What will the $100 genome mean?
In May 2022, Californian biotech Ultima Genomics announced that its UG 100 platform was capable of sequencing an entire human genome for just $100, a landmark moment in the history of the field. The announcement was particularly remarkable because few had previously heard of the company, a relative unknown in an industry long dominated by global giant Illumina which controls about 80 percent of the world’s sequencing market.
Ultima’s secret was to completely revamp many technical aspects of the way Illumina have traditionally deciphered DNA. The process usually involves first splitting the double helix DNA structure into single strands, then breaking these strands into short fragments which are laid out on a glass surface called a flow cell. When this flow cell is loaded into the sequencing machine, color-coded tags are attached to each individual base letter. A laser scans the bases individually while a camera simultaneously records the color associated with them, a process which is repeated until every single fragment has been sequenced.
Instead, Ultima has found a series of shortcuts to slash the cost and boost efficiency. “Ultima Genomics has developed a fundamentally new sequencing architecture designed to scale beyond conventional approaches,” says Josh Lauer, Ultima’s chief commercial officer.
This ‘new architecture’ is a series of subtle but highly impactful tweaks to the sequencing process ranging from replacing the costly flow cell with a silicon wafer which is both cheaper and allows more DNA to be read at once, to utilizing machine learning to convert optical data into usable information.
To put $100 genome in perspective, back in 2012 the cost of sequencing a single genome was around $10,000, a price tag which dropped to $1,000 a few years later. Before Ultima’s announcement, the cost of sequencing an individual genome was around $600.
Several studies have found that nearly 12 percent of healthy people who have their genome sequenced, then discover they have a variant pointing to a heightened risk of developing a disease that can be monitored, treated or prevented.
While Ultima’s new machine is not widely available yet, Illumina’s response has been rapid. Last month the company unveiled the NovaSeq X series, which it describes as its fastest most cost-efficient sequencing platform yet, capable of sequencing genomes at $200, with further price cuts likely to follow.
But what will the rapidly tumbling cost of sequencing actually mean for medicine? “Well to start with, obviously it’s going to mean more people getting their genome sequenced,” says Michael Snyder, professor of genetics at Stanford University. “It'll be a lot more accessible to people.”
At the moment sequencing is mainly limited to certain cancer patients where it is used to inform treatment options, and individuals with undiagnosed illnesses. In the past, initiatives such as SeqFirst have attempted further widen access to genome sequencing based on growing amounts of research illustrating the potential benefits of the technology in healthcare. Several studies have found that nearly 12 percent of healthy people who have their genome sequenced, then discover they have a variant pointing to a heightened risk of developing a disease that can be monitored, treated or prevented.
“While whole genome sequencing is not yet widely used in the U.S., it has started to come into pediatric critical care settings such as newborn intensive care units,” says Professor Michael Bamshad, who heads the genetic medicine division in the University of Washington’s pediatrics department. “It is also being used more often in outpatient clinical genetics services, particularly when conventional testing fails to identify explanatory variants.”
But the cost of sequencing itself is only one part of the price tag. The subsequent clinical interpretation and genetic counselling services often come to several thousand dollars, a cost which insurers are not always willing to pay.
As a result, while Bamshad and others hope that the arrival of the $100 genome will create new opportunities to use genetic testing in innovative ways, the most immediate benefits are likely to come in the realm of research.
Bigger Data
There are numerous ways in which cheaper sequencing is likely to advance scientific research, for example the ability to collect data on much larger patient groups. This will be a major boon to scientists working on complex heterogeneous diseases such as schizophrenia or depression where there are many genes involved which all exert subtle effects, as well as substantial variance across the patient population. Bigger studies could help scientists identify subgroups of patients where the disease appears to be driven by similar gene variants, who can then be more precisely targeted with specific drugs.
If insurers can figure out the economics, Snyder even foresees a future where at a certain age, all of us can qualify for annual sequencing of our blood cells to search for early signs of cancer or the potential onset of other diseases like type 2 diabetes.
David Curtis, a genetics professor at University College London, says that scientists studying these illnesses have previously been forced to rely on genome-wide association studies which are limited because they only identify common gene variants. “We might see a significant increase in the number of large association studies using sequence data,” he says. “It would be far preferable to use this because it provides information about rare, potentially functional variants.”
