Genetic engineers at the lab used the new tool to generate a catalog of 71 million possible missense variants, classifying 89% as either benign or pathogenic
Genetic engineers continue to use artificial intelligence (AI) and deep learning to develop research tools that have implications for clinical laboratories. The latest development involves Google’s DeepMind artificial intelligence lab which has created an AI tool that, they say, can predict whether a single-letter substitution in DNA—known as a missense variant (aka, missense mutation)—is likely to cause disease.
The Google engineers used their new model—dubbed AlphaMissense—to generate a catalog of 71 million possible missense variants. They were able to classify 89% as likely to be either benign or pathogenic mutations. That compares with just 0.1% that have been classified using conventional methods, according to the DeepMind engineers.
This is yet another example of how Google is investing to develop solutions for healthcare and medical care. In this case, DeepMind might find genetic sequences that are associated with disease or health conditions. In turn, these genetic sequences could eventually become biomarkers that clinical laboratories could use to help physicians make earlier, more accurate diagnoses and allow faster interventions that improve patient care.
“AI tools that can accurately predict the effect of variants have the power to accelerate research across fields from molecular biology to clinical and statistical genetics,” wrote Google DeepMind engineers Jun Cheng, PhD (left), and Žiga Avsec, PhD (right), in a blog post describing the new tool. Clinical laboratories benefit from the diagnostic biomarkers generated by this type of research. (Photo copyrights: LinkedIn.)
AI’s Effect on Genetic Research
Genetic experiments to identify which mutations cause disease are both costly and time-consuming, Google DeepMind engineers Jun Cheng, PhD, and Žiga Avsec, PhD, wrote in a blog post. However, artificial intelligence sped up that process considerably.
“By using AI predictions, researchers can get a preview of results for thousands of proteins at a time, which can help to prioritize resources and accelerate more complex studies,” they noted.
Of all possible 71 million variants, approximately 6%, or four million, have already been seen in humans, they wrote, noting that the average person carries more than 9,000. Most are benign, “but others are pathogenic and can severely disrupt protein function,” causing diseases such as cystic fibrosis, sickle-cell anemia, and cancer.
“A missense variant is a single letter substitution in DNA that results in a different amino acid within a protein,” Cheng and Avsec wrote in the blog post. “If you think of DNA as a language, switching one letter can change a word and alter the meaning of a sentence altogether. In this case, a substitution changes which amino acid is translated, which can affect the function of a protein.”
In the Google DeepMind study, AlphaMissense predicted that 57% of the 71 million variants are “likely benign,” 32% are “likely pathogenic,” and 11% are “uncertain.”
The AlphaMissense model is adapted from an earlier model called AlphaFold which uses amino acid genetic sequences to predict the structure of proteins.
“AlphaMissense was fed data on DNA from humans and closely related primates to learn which missense mutations are common, and therefore probably benign, and which are rare and potentially harmful,” The Guardian reported. “At the same time, the program familiarized itself with the ‘language’ of proteins by studying millions of protein sequences and learning what a ‘healthy’ protein looks like.”
The model assigned each variant a score between 0 and 1 to rate the likelihood of pathogenicity [the potential for a pathogen to cause disease]. “The continuous score allows users to choose a threshold for classifying variants as pathogenic or benign that matches their accuracy requirements,” Avsec and Cheng wrote in their blog post.
However, they also acknowledged that it doesn’t indicate exactly how the variation causes disease.
The engineers cautioned that the predictions in the catalog are not intended for clinical use. Instead, they “should be interpreted with other sources of evidence.” However, “this work has the potential to improve the diagnosis of rare genetic disorders, and help discover new disease-causing genes,” they noted.
Genomics England Sees a Helpful Tool
BBC noted that AlphaMissense has been tested by Genomics England, which works with the UK’s National Health Service. “The new tool is really bringing a new perspective to the data,” Ellen Thomas, PhD, Genomics England’s Deputy Chief Medical Officer, told the BBC. “It will help clinical scientists make sense of genetic data so that it is useful for patients and for their clinical teams.”
AlphaMissense is “a big step forward,” Ewan Birney, PhD, Deputy Director General of the European Molecular Biology Laboratory (EMBL) told the BBC. “It will help clinical researchers prioritize where to look to find areas that could cause disease.”
