Best of all, the researchers say the test could provide an inexpensive means of early diagnosis. This assay could also be used to monitor how well patients respond to cancer therapy, according to a news release.
The protein had previously been identified as a promising biomarker and is readily detectable in tumor tissue, they wrote. However, it is found in extremely low concentrations in blood plasma and is “well below detection limits of conventional clinical laboratory methods,” they noted.
To overcome that obstacle, they employed an ultra-sensitive immunoassay known as a Simoa (Single-Molecule Array), an immunoassay platform for measuring fluid biomarkers.
“We were shocked by how well this test worked in detecting the biomarker’s expression across cancer types,” said lead study author gastroenterologist Martin Taylor, MD, PhD, Instructor in Pathology, Massachusetts General Hospital and Harvard Medical School, in the press release. “It’s created more questions for us to explore and sparked interest among collaborators across many institutions.”
“We’ve known since the 1980s that transposable elements were active in some cancers, and nearly 10 years ago we reported that ORF1p was a pervasive cancer biomarker, but, until now, we haven’t had the ability to detect it in blood tests,” said pathologist and study co-author Kathleen Burns, MD, PhD (above), Chair of the Department of Pathology at Dana-Farber Cancer Institute and a Professor of Pathology at Harvard Medical School, in a press release. “Having a technology capable of detecting ORF1p in blood opens so many possibilities for clinical applications.” Clinical laboratories may soon have a new blood test to detect multiple types of cancer. (Photo copyright: Dana-Farber Cancer Institute.)
Simoa’s Advantages
In their press release, the researchers described ORF1p as “a hallmark of many cancers, particularly p53-deficient epithelial cancers,” a category that includes lung, breast, prostate, uterine, pancreatic, and head and neck cancers in addition to the cancers noted above.
“Pervasive expression of ORF1p in carcinomas, and the lack of expression in normal tissues, makes ORF1p unlike other protein biomarkers which have normal expression levels,” Taylor said in the press release. “This unique biology makes it highly specific.”
Simoa was developed at the laboratory of study co-author David R. Walt, PhD, the Hansjörg Wyss Professor of Bioinspired Engineering at Harvard Medical School, and Professor of Pathology at Harvard Medical School and Brigham and Women’s Hospital.
The Simoa technology “enables 100- to 1,000-fold improvements in sensitivity over conventional enzyme-linked immunosorbent assay (ELISA) techniques, thus opening the window to measuring proteins at concentrations that have never been detected before in various biological fluids such as plasma or saliva,” according to the Walt Lab website.
Simoa assays take less than two hours to run and require less than $3 in consumables. They are “simple to perform, scalable, and have clinical-grade coefficients of variation,” the researchers wrote.
Study Results
Using the first generation of the ORF1p Simoa assay, the researchers tested blood samples of patients with a variety of cancers along with 406 individuals, regarded as healthy, who served as controls. The test proved to be most effective among patients with colorectal and ovarian cancer, finding detectable levels of ORF1p in 58% of former and 71% of the latter. Detectable levels were found in patients with advanced-stage as well as early-stage disease, the researchers wrote in Cancer Discovery.
Among the 406 healthy controls, the test found detectable levels of ORF1p in only five. However, the control with the highest detectable levels, regarded as healthy when donating blood, “was six months later found to have prostate cancer and 19 months later found to have lymphoma,” the researchers wrote.
They later reengineered the Simoa assay to increase its sensitivity, resulting in improved detection of the protein in blood samples from patients with colorectal, gastroesophageal, ovarian, uterine, and breast cancers.
The researchers also employed the test on samples from 19 patients with gastroesophageal cancer to gauge its utility for monitoring therapeutic response. Although this was a small sample, they found that among 13 patients who had responded to therapy, “circulating ORF1p dropped to undetectable levels at follow-up sampling.”
“More Work to Be Done”
The Simoa assay has limitations, the researchers acknowledged. It doesn’t identify the location of cancers, and it “isn’t successful in identifying all cancers and their subtypes,” the press release stated, adding that the test will likely be used in conjunction with other early-detection approaches. The researchers also said they want to gauge the test’s accuracy in larger cohorts.
“The test is very specific, but it doesn’t tell us enough information to be used in a vacuum,” Walt said in the news release. “It’s exciting to see the early success of this ultrasensitive assessment tool, but there is more work to be done.”
More studies will be needed to valid these findings. That this promising new multi-cancer immunoassay is based on a clinical laboratory blood sample means its less invasive and less painful for patients. It’s a good example of an assay that takes a proteomic approach looking for protein cancer biomarkers rather than the genetic approach looking for molecular DNA/RNA biomarkers of cancer.
The 80 scientists and engineers that comprise the consortium believe synthetic biology can address key challenges in health and medicine, but technical hurdles remain
Synthetic biology now has a 20-year development roadmap. Many predict this fast-moving field of science will deliver valuable products that can be used in diagnostics—including clinical laboratory tests, therapeutics, and other healthcare products.
Eighty scientists from universities and companies around the world that comprise the Engineering Biology Research Consortium (EBRC) recently published the 20-year roadmap. They designed it to “provide researchers and other stakeholders (including government funders)” with what they hope will be “a go-to resource for engineering/synthetic biology research and related endeavors,” states the EBRC Roadmap website.