Cheaper sequencing will also aid researchers working on diseases which have traditionally been underfunded. Bamshad cites cystic fibrosis, a condition which affects around 40,000 children and adults in the U.S., as one particularly pertinent example.
“Funds for gene discovery for rare diseases are very limited,” he says. “We’re one of three sites that did whole genome sequencing on 5,500 people with cystic fibrosis, but our statistical power is limited. A $100 genome would make it much more feasible to sequence everyone in the U.S. with cystic fibrosis and make it more likely that we discover novel risk factors and pathways influencing clinical outcomes.”
For progressive diseases that are more common like cancer and type 2 diabetes, as well as neurodegenerative conditions like multiple sclerosis and ALS, geneticists will be able to go even further and afford to sequence individual tumor cells or neurons at different time points. This will enable them to analyze how individual DNA modifications like methylation, change as the disease develops.
In the case of cancer, this could help scientists understand how tumors evolve to evade treatments. Within in a clinical setting, the ability to sequence not just one, but many different cells across a patient’s tumor could point to the combination of treatments which offer the best chance of eradicating the entire cancer.
“What happens at the moment with a solid tumor is you treat with one drug, and maybe 80 percent of that tumor is susceptible to that drug,” says Neil Ward, vice president and general manager in the EMEA region for genomics company PacBio. “But the other 20 percent of the tumor has already got mutations that make it resistant, which is probably why a lot of modern therapies extend life for sadly only a matter of months rather than curing, because they treat a big percentage of the tumor, but not the whole thing. So going forwards, I think that we will see genomics play a huge role in cancer treatments, through using multiple modalities to treat someone's cancer.”
If insurers can figure out the economics, Snyder even foresees a future where at a certain age, all of us can qualify for annual sequencing of our blood cells to search for early signs of cancer or the potential onset of other diseases like type 2 diabetes.
“There are companies already working on looking for cancer signatures in methylated DNA,” he says. “If it was determined that you had early stage cancer, pre-symptomatically, that could then be validated with targeted MRI, followed by surgery or chemotherapy. It makes a big difference catching cancer early. If there were signs of type 2 diabetes, you could start taking steps to mitigate your glucose rise, and possibly prevent it or at least delay the onset.”
This would already revolutionize the way we seek to prevent a whole range of illnesses, but others feel that the $100 genome could also usher in even more powerful and controversial preventative medicine schemes.
Newborn screening
In the eyes of Kári Stefánsson, the Icelandic neurologist who been a visionary for so many advances in the field of human genetics over the last 25 years, the falling cost of sequencing means it will be feasible to sequence the genomes of every baby born.
“We have recently done an analysis of genomes in Iceland and the UK Biobank, and in 4 percent of people you find mutations that lead to serious disease, that can be prevented or dealt with,” says Stefansson, CEO of deCODE genetics, a subsidiary of the pharmaceutical company Amgen. “This could transform our healthcare systems.”
As well as identifying newborns with rare diseases, this kind of genomic information could be used to compute a person’s risk score for developing chronic illnesses later in life. If for example, they have a higher than average risk of colon or breast cancer, they could be pre-emptively scheduled for annual colonoscopies or mammograms as soon as they hit adulthood.
To a limited extent, this is already happening. In the UK, Genomics England has launched the Newborn Genomes Programme, which plans to undertake whole-genome sequencing of up to 200,000 newborn babies, with the aim of enabling the early identification of rare genetic diseases.
"I have not had my own genome sequenced and I would not have wanted my parents to have agreed to this," Curtis says. "I don’t see that sequencing children for the sake of some vague, ill-defined benefits could ever be justifiable.”
However, some scientists feel that it is tricky to justify sequencing the genomes of apparently healthy babies, given the data privacy issues involved. They point out that we still know too little about the links which can be drawn between genetic information at birth, and risk of chronic illness later in life.
“I think there are very difficult ethical issues involved in sequencing children if there are no clear and immediate clinical benefits,” says Curtis. “They cannot consent to this process. I have not had my own genome sequenced and I would not have wanted my parents to have agreed to this. I don’t see that sequencing children for the sake of some vague, ill-defined benefits could ever be justifiable.”
Curtis points out that there are many inherent risks about this data being available. It may fall into the hands of insurance companies, and it could even be used by governments for surveillance purposes.