Other experts, however, who spoke with MIT Technology Review were less enthusiastic.
Heidi Rehm, PhD, co-director of the Program in Medical and Population Genetics at the Broad Institute, suggested that the DeepMind engineers overstated the certainty of the model’s predictions. She told the publication that she was “disappointed” that they labeled the variants as benign or pathogenic.
“The models are improving, but none are perfect, and they still don’t get you to pathogenic or not,” she said.
“Typically, experts don’t declare a mutation pathogenic until they have real-world data from patients, evidence of inheritance patterns in families, and lab tests—information that’s shared through public websites of variants such as ClinVar,” the MIT article noted.
Is AlphaMissense a Biosecurity Risk?
Although DeepMind has released its catalog of variations, MIT Technology Review notes that the lab isn’t releasing the entire AI model due to what it describes as a “biosecurity risk.”
The concern is that “bad actors” could try using it on non-human species, DeepMind said. But one anonymous expert described the restrictions “as a transparent effort to stop others from quickly deploying the model for their own uses,” the MIT article noted.
And so, genetics research takes a huge step forward thanks to Google DeepMind, artificial intelligence, and deep learning. Clinical laboratories and pathologists may soon have useful new tools that help healthcare provider diagnose diseases. Time will tell. But the developments are certain worth watching.
Millions of cancelled healthcare appointments and lengthy waits for care abound in UK, New Zealand, and in the US
Strikes continue on multiple continents as thousands of healthcare workers walk off the job. Doctors, medical laboratory scientists, nurses, phlebotomists and others around the world have taken to the picket lines complaining about low wages, inadequate staffing, and dangerous working conditions.
In England, junior doctors (the general equivalent of medical interns in the US) continue their uphill battle to have their complaints heard by the UK government. As a result, at hospitals and clinics throughout the United Kingdom, more than one million appointments have been cancelled due to strikes, according to the BBC.
“The true scale of the disruption is likely to be higher—many hospitals reduce bookings on strike days to minimize last-minute cancellations,” the BBC reported. “A total of one million hospital appointments have had to be rescheduled along with more than 60,000 community and mental health appointments since December [2022], when industrial action started in the National Health Service (NHS).”
According to The Standard, “Consultants in England are to be re-balloted over the prospect of further strike action as doctors and the government remain in talks with a view to end the dispute. The British Medical Association (BMA) said that specialist, associate specialist, and specialty (SAS) doctors will also be balloted over potential strike action.”
“We must be prepared to take the next step and ballot for industrial action if we absolutely have to—and we will do this … if upcoming negotiations fail to achieve anything for our profession,” Ujjwala Anand Mohite, DRCPath, FEBPath (above), a histopathologist at the NHS, Dudley Group of Hospitals, and the first female Chair of the SAS committee UK, told The Guardian.
New Zealand Doctors, Clinical Laboratory Workers Strike
In September, the first-ever nationwide senior doctor strike occurred in New Zealand and was then followed by another strike of about 5,000 doctors and 100 dentists from New Zealand’s public hospitals, the World Socialist Web Site reported.
Similar to the UK, the strikes reflect mounting frustration over pay not keeping up with inflation and “decades of deteriorating conditions in the public health system,” the WSWS noted.
This follows months of strikes by the island nation’s medical laboratory workers, which are ongoing.
“Our pay scales, if you compare them internationally, are not competitive. About half of our specialists come from abroad, so it’s quite important for the country’s health system to be able to attract and keep people,” Andy Davies, a lung specialist who joined the picket outside 484-bed Wellington Hospital, told the WSWS.
“We’re not asking for the world, we’re asking for an inflationary pay rise, and we haven’t had an inflationary pay rise year-on-year, and it’s beginning to show,” he added.
“What type of health system do they want?” he continued. “Do we want one that treats all people and manages what they need, or do we want a hacked down system that does less?”
The conflicts over pay and working conditions have caused many healthcare workers in New Zealand to leave the field entirely. This has led to severe shortages of qualified workers.
“Patient waiting times—for cancer, hip replacements, cardiac problems, and many other conditions—have exploded due to understaffed and overwhelmed hospitals,” the WSWS reported.
