of this promising early research. Here is his story in his own words, as told to Editor-in-Chief Kira Peikoff.
There's been an incredible explosion of knowledge over the past 20 years, particularly since the genome was sequenced. The area of diagnostics has a tremendous amount of promise and has caught our lab's interest. If you catch cancer early, you can improve survival rates to as high as 98 percent, sometimes even now surpassing that.
My lab is interested in devices to improve the trajectory of cancer patients. So, once people get diagnosed, can we get really sophisticated information about the molecular origins of the disease, and can we measure it in real time? And then can we match that with the best treatment and monitor it in real time, too?
I think those approaches, also coupled with immunotherapy, where one dreams of monitoring the immune system simultaneously with the disease progress, will be the future.
But currently, the methodologies for cancer are still pretty old. So, for example, let's talk about biopsies in general. Liquid biopsy just means using a blood test or a urine test, rather than extracting out a piece of solid tissue. Now consider breast cancer. Still, the cutting-edge screening method is mammography or the physical interrogation for lumps. This has had a big impact in terms of early detection and awareness, but it's still primitive compared to interrogating, forensically, blood samples to look at traces of DNA.
Large machines like CAT scans, PET scans, MRIs, are very expensive and very subjective in terms of the operator. They don't look at the root causes of the cancer. Cancer is caused by changes in DNA. These can be changes in the hard drive of the DNA (the genomic changes) or changes in the apps that the DNA are running (the epigenetics and the transcriptomics).
We don't look at that now, even though we have, emerging, all of these technologies to do it, and those technologies are getting so much cheaper. I saw some statistics at a conference just a few months ago that, in the United States, less than 1 percent of cancer patients have their DNA interrogated. That's the current state-of-the-art in the modern medical system.
Professor Matt Trau, a cancer researcher at the University of Queensland in Australia.
(Courtesy)
Blood, as the highway of the body, is carrying all of this information. Cancer cells, if they are present in the body, are constantly getting turned over. When they die, they release their contents into the blood. Many of these cells end up in the urine and saliva. Having technologies that can forensically scan the highways looking for evidence of cancer is little bit like looking for explosives at the airport. That's very valuable as a security tool.
The trouble is that there are thousands of different types of cancer. Going back to breast cancer, there's at least a dozen different types, probably more, and each of them change the DNA (the hard drive of the disease) and the epigenetics (or the RAM memory). So one of the problems for diagnostics in cancer is to find something that is a signature of all cancers. That's been a really, really, really difficult problem.
Ours was a completely serendipitous discovery. What we found in the lab was this one marker that just kept coming up in all of the types of breast cancers we were studying.
No one believed it. I didn't believe it. I thought, "Gosh, okay, maybe it's a fluke, maybe it works just for breast cancer." So we went on to test it in prostate cancer, which is also many different types of diseases, and it seemed to be working in all of those. We then tested it further in lymphoma. Again, many different types of lymphoma. It worked across all of those. We tested it in gastrointestinal cancer. Again, many different types, and still, it worked, but we were skeptical.
Then we looked at cell lines, which are cells that have come from previous cancer patients, that we grow in the lab, but are used as model experimental systems. We have many of those cell lines, both ones that are cancerous, and ones that are healthy. It was quite remarkable that the marker worked in all of the cancer cell lines and didn't work in the healthy cell lines.
What could possibly be going on?
Well, imagine DNA as a piece of string, that's your hard drive. Epigenetics is like the beads that you put on that string. Those beads you can take on and off as you wish and they control which apps are run, meaning which genetic programs the cell runs. We hypothesized that for cancer, those beads cluster together, rather than being randomly distributed across the string.
Ultimately, I see this as something that would be like a pregnancy test you could take at your doctor's office.
The implications of this are profound. It means that DNA from cancer folds in water into three-dimensional structures that are very different from healthy cells' DNA. It's quite literally the needle in a haystack. Because when you do a liquid biopsy for early detection of cancer, most of the DNA from blood contains a vast abundance of healthy DNA. And that's not of interest. What's of interest is to find the cancerous DNA. That's there only in trace.
Once we figured out what was going on, we could easily set up a system to detect the trace cancerous DNA. It binds to gold nanoparticles in water and changes color. The test takes 10 minutes, and you can detect it by eye. Red indicates cancer and blue doesn't.
We're very, very excited about where we go from here. We're starting to test the test on a greater number of cancers, in thousands of patient samples. We're looking to the scientific community to engage with us, and we're getting a really good response from groups around the world who are supplying more samples to us so we can test this more broadly.
We also are very interested in testing how early can we go with this test. Can we detect cancer through a simple blood test even before there are any symptoms whatsoever? If so, we might be able to convert a cancer diagnosis to something almost as good as a vaccine.
Of course, we have to watch what are called false positives. We don't want to be detecting people as positives when they don't have cancer, and so the technology needs to improve there. We see this version as the iPhone 1. We're interested in the iPhone 2, 3, 4, getting better and better.
Ultimately, I see this as something that would be like a pregnancy test you could take at your doctor's office. If it came back positive, your doctor could say, "Look, there's some news here, but actually, it's not bad news, it's good news. We've caught this so early that we will be able to manage this, and this won't be a problem for you."
If this were to be in routine use in the medical system, countless lives could be saved. Cancer is now becoming one of the biggest killers in the world. We're talking millions upon millions upon millions of people who are affected. This really motivates our work. We might make a difference there.