Medical laboratories and clinical pathologists may soon have new tools and therapies for targeting specific diseases. The EBRC defines synthetic biology as “the design and construction of new biological entities such as enzymes, genetic circuits, and cells or the redesign of existing biological systems. Synthetic biology builds on the advances in molecular, cell, and systems biology and seeks to transform biology in the same way that synthesis transformed chemistry and integrated circuit design transformed computing.”
Synthetic biology is an expanding field and there are predictions that it may produce research findings that can be adapted for use in clinical pathology diagnostics and treatment for chronic diseases, such as cancer.
Another goal of the roadmap is to encourage federal
government funding for synthetic biology.
“The question for government is: If all of these avenues are now open for biotechnology development, how does the US stay ahead in those developments as a country?” said Douglas Friedman, EBRC’s Executive Director, in a news release. “This field has the ability to be truly impactful for society and we need to identify engineering biology as a national priority, organize around that national priority, and take action based on it.”
Designing or Redesigning Life Forms for Specific
Applications
Synthetic biology is an interdisciplinary field that combines
elements of engineering, biology, chemistry, and computer science. It enables
the design and construction of new life forms—or redesign of existing ones—for
a multitude of applications in medicine and other fields.
Another recent example comes from the Wyss Institute at Harvard. Scientist there developed a direct-to-consumer molecular diagnostics platform called INSPECTR that, they say, uses programmable synthetic biosensors to detect infectious pathogens or host cells.
The Wyss Institute says on its website that the platform can
be packaged as a low-cost, direct-to-consumer test similar to a home pregnancy
test. “This novel approach combines the specificity, rapid development, and
broad applicability of a molecular diagnostic with the low-cost, stability, and
direct-to-consumer applicability of lateral flow immunoassays.”
In March, Harvard announced that it had licensed the technology to Sherlock Biosciences.
Howard Salis, PhD (above), Associate Professor of biological engineering and chemical engineering at Pennsylvania State University (Penn State), co-chaired the EBRC Roadmapping Working Group that produced the roadmap. In a Penn State news story, Salis explained synthetic biology’s potential. “There are both traditional and startup companies leveraging synthetic biology technologies to develop novel biotech products,” he said. “Organisms that produce biorenewable materials; diagnostics to detect the Zika virus, Ebola and tuberculosis; and soil bacteria that fix nitrogen into ammonia for improved plant growth.” (Photo copyright: Twitter.)
Fundamental Challenges with Synthetic Biology
The proponents of synthetic biology hope to make it easier
to design and build these systems, in much the same way computer engineers
design integrated circuits and processors. The EBRC Roadmap may help scientist
worldwide achieve this goal.
However, in “What is Synthetic/Engineering Biology?” the EBRC also identifies the fundamental challenges facing the field. Namely, the complexity and unpredictability inherent in biology, and a limited understanding of how biological components interact.
The EBRC roadmap report, “Engineering Biology: A Research
Roadmap for the Next-Generation Bioeconomy,” covers five categories of applications:
Health and medicine are of primary interest to pathologists.
Synthetic Biology in Health and Medicine
The Health and Medicine section of the report identifies
four broad societal challenges that the EBRC believes can be addressed by
synthetic biology. For each, the report specifies engineering biology
objectives, including efforts to develop new diagnostic technologies. They
include:
Existing and emerging infectious diseases: Objectives include development of tools for treating infections, improving immunity, reducing dependence on antibiotics, and diagnosing antimicrobial-resistant infections. The authors also foresee tools for rapid characterization and response to “known and unknown pathogens in real time at population scales.”
Non-communicable diseases and disorders, including cancer, heart disease, and diabetes: Objectives include development of biosensors that will measure metabolites and other biomolecules in vivo. Also: tools for identifying patient-specific drugs; tools for delivering gene therapies; and genetic circuits that will foster tissue formation and repair.
Environmental health threats, such as toxins, pollution, and injury: Objectives include systems that will integrate wearable tech with living cells, improve interaction with prosthetics, prevent rejection of transplanted organs, and detect and repair of biochemical damage.
Healthcare access and personalized medicine: The authors believe that synthetic biology can enable personalized treatments and make new therapies more affordable.
Technical Themes
In addition to these applications, the report identifies
four “technical themes,” broad categories of technology that will spur the
advancement of synthetic biology:
Gene editing, synthesis, and assembly: This refers to tools for producing chromosomal DNA and engineering whole genomes.
Biomolecule, pathway, and circuit engineering: This “focuses on the importance, challenges, and goals of engineering individual biomolecules themselves to have expanded or new functions,” the roadmap states. This theme also covers efforts to combine biological components, both natural and non-natural, into larger, more-complex systems.
Host and consortia engineering: This “spans the development of cell-free systems, synthetic cells, single-cell organisms, multicellular tissues and whole organisms, and microbial consortia and biomes,” the roadmap states.
Data Integration, modeling, and automation: This refers to the ability to apply engineering principles of Design, Build, Test and Learn to synthetic biology.
The roadmap also describes the current state of each
technology and projects likely milestones at two, five, 10, and 20 years into
the future. The 2- and 5-year milestones are based on “current or recently
implemented funding programs, as well as existing infrastructure and facilities
resources,” the report says.
The longer-term milestones are more ambitious and may
require “significant technical advancements and/or increased funding and
resources and new and improved infrastructure.”
Synthetic biology is a significant technology that could
bring about major changes in clinical pathology diagnostics and treatments.
It’s well worth watching.