US Healthcare Workers also Striking
The US has its share of striking healthcare workers as well. Healthcare Dive tracked 23 ongoing or anticipated strikes throughout the nation’s healthcare industry since January 1, 2023. In 2022, there were 15 strikes of healthcare workers at the nation’s hospitals and health systems.
These walkouts include doctors, nurses, pharmacy workers, imaging specialists, and thousands of frontline healthcare workers striking over dangerously low staffing levels, unsafe working conditions, and low pay.
In October, 75,000 nurses, support staff, and medical technicians from Kaiser Permanente participated in a 72-hour strike comprised of hundreds of hospitals and clinics throughout California, Washington state, Oregon, Virginia, and the District of Columbia, Reuters reported.
The three-day strike, “Marked the largest work stoppage to date in the healthcare sector,” Reuters noted. Doctors, managers, and contingency workers were employed to keep hospitals and emergency departments functioning.
“The dispute is focused on workers’ demands for better pay and measures to ease chronic staff shortages and high turnover that union officials say has undermined patient care at Kaiser,” Reuters stated.
Staffing shortages following the COVID-19 pandemic are partly to blame for current struggles, but contract staffing to fill critical positions has exacerbated the problem.
“Kaiser’s outsourcing of healthcare duties to third-party vendors and subcontractors has also emerged as a major sticking point in talks that have dragged on for six months. … The clash has put Kaiser Permanente at the forefront of growing labor unrest in the healthcare industry—and across the US economy—driven by the erosion of workers’ earning power from inflation and pandemic-related disruptions in the workforce,” Reuters noted.
Across the globe, many healthcare workers—including clinical laboratory scientists in countries like New Zealand—are feeling burnt out from working in understaffed departments for inadequate pay. Hopefully, in response to these strikes, governments and healthcare leaders can come to resolutions that bring critical medical specialists back to work.
Cellular healthcare is an approach that goes beyond clinical laboratory testing to identify the location of specific cancer cells and aid in treatment decisions
Advances in synthetic biology and genetic engineering are leading to development of bacterial biosensors that could eventually aid pathologists and clinical laboratories in diagnosis of many types of cancers.
One recent example comes from researchers at the University of California San Diego (UCSD) who worked with colleagues in Australia to engineer bacteria that work as “capture agents” and bind to tumorous material.
The KRAS gene is associated with colorectal cancer. The researchers named their development the Cellular Assay for Targeted CRISPR-discriminated Horizontal gene transfer (CATCH).
CATCH successfully detected cancer in the colons of mice. The researchers believe it could be used to diagnose cancers, as well as infections and other diseases, in humans as well, according to a UCSD news release.
“If bacteria can take up DNA, and cancer is defined genetically by a change in its DNA, then, theoretically, bacteria could be engineered to detect cancer,” gastroenterologist Daniel Worthley, PhD, a cancer researcher at Colonoscopy Clinic in Brisbane, Australia, told MedicalResearch.com. This research could eventually provide clinical laboratories and anatomic pathologists with new tools to use in diagnosing certain types of cancer. (Photo copyright: Colonoscopy Clinic.)
Tapping Bacteria’s Natural Competence
In their Science paper, the researchers acknowledged other synthetic biology achievements in cellular biosensors aimed at human disease. But they noted that more can be done by leveraging the “natural competence” skill of bacteria.
“Biosensors have not yet been engineered to detect specific extracellular DNA sequences and mutations. Here, we engineered naturally competent Acinetobacter baylyi (A. baylyi) to detect donor DNA from the genomes of colorectal cancer cells, organoids, and tumors,” they wrote.
“Many bacteria can take up DNA from their environment, a skill known as natural competence,” said Rob Cooper, PhD, co-first author of the study and a scientist at US San Diego’s Synthetic Biology Institute, in the news release. A. baylyi is a type of bacteria renowned for success in doing just that, the NCI article pointed out.
This enabled them to explore “free-floating DNA sequences on a genomic level.”
Those sequences were compared to “known cancer DNA sequences.”
A. baylyi (genetically modified) was tested on its ability to detect “mutated and healthy KRAS DNA.”
Only bacteria that had “taken up mutated copies of KRAS … would survive treatment with a specific drug.”
