Experts list the top challenges facing widespread adoption of proteomics in the medical laboratory industry
Year-by-year, clinical
laboratories find new ways to use mass spectrometry to
analyze clinical specimens, producing results that may be more precise than
test results produced by other methodologies. This is particularly true in the
field of proteomics.
However, though mass spectrometry is highly accurate and
fast, taking only minutes to convert a specimen into a result, it is not fully
automated and requires skilled technologists to operate the instruments.
Thus, although the science of proteomics is advancing
quickly, the average pathology laboratory isn’t likely to be using mass
spectrometry tools any time soon. Nevertheless, medical
laboratory scientists are keenly interested in adapting mass spectrometry
to medical lab test technology for a growing number of assays.
Molly Campbell, Science Writer and Editor in Genomics, Proteomics, Metabolomics, and Biopharma at Technology Networks, asked proteomics experts “what, in their opinion, are the greatest challenges currently existing in proteomics, and how can we look to overcome them?” Here’s a synopsis of their answers:
Lack of High Throughput Impacts Commercialization
Proteomics isn’t as efficient as it needs to be to be
adopted at the commercial level. It’s not as efficient as its cousin genomics. For it to become
sufficiently efficient, manufacturers must be involved.
John Yates
III, PhD, Professor, Department of Molecular Medicine at Scripps Research California
campus, told Technology
Networks, “One of the complaints from funding agencies is that you can
sequence literally thousands of genomes very quickly, but you can’t do the same
in proteomics. There’s a push to try to increase the throughput of proteomics
so that we are more compatible with genomics.”
For that to happen, Yates says manufacturers need to
continue advancing the technology. Much of the research is happening at
universities and in the academic realm. But with commercialization comes
standardization and quality control.
“It’s always exciting when you go to ASMS [the conference for the American Society
for Mass Spectrometry] to see what instruments or technologies are going to be
introduced by manufacturers,” Yates said.
There are signs that commercialization isn’t far off. SomaLogic, a privately-owned American protein
biomarker discovery and clinical diagnostics company located in Boulder, Colo.,
has reached the commercialization stage for a proteomics assay platform called SomaScan. “We’ll be
able to supplant, in some cases, expensive diagnostic modalities simply from a
blood test,” Roy
Smythe, MD, CEO of SomaLogic, told Techonomy.
Achieving the Necessary Technical Skillset
One of the main reasons mass spectrometry is not more widely
used is that it requires technical skill that not many professionals possess.
“For a long time, MS-based proteomic analyses were technically demanding at
various levels, including sample processing, separation science, MS and the
analysis of the spectra with respect to sequence, abundance and
modification-states of peptides and proteins and false discovery rate
(FDR) considerations,” Ruedi
Aebersold, PhD, Professor of Systems Biology at the Institute of Molecular Systems Biology (IMSB) at
ETH Zurich, told Technology
Networks.
Aebersold goes on to say that he thinks this specific
challenge is nearing resolution. He says that, by removing the problem created
by the need for technical skill, those who study proteomics will be able to
“more strongly focus on creating interesting new biological or clinical
research questions and experimental design.”
Yates agrees. In a paper titled, “Recent Technical Advances in
Proteomics,” published in F1000 Research, a peer-reviewed open research
publishing platform for scientists, scholars, and clinicians, he wrote, “Mass
spectrometry is one of the key technologies of proteomics, and over the last
decade important technical advances in mass spectrometry have driven an
increased capability of proteomic discovery. In addition, new methods to
capture important biological information have been developed to take advantage
of improving proteomic tools.”
No High-Profile Projects to Stimulate Interest
Genomics had the Human Genome Project
(HGP), which sparked public interest and attracted significant funding. One of
the big challenges facing proteomics is that there are no similarly big,
imagination-stimulating projects. The work is important and will result in
advances that will be well-received, however, the field itself is complex and difficult
to explain.
Emanuel
Petricoin, PhD, is a professor and co-director of the Center for Applied
Proteomics and Molecular Medicine at George
Mason University. He told Technology
Networks, “the field itself hasn’t yet identified or grabbed onto a
specific ‘moon-shot’ project. For example, there will be no equivalent to the
human genome project, the proteomics field just doesn’t have that.”