“Genetic sequence data is very useful indeed for forensic purposes. Its full potential has yet to be realized but identifying rare variants could provide a quick and easy way to find relatives of a perpetrator,” he says. “If large numbers of people had been sequenced in a healthcare system then it could be difficult for a future government to resist the temptation to use this as a resource to investigate serious crimes.”
While sequencing becoming more widely available will present difficult ethical and moral challenges, it will offer many benefits for society as a whole. Cheaper sequencing will help boost the diversity of genomic datasets which have traditionally been skewed towards individuals of white, European descent, meaning that much of the actionable medical information which has come out of these studies is not relevant to people of other ethnicities.
Ward predicts that in the coming years, the growing amount of genetic information will ultimately change the outcomes for many with rare, previously incurable illnesses.
“If you're the parent of a child that has a susceptible or a suspected rare genetic disease, their genome will get sequenced, and while sadly that doesn’t always lead to treatments, it’s building up a knowledge base so companies can spring up and target that niche of a disease,” he says. “As a result there’s a whole tidal wave of new therapies that are going to come to market over the next five years, as the genetic tools we have, mature and evolve.”
From infections with no symptoms to why men are more likely to be hospitalized in the ICU and die of COVID-19, new research shows that your genes play a significant role
Early in the pandemic, genetic research focused on the virus because it was readily available. Plus, the virus contains only 30,000 bases in a dozen functional genes, so it's relatively easy and affordable to sequence. Additionally, the rapid mutation of the virus and its ability to escape antibody control fueled waves of different variants and provided a reason to follow viral genetics.
In comparison, there are many more genes of the human immune system and cellular functions that affect viral replication, with about 3.2 billion base pairs. Human studies require samples from large numbers of people, the analysis of each sample is vastly more complex, and sophisticated computer analysis often is required to make sense of the raw data. All of this takes time and large amounts of money, but important findings are beginning to emerge.
Asymptomatics
About half the people exposed to SARS-CoV-2, the virus that causes the COVID-19 disease, never develop symptoms of this disease, or their symptoms are so mild they often go unnoticed. One piece of understanding the phenomena came when researchers showed that exposure to OC43, a common coronavirus that results in symptoms of a cold, generates immune system T cells that also help protect against SARS-CoV-2.
Jill Hollenbach, an immunologist at the University of California at San Francisco, sought to identify the gene behind that immune protection. Most COVID-19 genetic studies are done with the most seriously ill patients because they are hospitalized and thus available. “But 99 percent of people who get it will never see the inside of a hospital for COVID-19,” she says. “They are home, they are not interacting with the health care system.”
Early in the pandemic, when most labs were shut down, she tapped into the National Bone Marrow Donor Program database. It contains detailed information on donor human leukocyte antigens (HLAs), key genes in the immune system that must match up between donor and recipient for successful transplants of marrow or organs. Each HLA can contain alleles, slight molecular differences in the DNA of the HLA, which can affect its function. Potential HLA combinations can number in the tens of thousands across the world, says Hollenbach, but each person has a smaller number of those possible variants.
She teamed up with the COVID-19 Citizen Science Study a smartphone-based study to track COVID-19 symptoms and outcomes, to ask persons in the bone marrow donor registry about COVID-19. The study enlisted more than 30,000 volunteers. Those volunteers already had their HLAs annotated by the registry, and 1,428 tested positive for the virus.
Analyzing five key HLAs, she found an allele in the gene HLA-B*15:01 that was significantly overrepresented in people who didn’t have any symptoms. The effect was even stronger if a person had inherited the allele from both parents; these persons were “more than eight times more likely to remain asymptomatic than persons who did not carry the genetic variant,” she says. Altogether this HLA was present in about 10 percent of the general European population but double that percentage in the asymptomatic group. Hollenbach and her colleagues were able confirm this in other different groups of patients.
What made the allele so potent against SARS-CoV-2? Part of the answer came from x-ray crystallography. A key element was the molecular shape of parts of the cold virus OC43 and SARS-CoV-2. They were virtually identical, and the allele could bind very tightly to them, present their molecular antigens to T cells, and generate an extremely potent T cell response to the viruses. And “for whatever reasons that generated a lot of memory T cells that are going to stick around for a long time,” says Hollenbach. “This T cell response is very early in infection and ramps up very quickly, even before the antibody response.”