“It was incredible when I saw the bacteria that had taken up the tumor DNA under the microscope. The mice with tumors grew green bacterial colonies that had acquired the ability to be grown on antibiotic plates,” said Josephine Wright, PhD, Senior Research Fellow, Gut Cancer Group, South Australian Health and Medical Research Institute (SAHMRI), in the news release.
Detecting DNA from Cancer Cells In Vitro and in Mice
Findings in vitro and in mice include the following:
The engineered bacteria enabled detection of DNA with KRAS G12D from colorectal cancer cells made in the lab, NCI reported.
When mice were injected with colorectal cancer cells, the researchers’ technology found tumor DNA, Engadget reported.
The study adds to existing knowledge of horizontal gene transfer from bacteria to bacteria, according to UCSD.
“We observed horizontal gene transfer from the tumor to the sensor bacteria in our mouse model of colorectal cancer. This cellular assay for targeted, CRISPR-discriminated horizontal gene transfer (CATCH) enables the biodetection of specific cell-free DNA,” the authors wrote in Science.
“Colorectal cancer seemed a logical proof of concept as the colorectal lumen is full of microbes and, in the setting of cancer, full of tumor DNA,” gastroenterologist Daniel Worthley, PhD, a cancer researcher at Colonoscopy Clinic in Brisbane, Australia, told MedicalResearch.com.
Finding More Cancers and Treatment
More research is needed before CATCH is used in clinical settings. The scientists are reportedly planning on adapting CATCH to multiple bacteria that can locate other cancers and infections.
“The most exciting aspect of cellular healthcare … is not in the mere detection of disease. A laboratory can do that,” wrote Worthley in The Conversation. “But what a laboratory cannot do is pair the detection of disease (a diagnosis) with the cells actually responding to the disease [and] with appropriate treatment.
“This means biosensors can be programmed so that a disease signal—in this case, a specific sequence of cell-free DNA—could trigger a specific biological therapy, directly at the spot where the disease is detected in real time,” he added.
Clinical laboratory scientists, pathologists, and microbiologists may want to stay abreast of how the team adapts CATCH, and how bacterial biosensors in general continue to develop to aid diagnosis of diseases and improve ways to target treatment.
Federal class action lawsuit looms as genetics company searches for what went wrong; a reminder to clinical laboratories of the importance of protecting patient information
Several years ago, security experts warned that biotechnology and genomics company 23andMe, along with other similar genetics companies, would be attacked by hackers. Now those predictions appear to have come true, and it should be a cautionary tale for clinical laboratories. In an October 6 blog post, the genetic testing company confirmed that private information from thousands of its customers was exposed and may be being sold on the dark web.
According to Wired, “At least a million data points from 23andMe accounts appear to have been exposed on BreachForums.” BreachForums is an online forum where users can discuss internet hacking, cyberattacks, and database leaks, among other topics.
“Hackers posted an initial data sample on the platform BreachForums earlier this week, claiming that it contained one million data points exclusively about Ashkenazi Jews,” Wired reported, adding that “hundreds of thousands of users of Chinese descent” also appear to be impacted.
The leaked information included full names, dates of birth, sex, locations, photos, and both genetic and ancestry results, Bleeping Computer reported.
For its part, 23andMe acknowledges the data theft but claims “it does not see evidence that its systems have been breached,” according to Wired.
Anne Wojcicki (above) is the co-founder and CEO of genetics company 23andMe, which on October 24 told its customers in an email, “There was unauthorized access to one or more 23andMe accounts that were connected to you through DNA Relatives. As a result, the DNA Relatives profile information you provided in this feature was exposed to the threat actor.” Clinical laboratories must work to ensure their patient data is fully secured from similar cyber theft. (Photo copyright: TechCrunch.)
23andMe Claims Data Leak Not a Security Incident
The data leaked has been confirmed by 23andMe to be legitimate. “Threat actors used exposed credentials from other breaches [of other company’s security] to access 23andMe accounts and steal the sensitive data. Certain 23andMe customer profile information was compiled through access to individual 23andMe.com accounts,” a 23andMe spokesperson told Bleeping Computer.