He added, “The equipment needs to be in the background and
what you are doing with it needs to be in the foreground, as is what happened
in the genomics space. If it’s just about the machinery, then proteomics will
always be a ‘poor step-child’ to genomics.”
Democratizing Proteomics
Alexander
Makarov, PhD, is Director of Research in Life Sciences Mass Spectrometry
(MS) at Thermo Fisher
Scientific. He told Technology
Networks that as mass spectrometry grew into the industry we have today,
“each new development required larger and larger research and development teams
to match the increasing complexity of instruments and the skyrocketing
importance of software at all levels, from firmware to application. All this
extends the cycle time of each innovation and also forces [researchers] to
concentrate on solutions that address the most pressing needs of the scientific
community.”
Makarov describes this change as “the increasing democratization of MS,” and says that it “brings with it new requirements for instruments, such as far greater robustness and ease-of-use, which need to be balanced against some aspects of performance.”
One example of the increasing democratization of MS may be
several public proteomic datasets available to scientists. In European
Pharmaceutical Review, Juan
Antonio Viscaíno, PhD, Proteomics Team Leader at the European Bioinformatics Institute (EMBL-EBI)
wrote, “These datasets are increasingly reused for multiple applications, which
contribute to improving our understanding of cell biology through proteomics
data.”
Sparse Data and Difficulty Measuring It
Evangelia
Petsalaki, PhD, Group Leader EMBL-EBI, told Technology
Networks there are two related challenges in handling proteomic data.
First, the data is “very sparse” and second “[researchers] have trouble
measuring low abundance proteins.”
Petsalaki notes, “every time we take a measurement, we
sample different parts of the proteome or phosphoproteome and
we are usually missing low abundance players that are often the most important
ones, such as transcription
factors.” She added that in her group they take steps to mitigate those
problems.
“However, with the advances in MS technologies developed by
many companies and groups around the world … and other emerging technologies
that promise to allow ‘sequencing’ proteomes, analogous to genomes … I expect
that these will not be issues for very long.”
So, what does all this mean for clinical laboratories? At the
current pace of development, its likely assays based on proteomics could become
more common in the near future. And, if throughput and commercialization ever
match that of genomics, mass spectrometry and other proteomics tools could
become a standard technology for pathology laboratories.
The UE study sheds light on the types of bacteria in
wastewater that goes down hospital pipes to sewage treatment plants. The study
also revealed that not all infectious agents are killed after passing through
waste treatment plants. Some bacteria with antimicrobial (or antibiotic)
resistance survive to enter local food sources.
The scientists concluded that the amount of AMR genes found
in hospital wastewater was linked to patients’ length-of-stays and consumption
of antimicrobial resistant bacteria while in the hospital.
In a paper the University of Edinburgh published on medRxiv, the researchers wrote: “There was a higher abundance of antimicrobial-resistance genes in the hospital wastewater samples when compared to Seafield community sewage works … Sewage treatment does not completely eradicate antimicrobial-resistance genes and thus antimicrobial-resistance genes can enter the food chain through water and the use of [processed] sewage sludge in agriculture. As hospital wastewater contains inpatient bodily waste, we hypothesized that it could be used as a representation of inpatient community carriage of antimicrobial resistance and as such may be a useful surveillance tool.”
Additionally, they wrote, “Using metagenomics to identify
the full range of AMR genes in hospital wastewater could represent a useful
surveillance tool to monitor hospital AMR gene outflow and guide environmental
policy on AMR.”
Antibiotic resistance occurs when bacteria change in response to medications to prevent and treat bacterial infections, according to a World Health Organization (WHO) fact sheet. The CDC estimates that more than 23,000 people die annually from two million antibiotic-resistance infections.
Wastewater, the UE scientists suggest, should not go to
waste. It could be leveraged to improve hospitals’ detection of patients with antimicrobial
resistance, as well as to boost environment antimicrobial-resistance polices.