Understanding the genetics of the immune response to SARS-CoV-2 is important because it provides clues into the conditions of T cells and antigens that support a response without any symptoms, she says. “It gives us an opportunity to think about whether this might be a vaccine design strategy.”
Dead men
A researcher at the Leibniz Institute of Virology in Hamburg Germany, Guelsah Gabriel, was drawn to a question at the other end of the COVID-19 spectrum: why men more likely to be hospitalized and die from the infection. It wasn't that men were any more likely to be exposed to the virus but more likely, how their immune system reacted to it
Several studies had noted that testosterone levels were significantly lower in men hospitalized with COVID-19. And, in general, the lower the testosterone, the worse the prognosis. A year after recovery, about 30 percent of men still had lower than normal levels of testosterone, a condition known as hypogonadism. Most of the men also had elevated levels of estradiol, a female hormone (https://pubmed.ncbi.nlm.nih.gov/34402750/).
Every cell has a sex, expressing receptors for male and female hormones on their surface. Hormones docking with these receptors affect the cells' internal function and the signals they send to other cells. The number and role of these receptors varies from tissue to tissue.
Gabriel began her search by examining whole exome sequences, the protein-coding part of the genome, for key enzymes involved in the metabolism of sex hormones. The research team quickly zeroed in on CYP19A1, an enzyme that converts testosterone to estradiol. The gene that produces this enzyme has a number of different alleles, the molecular variants that affect the enzyme's rate of metabolizing the sex hormones. One genetic variant, CYP19A1 (Thr201Met), is typically found in 6.2 percent of all people, both men and women, but remarkably, they found it in 68.7 percent of men who were hospitalized with COVID-19.
Lung surprise
Lungs are the tissue most affected in COVID-19 disease. Gabriel wondered if the virus might be affecting expression of their target gene in the lung so that it produces more of the enzyme that converts testosterone to estradiol. Studying cells in a petri dish, they saw no change in gene expression when they infected cells of lung tissue with influenza and the original SARS-CoV viruses that caused the SARS outbreak in 2002. But exposure to SARS-CoV-2, the virus responsible for COVID-19, increased gene expression up to 40-fold, Gabriel says.
Did the same thing happen in humans? Autopsy examination of patients in three different cites found that “CYP19A1 was abundantly expressed in the lungs of COVID-19 males but not those who died of other respiratory infections,” says Gabriel. This increased enzyme production led likely to higher levels of estradiol in the lungs of men, which “is highly inflammatory, damages the tissue, and can result in fibrosis or scarring that inhibits lung function and repair long after the virus itself has disappeared.” Somehow the virus had acquired the capacity to upregulate expression of CYP19A1.
Only two COVID-19 positive females showed increased expression of this gene. The menopause status of these women, or whether they were on hormone replacement therapy was not known. That could be important because female hormones have a protective effect for cardiovascular disease, which women often lose after going through menopause, especially if they don’t start hormone replacement therapy. That sex-specific protection might also extend to COVID-19 and merits further study.
The team was able to confirm their findings in golden hamsters, the animal model of choice for studying COVID-19. Testosterone levels in male animals dropped 5-fold three days after infection and began to recover as viral levels declined. CYP19A1 transcription increased up to 15-fold in the lungs of the male but not the females. The study authors wrote, “Virus replication in the male lungs was negatively associated with testosterone levels.”
The medical community studying COVID-19 has slowly come to recognize the importance of adipose tissue, or fat cells. They are known to express abundant levels of CYP19A1 and play a significant role as metabolic tissue in COVID-19. Gabriel adds, “One of the key findings of our study is that upon SARS-CoV-2 infection, the lung suddenly turns into a metabolic organ by highly expressing” CYP19A1.
She also found evidence that SARS-CoV-2 can infect the gonads of hamsters, thereby likely depressing circulating levels of sex hormones. The researchers did not have autopsy samples to confirm this in humans, but others have shown that the virus can replicate in those tissues.
A possible treatment
Back in the lab, substituting low and high doses of testosterone in SARS-COV-2 infected male hamsters had opposite effects depending on testosterone dosage used. Gabriel says that hormone levels can vary so much, depending on health status and age and even may change throughout the day, that “it probably is much better to inhibit the enzyme” produced by CYP19A1 than try to balance the hormones.