However, according to the company, the leak does not appear to be a data security incident within the 23andMe systems. “The preliminary results of this investigation suggest that the login credentials used in these access attempts may have been gathered by a threat actor from data leaked during incidents involving other online platforms where users have recycled login credentials,” the spokesperson added.
What the genetics company has determined is that compromised accounts were from users choosing the DNA Relative feature on their website as a means to find and connect to individuals related to them. Additionally, “the number of accounts sold by the cybercriminal does not reflect the number of 23andMe accounts breached using exposed credentials,” Bleeping Computer noted.
Price of Private Information
Following the 23andMe data leak, the private genetic information was quickly available online … for a price.
“On October 4, the threat actor offered to sell data profiles in bulk for $1-$10 per 23andMe account, depending on how many were purchased,” Bleeping Computer reported.
Stolen medical records are becoming hotter than credit card information, the experts say. “Stolen records sell for as much as $1,000 each,” according to credit rating agency Experian, Bleeping Computer noted.
In its 2018 Global Security Report, “cybersecurity firm Trustwave pegged the black-market value of medical records at $250 each. Credit card numbers, on the other hand, sell for around $5 each on the dark web … while Social Security numbers can be purchased for as little as $1 each,” Fierce Healthcare reported.
Clinical laboratory managers and pathologists should take note of the value that the dark web places on the medical records of a patient, compared to the credit card numbers of the same individual. From this perspective, hacking a medical laboratory to steal patient health data can be much more lucrative than hacking the credit card data from a retailer.
“Victims of the breach are now at increased risk of fraud and identity theft, and have suffered damages in the form of invasion of privacy, lost time and out-of-pocket expenses incurred responding to the breach, diminished value of their personal information, and lost benefit of the bargain with 23andMe,” according to court documents.
“The lawsuit brings claims of negligence, breach of implied contract, invasion of privacy/intrusion upon seclusion, unjust enrichment, and declaratory judgment,” Bloomberg Law noted. Additionally, the claim states that 23andMe “failed to provide prompt and adequate notice of the incident.”
Plaintiffs are “seeking actual damages, compensatory damages, statutory damages, punitive damages, lifetime credit-monitoring services, restitution, disgorgement, injunctive relief, attorneys’ fees and costs, and pre-and post-judgment interest,” Bloomberg Law reported.
Preventing Future Data Leaks
Years of experts warning genetics companies like 23andMe that they need more strict data security have proven to be true. “This incident really highlights the risks associated with DNA databases,” Brett Callow, a threat analyst at data security firm Emsisoft, told Wired. “The fact that accounts had reportedly opted into the ‘DNA Relatives’ feature is particularly concerning as it could potentially result in extremely sensitive information becoming public.”
“Callow notes that the situation raises broader questions about keeping sensitive genetic information safe and the risks of making it available in services that are designed like social networks to facilitate sharing. With such platforms come all of the data privacy and security issues that have plagued traditional social networks, including issues related to data centralization and scraping,” Wired noted.
Clinical laboratory databases are full of protected health information (PHI). Wise lab managers will work to ensure that their medical lab’s patient data is secure from today’s cyberthreats.
Studying gut bacteria continues to intrigue investors, but can the results produce viable diagnostic data for healthcare providers?
Even as microbiologists and clinical pathologists closely watch research into the human microbiome and anticipate study findings that could lead to new medical laboratory tests based on microbiome testing, there are entrepreneurs ready to tout the benefits of microbiome testing to consumers. That’s the impetus behind an announced deal between a microbiome testing company and a national pharmacy chain.
That deal involves health startup Viome Life Sciences, which recently closed a $86.5 million Series C funding round to support research and development of its consumer health at-home test kits, and CVS, which will sell Viome’s Gut Intelligence Test at 200 of the pharmacy company’s retail locations nationwide, according to an August press release.
“Founded seven years ago by serial entrepreneur Naveen Jain, Viome sells at-home kits that analyze the microbial composition of stool samples and provide food recommendations, as well as supplements and probiotics. Viome says it is the first company to sell gut tests at CVS, both online and in-store. The tests will sell for $179,” GeekWire reported.
Investors appear to be intrigued by these types of opportunities. To date, Viome has raised a total of $175 million.