They used metagenomics (the study of genetic material
relative to environmental samples) to compare the antimicrobial-resistance
genes in hospital wastewater against wastewater from community sewage
points.
The UE researchers:
First collected samples over a 24-hour period from various areas in a tertiary hospital;
They then obtained community sewage samples from various locations around Seafield, Scotland;
Antimicrobial-resistance genes increased with longer length of patient stays, which “likely reflects transmission amongst hospital inpatients,” researchers noted.
Fey suggests that further research into using sequencing
technology to monitor patients is warranted.
“I think that monitoring each patient and sequencing their
bowel flora is more likely where we’ll be able to see if there’s a significant
carriage of antibiotic-resistant organisms,” Fey told MedPage Today. “In
five years or so, sequencing could become so cheap that we could monitor every
patient like that.”
Fey was not involved in the University of Edinburgh
research.
Given the rate at which AMR bacteria spreads, finding antibiotic-resistance
genes in hospital wastewater may not be all that surprising. Still, the University
of Edinburgh study could lead to cost-effective ways to test the genes of
bacteria, which then could enable researchers to explore different sources of
infection and determine how bacteria move through the environment.
And, perhaps most important, the study suggests clinical
laboratories have many opportunities to help eliminate infections and slow
antibiotic resistance. Microbiologists can help move their organizations forward
too, along with infection control colleagues.
The proof-of-concept experiment showed data can be encoded in DNA and retrieved using automated systems, a development that may have positive significance for clinical laboratories
It may seem far-fetched, but computer scientists and research groups have worked for years to discover if it is possible to store data on Deoxyribonucleic acid (DNA). Now, Microsoft Research (MR) and the University of Washington (UW) have achieved just that, and the implications of their success could be far-reaching.
Clinical pathologists are increasingly performing genetic DNA sequencing in their medical laboratories to identify biomarkers for disease, help clinicians understand their patients’ risk for a specific disease, and track the progression of a disease. The ability to store data in DNA would take that to another level and could have an impact on diagnostic pathology. Pathologist familiar with DNA sequencing may find a whole new area of medical service open to them.
The MR/UW researchers recently demonstrated a fully automated system that encoded data into DNA and then recovered the information as digital data. “In a simple proof-of-concept test, the team successfully encoded the word ‘hello’ in snippets of fabricated DNA and converted it back to digital data using a fully automated end-to-end system,” Microsoft stated in a news release.
DNA’s Potential Storage Capacity and Why We Need It
Thus far, the challenge of using DNA for data storage has
been that there wasn’t a way to easily code and retrieve the information. That,
however, seems to be changing quite rapidly. Several major companies have
invested heavily in research, with consumer offerings expected soon.
At Microsoft Research, ‘consumer interest’ in genetic testing has driven the research into using DNA for data storage. “As People get better access to their own DNA, why not also give them the ability to read any kind of data written in DNA?” asked Doug Carmean, an Architect at Microsoft, during an interview with Wired.
Scientists are interested in using DNA for data storage because
humanity is creating more data than ever before, and the pace is accelerating.
Currently, most of that data is stored on tape, which is inexpensive, but has
drawbacks. Tape degrades and has to be replaced every 10 years or so. But DNA,
on the other hand, lasts for thousands of years!
“DNA won’t degrade over time like cassette tapes and CDs, and it won’t become obsolete,” Yaniv Erlich, PhD, Chief Science Officer at MyHeritage, an online genealogy platform located in Israel, and Associate Professor, Columbia University, told Science Mag.
Tape also takes up an enormous amount of physical space compared to DNA. One single gram of DNA can hold 215 petabytes (roughly one zettabyte) of data. Wired puts the storage capacity of DNA into perspective: “Imagine formatting every movie ever made into DNA; it would be smaller than the size of a sugar cube. And it would last for 10,000 years.”