Results were better with letrozole, a drug approved to treat hypogonadism in males, which reduces estradiol levels. The drug also showed benefit in male hamsters in terms of less severe disease and faster recovery. She says more details need to be worked out in using letrozole to treat COVID-19, but they are talking with hospitals about clinical trials of the drug.
Gabriel has proposed a four hit explanation of how COVID-19 can be so deadly for men: the metabolic quartet. First is the genetic risk factor of CYP19A1 (Thr201Met), then comes SARS-CoV-2 infection that induces even greater expression of this gene and the deleterious increase of estradiol in the lung. Age-related hypogonadism and the heightened inflammation of obesity, known to affect CYP19A1 activity, are contributing factors in this deadly perfect storm of events.
Studying host genetics, says Gabriel, can reveal new mechanisms that yield promising avenues for further study. It’s also uniting different fields of science into a new, collaborative approach they’re calling “infection endocrinology,” she says.
New device finds breast cancer like earthquake detection
Mammograms are necessary breast cancer checks for women as they reach the recommended screening age between 40 and 50 years. Yet, many find the procedure uncomfortable. “I have large breasts, and to be able to image the full breast, the radiographer had to manipulate my breast within the machine, which took time and was quite uncomfortable,” recalls Angela, who preferred not to disclose her last name.
Breast cancer is the most widespread cancer in the world, affecting 2.3 million women in 2020. Screening exams such as mammograms can help find breast cancer early, leading to timely diagnosis and treatment. If this type of cancer is detected before the disease has spread, the 5-year survival rate is 99 percent. But some women forgo mammograms due to concerns about radiation or painful compression of breasts. Other issues, such as low income and a lack of access to healthcare, can also serve as barriers, especially for underserved populations.
Researchers at the University of Canterbury and startup Tiro Medical in Christchurch, New Zealand are hoping their new device—which doesn’t involve any radiation or compression of the breasts—could increase the accuracy of breast cancer screening, broaden access and encourage more women to get checked. They’re digging into clues from the way buildings move in an earthquake to help detect more cases of this disease.
Earthquake engineering inspires new breast cancer screening tech
What’s underneath a surface affects how it vibrates. Earthquake engineers look at the vibrations of swaying buildings to identify the underlying soil and tissue properties. “As the vibration wave travels, it reflects the stiffness of the material between that wave and the surface,” says Geoff Chase, professor of engineering at the University of Canterbury in Christchurch, New Zealand.
Chase is applying this same concept to breasts. Analyzing the surface motion of the breast as it vibrates could reveal the stiffness of the tissues underneath. Regions of high stiffness could point to cancer, given that cancerous breast tissue can be up to 20 times stiffer than normal tissue. “If in essence every woman’s breast is soft soil, then if you have some granite rocks in there, we’re going to see that on the surface,” explains Chase.
The earthquake-inspired device exceeds the 87 percent sensitivity of a 3D mammogram.
That notion underpins a new breast screening device, the brainchild of Chase. Women lie face down, with their breast being screened inside a circular hole and the nipple resting on a small disc called an actuator. The actuator moves up and down, between one and two millimeters, so there’s a small vibration, “almost like having your phone vibrate on your nipple,” says Jessica Fitzjohn, a postdoctoral fellow at the University of Canterbury who collaborated on the device design with Chase.
Cameras surrounding the device take photos of the breast surface motion as it vibrates. The photos are fed into image processing algorithms that convert them into data points. Then, diagnostic algorithms analyze those data points to find any differences in the breast tissue. “We’re looking for that stiffness contrast which could indicate a tumor,” Fitzjohn says.
A nascent yet promising technology
The device has been tested in a clinical trial of 14 women: one with healthy breasts and 13 with a tumor in one breast. The cohort was small but diverse, varying in age, breast volume and tumor size.