As gene therapies and small molecule drugs are being studied in clinical trials, companies increasingly see the value in hiring patients to help explain the potential benefits.
Biomedical corporations and government research agencies are now incorporating patient advocacy more than ever, says Alice Lara, president and CEO of the Sudden Arrhythmia Death Syndromes Foundation in Salt Lake City, Utah. These organizations have seen the effectiveness of including patient voices to communicate and exemplify the benefits that key academic research institutions have shown in their medical studies.
“From our side of the aisle,” Lara says, “what we know as patient advocacy organizations is that educated patients do a lot better. They have a better course in their therapy and their condition, and understanding the genetics is important because all of our conditions are genetic.”
Founded in 2016, Tenaya is advancing gene therapies and small molecule drugs in clinical trials for both prevalent and rare forms of heart disease, says Ali, the CEO.
The firm's first small molecule, now in a Phase 1 clinical trial, is intended to treat heart failure with preserved ejection fraction, where the amount of blood pumped by the heart is reduced due to the heart chambers becoming weak or stiff. The condition accounts for half or more of all heart failure in the U.S., according to Ali, and is growing quickly because it's closely associated with diabetes. It’s also linked with metabolic syndrome, or a cluster of conditions including high blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol levels.
“We have a novel molecule that is first in class and, to our knowledge, best in class to tackle that, so we’re very excited about the clinical trial,” Ali says.
The first phase of the trial is being performed with healthy participants, rather than people with the disease, to establish safety and tolerability. The researchers can also look for the drug in blood samples, which could tell them whether it's reaching its target. Ali estimates that, if the company can establish safety and that it engages the right parts of the body, it will likely begin dosing patients with the disease in 2024.
Tenaya’s therapy delivers a healthy copy of the gene so that it makes a copy of the protein missing from the patients' hearts because of their mutation. The study will start with adult patients, then pivot potentially to children and even newborns, Ali says, “where there is an even greater unmet need because the disease progresses so fast that they have no options.”
Although this work still has a long way to go, Ali is excited about the potential because the gene therapy achieved positive results in the preclinical mouse trial. This animal trial demonstrated that the treatment reduced enlarged hearts, reversed electrophysiological abnormalities, and improved the functioning of the heart by increasing the ejection fraction after the single-dose of gene therapy. That measurement remained stable to the end of the animals’ lives, roughly 18 months, Ali says.
He’s also energized by the fact that heart disease has “taken a page out of the oncology playbook” by leveraging genetic research to develop more precise and targeted drugs and gene therapies.
“Now we are talking about a potential cure of a disease for which there was no cure and using a very novel concept,” says Melind Desai of the Cleveland Clinic.
Tenaya’s second program focuses on developing a gene therapy to mitigate the leading cause of hypertrophic cardiomyopathy through a specific gene called MYPBC3. The disease affects approximately 600,000 patients in the U.S. This particular genetic form, Ali explains, affects about 115,000 in the U.S. alone, so it is considered a rare disease.
“There are infants who are dying within the first weeks to months of life as a result of this mutation,” he says. “There are also adults who start having symptoms in their 20s, 30s and 40s with early morbidity and mortality.” Tenaya plans to apply before the end of this year to get the FDA’s approval to administer an investigational drug for this disease humans. If approved, the company will begin to dose patients in 2023.
“We now understand the genetics of the heart much better,” he says. “We now understand the leading genetic causes of hypertrophic myopathy, dilated cardiomyopathy and others, so that gives us the ability to take these large populations and stratify them rationally into subpopulations.”
Melind Desai, MD, who directs Cleveland Clinic’s Hypertrophic Cardiomyopathy Center, says that the goal of Tenaya’s second clinical study is to help improve the basic cardiac structure in patients with hypertrophic cardiomyopathy related to the MYPBC3 mutation.
“Now we are talking about a potential cure of a disease for which there was no cure and using a very novel concept,” he says. “So this is an exciting new frontier of therapeutic investigation for MYPBC3 gene-positive patients with a chance for a cure.
Neither of Tenaya’s two therapies address the gene mutation that has affected Borsari and her family. But Ali sees opportunity down the road to develop a gene therapy for her particular gene mutation, since it is the second leading cause of cardiomyopathy. Treating the MYH7 gene is especially challenging because it requires gene editing or silencing, instead of just replacing the gene.
Wendy Borsari was diagnosed at age 24 with a commonly inherited heart disease. She joined Tenaya as a patient advocate in 2021.
Wendy Borsari
“If you add a healthy gene it will produce healthy copies,” Ali explains, “but it won’t stop the bad effects of the mutant protein the gene produces. You can only do that by silencing the gene or editing it out, which is a different, more complicated approach.”
Euan Ashley, professor of medicine and genetics at Stanford University and founding director of its Center for Inherited Cardiovascular Disease, is confident that we will see genetic therapies for heart disease within the next decade.
“We are at this really exciting moment in time where we have diseases that have been under-recognized and undervalued now being attacked by multiple companies with really modern tools,” says Ashley, author of The Genome Odyssey. “Gene therapies are unusual in the sense that they can reverse the cause of the disease, so we have the enticing possibility of actually reversing or maybe even curing these diseases.”
Although no one is doing extensive research into a gene therapy for her particular mutation yet, Borsari remains hopeful, knowing that companies such as Tenaya are moving in that direction.
“I know that’s now on the horizon,” she says. “It’s not just some pipe dream, but will happen hopefully in my lifetime or my kids’ lifetime to help them.”