Victor Zhirnov, Chief Scientist at Semiconductor Research Corporation says the worries over storage space aren’t simply theoretical. “Today’s technology is already close to the physical limits of scaling,” he told Wired, which stated, “Five years ago humans had produced 4.4 zettabytes of data; that’s set to explode to 160 zettabytes (each year!) by 2025. Current infrastructure can handle only a fraction of the coming data deluge, which is expected to consume all the world’s microchip-grade silicon by 2040.”
MIT Technology Review agrees, stating, “Humanity is creating information at an unprecedented rate—some 16 zettabytes every year. And this rate is increasing. Last year, the research group IDC calculated that we’ll be producing over 160 zettabytes every year by 2025.”
Heavy Investment by Major Players
The whole concept may seem like something out of a science
fiction story, but the fact that businesses are investing real dollars into it
is evidence that DNA for data storage will likely be a reality in the near
future. Currently, there are a couple of barriers, but work is commencing to
overcome them.
First, the cost of synthesizing DNA in a medical laboratory
for the specific purpose of data storage must be cheaper for the solution to
become viable. Second, the sequencing process to read the information must also
become less expensive. And third is the problem of how to extract the data
stored in the DNA.
In a paper published in ASPLOS ‘16, the MR/UW scientists wrote: “Today, neither the performance nor the cost of DNA synthesis and sequencing is viable for data storage purposes. However, they have historically seen exponential improvements. Their cost reductions and throughput improvements have been compared to Moore’s Law in Carlson’s Curves … Important biotechnology applications such as genomics and the development of smart drugs are expected to continue driving these improvements, eventually making data storage a viable application.”
Automation appears to be the final piece of the puzzle. Currently,
too much human labor is necessary for DNA to be used efficiently as data
storage.
It may take some time before DNA becomes a viable medium for
data storage. However, savvy pathology laboratory managers should be aware of,
and possibly prepared for, this coming opportunity.
While it’s unlikely the average consumer will see much
difference in how they save and retrieve data, medical laboratories with the
ability to sequence DNA may find themselves very much in demand because of
their expertise in sequencing DNA and interpreting gene sequences.
Following two partially successful years of predictions, a pair of venture capitalists look into their crystal ball and share another batch of predictions for the coming year
Healthcare has its fair share of fortune tellers. Rarely are they consistent. However, the predictions of two healthcare investors in California have been so accurate that Fortune magazine now publishes an article each year featuring the duo’s Top Healthcare Predictions.
These predictions will be of interest to clinical laboratory managers and pathologists because several describe the changes coming to the hospitals, physicians, and health insurers who use and pay for medical laboratory tests.
The two individuals with the crystal ball are Bob Kocher, MD, and Bryan Roberts, PhD. Both are healthcare investors and partners at Venrock, a silicon-valley venture capital firm located in Palo Alto, Calif. They’ve been making fairly accurate predictions for the past few years.
Here are their predictions for healthcare in 2019:
More
payer consolidation: The authors foresee that the largest health insurance companies
with low administrative costs and high profit margins will become more
competitive in obtaining clients. This type of competition could force smaller
payers to struggle to gain and retain national accounts and have difficulty
competing in the Medicare
Advantage and Medicaid markets. They also anticipate “the growth of
Medicaid, with several states electing to expand, and Medicare Advantage will
also trigger [mergers and acquisitions] in order to enter these growing and
more profitable market segments.”
If small health plans are acquired and merged, clinical laboratories and anatomic pathology groups could lose access to patients because the biggest payers have narrow networks and favor the national labs.
Physician-led Accountable Care Organizations (ACOs) will grow rapidly: Their prediction is that primary care doctors will realize they can make more money and have more successful practices if they detach from hospitals and create independent businesses. With Medicare’s latest ACO regulations favoring doctor-led accountable care organizations over hospital-led ACOs, physicians may find it easier to expand independent practices.
If this prediction comes to fruition, small local medical laboratories
may be able to reap the benefits of an increase in the number of physician-led
ACOs by delivering enriched data and analytical services to those practices.