“In a world where healthcare has often been reactive, treating symptoms and targeting diseases only after they manifest, Viome is pioneering a transformative shift by harnessing the innate power of food and nutrition,” stated Naveen Jain (above), Founder and CEO of Viome, in a press release. “Our mission is not just to prolong life but to enrich it, enabling everyone to thrive in health and vitality.” But some microbiologists and clinical laboratory scientists would consider that the current state of knowledge about the human microbiome is not well-developed enough to justify offering direct-to-consumer microbiology tests that encourage consumers to purchase nutritional products. (Photo copyright: Viome Life Sciences.)
Empowering People to Make Informed Decisions about Their Health
Established in 2016, Bellevue, Washington-based Viome produces and sells, among other tests, its Gut Intelligence at-home test kit, which analyzes the microbial composition of stool samples. This kit relies on RNA sequencing to detect bacteria and other elements present in the gut, such as yeasts and viruses.
The genetic data is then entered into an artificial intelligence (AI) algorithm to provide individuals with information regarding their personal gut health. Viome partnered with Los Alamos National Laboratory to create their AI platform. The company has collected more than 600,000 test samples to date.
“We are the only company that looks at the gene expression and what these microbes are doing,” said Naveen Jain, Founder and CEO of Viome in the press release.
Viome uses technology combined with science to determine the optimal outcomes for each individual consumer based on his or her unique human and microbial gene expression. The data derived from the microbiome is also utilized to offer nutritional recommendations and supplement advice to test takers.
“At Viome, we’re empowering our customers with an individualized nutrition strategy, cutting through the noise of temporary trends and one-size-fits-all advice,” Jain added. “We’re on a journey to redefine aging itself, and we’re invigorated by the support of our investors and customers. Together, we’re building pathways to wellness that hold the potential to enhance the lives of billions of fellow humans across the globe.”
Manipulating Microbiome through Diet
Some scientists, however, are not sold on the idea of microbiome test kits and the data they offer to healthcare providers for treating illnesses.
“The best thing anybody can do for their microbiome is to eat a healthy diet. That’s the best way of manipulating your microbiome,” David Suskind, MD, a gastroenterologist at Seattle Children’s Hospital and Professor of Pediatrics at the University of Washington, told GeekWire.
Verdu, GeekWire reported, added that “there needs to be standardization of protocols and better understanding of microbiome function in health and disease.”
“Recommendations for such commercial kits would have to be based on evidence-based guidelines, which currently do not exist,” she told GeekWire.
Nevertheless, Jain remains positive about the value of microbiome testing. “The future of medicine will be delivered at home, not at the hospital. And the medicines of the future are going to come from a farm, not a pharmacy,” he told GeekWire.
Other Viome At-home Tests
According to a paper published in the journal Therapeutic Advances in Gastroenterology titled, “Role of the Gut Microbiota in Health and Chronic Gastrointestinal Disease: Understanding a Hidden Metabolic Organ,” the human gut contains trillions of microbes, and no two people share the exact same microbiome composition. This complex community of microbial cells influences human physiology, metabolism, nutrition and immune function, and performs a critical role in overall health.
CVS currently sells Viome’s “Gut Intelligence Health Insights Plus Personalized Nutrition Plan” on its website for $149.99. Prices may vary from online to in-store. The test is intended for individuals who want to monitor and address gut imbalances or health symptoms, such as:
Constipation
Diarrhea
Stomach pain
Bloating
Heartburn
Itchy skin
Trouble maintaining a healthy weight
Viome sells the Gut Intelligence Test for $179 on its own website, as well as the following health tests:
Viome also sell precision probiotics and prebiotics, as well as supplements and oral health lozenges.
Gut microbiome testing kits, such as the one from Viome, typically require the collection of a stool sample. Healthcare consumers have in the past been reluctant to perform such testing, but as more information regarding gut health is published, that reluctance may diminish.
Clinical laboratories also have a stake in the game. Dynamic direct to consumer at-home testing has the potential to generate revenue for clinical laboratories, while helping consumers who want to monitor different aspects of their health. But this would be an adjunct to the primary mission of medical laboratories to provide testing services to local physicians and their patients.