Results from the trial yielded a sensitivity rate, or the likelihood of correctly detecting breast cancer, of 85 percent. Meanwhile, the device’s specificity rate, or the probability of diagnosing healthy breasts, was 77 percent. By combining and optimizing certain diagnostic algorithms, the device reached between 92 and 100 percent sensitivity and between 80 and 86 percent specificity, which is comparable to the latest 3D mammogram technology. Called tomosynthesis, these 3D mammograms take a number of sharper, clearer and more detailed 3D images compared to the single 2D image of a conventional mammogram, and have a specificity score of 92 percent. Although the earthquake-inspired device’s specificity is lower, it exceeds the 87 percent sensitivity of a 3D mammogram.
The team hopes that cameras with better resolution can help improve the numbers. And with a limited amount of data in the first trial, the researchers are looking into funding for another clinical trial to validate their results on a larger cohort size.
Additionally, during the trial, the device correctly identified one woman’s breast as healthy, while her prior mammogram gave a false positive. The device correctly identified it as being healthy tissue. It was also able to capture the tiniest tumor at 7 millimeters—around a third of an inch or half as long as an aspirin tablet.
Diagnostic findings from the device are immediate.
When using the earthquake-inspired device, women lie face down, with their breast being screened inside circular holes.
University of Canterbury.
But more testing is needed to “prove the device’s ability to pick up small breast cancers less than 10 to 15 millimeters in size, as we know that finding cancers when they are small is the best way of improving outcomes,” says Richard Annand, a radiologist at Pacific Radiology in New Zealand. He explains that mammography already detects most precancerous lesions, so if the device will only be able to find large masses or lumps it won’t be particularly useful. While not directly involved in administering the clinical trial for the device, Annand was a director at the time for Canterbury Breastcare, where the trial occurred.
Meanwhile, Monique Gary, a breast surgical oncologist and medical director of the Grand View Health Cancer program in Pennsylvania, U.S., is excited to see new technologies advancing breast cancer screening and early detection. But she notes that the device may be challenging for “patients who are unable to lay prone, such as pregnant women as well as those who are differently abled, and this machine might exclude them.” She adds that it would also be interesting to explore how breast implants would impact the device’s vibrational frequency.
Diagnostic findings from the device are immediate, with the results available “before you put your clothes back on,” Chase says. The absence of any radiation is another benefit, though Annand considers it a minor edge “as we know the radiation dose used in mammography is minimal, and the advantages of having a mammogram far outweigh the potential risk of radiation.”
The researchers also conducted a separate ergonomic trial with 40 women to assess the device’s comfort, safety and ease of use. Angela was part of that trial and described the experience as “easy, quick, painless and required no manual intervention from an operator.” And if a person is uncomfortable being topless or having their breasts touched by someone else, “this type of device would make them more comfortable and less exposed,” she says.
While mammograms remain “the ‘gold standard’ in breast imaging, particularly screening, physicians need an option that can be used in combination with mammography.
Fitzjohn acknowledges that “at the moment, it’s quite a crude prototype—it’s just a block that you lie on.” The team prioritized function over form initially, but they’re now planning a few design improvements, including more cushioning for the breasts and the surface where the women lie on.
While mammograms remains “the ‘gold standard’ in breast imaging, particularly screening, physicians need an option that is good at excluding breast cancer when used in combination with mammography, has good availability, is easy to use and is affordable. There is the possibility that the device could fill this role,” Annand says.
Indeed, the researchers envision their new breast screening device as complementary to mammograms—a prescreening tool that could make breast cancer checks widely available. As the device is portable and doesn’t require specialized knowledge to operate, it can be used in clinics, pop-up screening facilities and rural communities. “If it was easily accessible, particularly as part of a checkup with a [general practitioner] or done in a practice the patient is familiar with, it may encourage more women to access this service,” Angela says. For those who find regular mammograms uncomfortable or can’t afford them, the earthquake-inspired device may be an option—and an even better one.
Broadening access could prompt more women to go for screenings, particularly younger women at higher risk of getting breast cancer because of a family history of the disease or specific gene mutations. “If we can provide an option for them then we can catch those cancers earlier,” Fitzjohn syas. “By taking screening to people, we’re increasing patient-centric care.”
With the team aiming to lower the device’s cost to somewhere between five and eight times less than mammography equipment, it would also be valuable for low-to-middle-income nations that are challenged to afford the infrastructure for mammograms or may not have enough skilled radiologists.
For Fitzjohn, the ultimate goal is to “increase equity in breast screening and catch cancer early so we have better outcomes for women who are diagnosed with breast cancer.”