Doctors get less dissatisfied: Kocher and Roberts feel that health systems have listened to the complaints from doctors about their bad experiences using electronic health records (EHRs) and will take the necessary steps to ensure physicians are more satisfied with their EHR experiences. New innovations like machine learning and improvement in voice interfaces should help ease the burden of physicians when using EHRs. Improved voice technology can reduce the time doctors spend typing, clicking, and searching in their databases. The authors noted that “it may be easier to use voice for healthcare than for consumer applications since the vocabulary is smaller and context is far more predictable.”
Interoperability becomes interoperable: EHRs will start to better communicate with each other across different health systems. The Centers for Medicare and Medicaid Services (CMS) Patients Over Paperwork initiative is intended to help states that are “pushing for connectivity as one tactic to address the opioid epidemic and to improve resiliency from natural disasters, necessitating the need to access data.”
This prediction could be favorable for clinical laboratories and pathology groups that must create and support interfaces between their laboratory information management system (LIMS) and outside EHRs.
Consolidation
in digital health: The authors predict that “growth equity will get tighter
in 2019 for small companies that have not achieved product market fit” which
“will lead to a flurry of consolidation into platforms.” They also forecast
that large healthcare employers may transition from being the early adopters of
digital platforms to relying on the advice of partners who have already been
using those platforms in their businesses.
InsureTech takes a lump or two: InsureTech—a portmanteau from the words insurance and technology—as a business sector, may have some setbacks with payers examining and auditing charts more closely for errors and issuing fines accordingly. The practice of upcoding—where a biller assigns a medical code for a more expensive service or procedure than the one that was actually performed—is emerging as an area of risk for providers using the capabilities of InsureTech products and services. CMS actually has a “coding intensity adjustment” in place when reimbursing for Medicare Advantage claims because upcoding has become so prevalent.
Dialysis disrupted: Dialysis centers will become less plentiful as more patients opt to have their blood cleansed at home. Studies have shown that self-serve dialysis in the home can be safer, more reliable, and less expensive than traditional dialysis centers. Advantages of home dialysis include fewer trips to dialysis centers, more flexible scheduling for treatments, increased privacy, less dietary restrictions, and less problems with the fistula or graft area.
Telemedicine takes off: The authors expect telemedicine usage will more than double in 2019 as more payers, healthcare providers, and patients recognize its benefits. More health plans, including Medicare, are adding billing codes to reimburse patients for telemedicine visits with their healthcare providers. Becker’s Hospital Review in 2016 predicted that seven million people would be using telemedicine services by 2018.
PBM disruption talk becomes reality: The authors “expect next generation pharmacy supply ecosystem efforts to gain real traction in 2019.” Third-party administrators of prescription drug programs for health insurance plans, known as Pharmacy Benefit Managers (PBMs) will be scrutinized by the government in an effort to determine why drug costs are so high and to find ways those costs can be lowered. As pharmaceutical companies continue to aggressively raise prices for their products, patients are paying more for their medications and intermediaries are reaping the financial rewards. Drugs are currently being marked up an average of 40% by the distribution system, according to Fortune.
Real
progress with new DNA sequencing platforms: Kocher and Roberts see the
emergence of new Deoxyribonucleic
acid (DNA) sequencing applications and platforms being developed and
released into the market. These new technologies could lead to less expensive
costs for sequencing services and more competition among genomics companies. This
will be a favorable development for clinical laboratories and pathology groups
because it will make gene sequencing cheaper, faster, and more accurate.
Fortune is a
business magazine, headquartered in New York City, that publishes feature
articles on multinational business topics as well as popular ranked lists,
including the Fortune 500 list which annually ranks companies by revenue.
Given the track record of the two experts making these
predictions, it would be appropriate for the business leaders of clinical labs
and pathology groups to consider how each prediction may change how the
providers and payers they serve use lab testing services and pay for same.
If this technology proves viable on large scale, medical laboratories in hospitals that manage blood banks could have larger supplies of universal blood units
Once again, the amazing human microbiome is
at the heart of a new scientific breakthrough that could offer new tools for clinical
laboratories and provide much needed resources to emergency departments and
hospitals.
Canadian researchers at the University
of British Columbia (UBC) in Vancouver have discovered a microbe in the human gut
they believe is capable of converting donor blood into “universal” type-O blood.
“We have been particularly interested in enzymes that allow
us to remove the A or B antigens from red blood cells. If you can remove those
antigens, which are just simple sugars, then you can convert A or B to O blood,”
Stephen
Withers, PhD, a professor and biochemist at UBC explained in an American
Chemical Society (ACS) news release.
Such a breakthrough would be game-changing not only for
emergency departments that rely on much-needed supplies of universal-donor
blood, but also for the medical
laboratories that run most hospital blood banks.
Uncovering a method to transform type A blood into type O
would greatly enlarge the current blood supply because type-O blood can be
donated to patients regardless of which of the four main blood groups they
belong to—O, A, B, or AB.
This is yet another addition to a growing list of
discoveries involving human gut bacteria that Dark Daily has reported on in past years.
UBC scientists relied on metagenomics—a technique
that enables researchers to study microbial communities using DNA sequencing—to investigate
enzymes that potentially could destroy all the A and B antigens from red blood cells,
thereby converting type A and B blood into Type O universal blood.
“With metagenomics, you take all of the organisms from an
environment and extract the sum total DNA of those organisms all mixed up
together,” Withers said in the ACS news release.
Withers’ team considered sampling DNA from mosquitoes and
leaches but ultimately turned to the human body, where they found successful
candidate enzymes in the gut
microbiota. They focused on glycosylated proteins
called mucins that line the
gut wall, providing sugars that serve as attachment points for gut bacteria,
while also feeding them as they aid in digestion, the ACS report noted.
“By honing in on the bacteria feeding on those sugars, we
isolated the enzymes the bacteria use to pluck off the sugar molecules,”
Withers said in a UBC
statement. “We then produced quantities of those enzymes through cloning
and found that they were capable of performing a similar action on blood
antigens.”
Although enzymes long have been considered a key to transforming
donated blood to a common type, the gut enzymes the UBC team identified are 30
times more efficient at removing red blood cell antigens than previously
studied enzymes, the ACS news release noted. Their findings demonstrate once
again how the human microbiome is intertwined with many processes happening
within the body, opening the possibility of future novel uses of enzymes.
Zuri
Sullivan, an immunologist and PhD candidate at Yale University, believes the blood-converting
enzymes discovered by the USB team may be the first of many discoveries
revealed as researchers investigate the untapped potential of the gut
microbiome to solve medical challenges.
“The premise here is really powerful. There’s an untapped
genetic resource in the [genes] encoded by the gut microbiome,” she told Smithsonian Magazine.
Researchers Have High
Hopes but More Testing Is Needed
According to the UBC statement, Withers and UBC colleagues microbiologist
Steven Hallam,
PhD, and pathologist Jay
Kizhakkedathu, PhD, of the UBC Center for
Blood Research, are applying for a patent on the new enzymes, while working
to validate the enzymes and test them on a larger scale in preparation for
clinical testing.
In addition, the ACS news release notes that the UBC team “plans
to carry out directed
evolution, a protein engineering technique that simulates natural
evolution, with the goal of creating the most efficient sugar-removing enzyme.”
“I am optimistic that we have a very interesting candidate
to adjust donated blood to a common type,” Withers said in the ACS statement.
“Of course, it will have to go through lots of clinical trials to make sure
that it doesn’t have any adverse consequences, but it is looking very
promising.”
Fortune health journalist Sy Mukherjee praised the
UBC discovery, but warned against “coming to any overhyped conclusions” until
more testing is done.
“But if it’s a sustainable technique, the implications are
multifold,” he noted. “Especially given the nature of the technique itself,
which involves lopping off certain antigens (which are, in essence, simple
sugars) from particular red blood cells. The question is whether it can be used
on a wide-scale in a safe and efficient manner to create larger blood supplies
in times of need.”
That certainly is the question. For decades, scientists have
searched for the secret to creating universal blood and now it appears the
answer may have been lurking inside our bodies all along. Clinical laboratories
may soon see human microbiome become linked to even more discoveries that lead
to new tests and diagnostic tools.