The Brave New World of Using DNA to Store Data
Netscape co-founder-turned-venture capitalist billionaire investor Marc Andreessen once posited that software was eating the world. He was right, and the takeover of software resulted in many things. One of them is data. Lots and lots and lots of data. In the previous two years, humanity created more data than it did during its entire existence combined, and the amount will only increase. Think about it: The hundreds of 50KB emails you write a day, the dozens of 10MB photos, the minute-long, 350MB 4K video you shoot on your iPhone X add up to vast quantities of information. All that information needs to be stored. And that's becoming an issue as data volume outpaces storage space.
The race is on to find another medium capable of storing massive amounts of information in as small a space as possible.
"There won't be enough silicon to store all the data we need. It's unlikely that we can make flash memory smaller. We have reached the physical limits," Victor Zhirnov, chief scientist at the Semiconductor Research Corporation, says. "We are facing a crisis that's comparable to the oil crisis in the 1970s. By 2050, we're going to need to store 10 to the 30 bits, compared to 10 to the 23 bits in 2016." That amount of storage space is equivalent to each of the world's seven billion people owning almost six trillion -- that's 10 to the 12th power -- iPhone Xs with 256GB storage space.
The race is on to find another medium capable of storing massive amounts of information in as small a space as possible. Zhirnov and other scientists are looking at the human body, looking to DNA. "Nature has nailed it," Luis Ceze, a professor in the Department of Computer Science and Engineering at the University of Washington, says. "DNA is a molecular storage medium that is remarkable. It's incredibly dense, many, many thousands of times denser than the densest technology that we have today. And DNA is remarkably general. Any information you can map in bits you can store in DNA." It's so dense -- able to store a theoretical maximum of 215 petabytes (215 million gigabytes) in a single gram -- that all the data ever produced could be stored in the back of a tractor trailer truck.
Writing DNA can be an energy-efficient process, too. Consider how the human body is constantly writing and rewriting DNA, and does so on a couple thousand calories a day. And all it needs for storage is a cool, dark place, a significant energy savings when compared to server farms that require huge amounts of energy to run and even more energy to cool.
Picture it: tiny specks of inert DNA made from silicon or another material, stored in cool, dark, dry areas, preserved for all time.
Researchers first succeeded in encoding data onto DNA in 2012, when Harvard University geneticists George Church and Sri Kosuri wrote a 52,000-word book on A, C, G, and T base pairs. Their method only produced 1.28 petabytes per gram of DNA, however, a volume exceeded the next year when a group encoded all 154 Shakespeare sonnets and a 26-second clip of Martin Luther King's "I Have A Dream" speech. In 2017, Columbia University researchers Yaniv Erlich and Dina Zielinski made the process 60 percent more efficient.
The limiting factor today is cost. Erlich said the work his team did cost $7,000 to encode and decode two megabytes of data. To become useful in a widespread way, the price per megabyte needs to plummet. Even advocates concede this point. "Of course it is expensive," Zhirnov says. "But look how much magnetic storage cost in the 1980s. What you store today in your iPhone for virtually nothing would cost many millions of dollars in 1982." There's reason to think the price will continue to fall. Genome readers are improving, getting cheaper, faster, and smaller, and genome sequencing becomes cheaper every year, too. Picture it: tiny specks of inert DNA made from silicon or another material, stored in cool, dark, dry areas, preserved for all time.
"It just takes a few minutes to double a sample. A few more minutes, you double it again. Very quickly, you have thousands or millions of new copies."
Plus, DNA has another advantage over more traditional forms of storage: It's very easy to reproduce. "If you want a second copy of a hard disk drive, you need components for a disk drive, hook both drives up to a computer, and copy. That's a pain," Nick Goldman, a researcher at the European Bioinformatics Institute, says. "DNA, once you have that first sample, it's a process that is absolutely routine in thousands of laboratories around the world to multiply that using polymerase chain reaction [which uses temperature changes or other processes]. It just takes a few minutes to double a sample. A few more minutes, you double it again. Very quickly, you have thousands or millions of new copies."
This ability to duplicate quickly and easily is a positive trait. But, of course, there's also the potential for danger. Does encoding on DNA, the very basis for life, present ethical issues? Could it get out of control and fundamentally alter life as we know it?
The chance is there, but it's remote. The first reason is that storage could be done with only two base pairs, which would serve as replacements for the 0 and 1 digits that make up all digital data. While doing so would decrease the possible density of the storage, it would virtually eliminate the risk that the sequences would be compatible with life.
But even if scientists and researchers choose to use four base pairs, other safeguards are in place that will prevent trouble. According to Ceze, the computer science professor, the snippets of DNA that they write are very short, around 150 nucleotides. This includes the title, the information that's being encoded, and tags to help organize where the snippet should fall in the larger sequence. Furthermore, they generally avoid repeated letters, which dramatically reduces the chance that a protein could be synthesized from the snippet.
"In the future, we'll know enough about someone from a sample of their DNA that we could make a specific poison. That's the danger, not those of us who want to encode DNA for storage."
Inevitably, some DNA will get spilt. "But it's so unlikely that anything that gets created for storage would have a biological interpretation that could interfere with the mechanisms going on in a living organism that it doesn't worry me in the slightest," Goldman says. "We're not of concern for the people who are worried about the ethical issues of synthetic DNA. They are much more concerned about people deliberately engineering anthrax. In the future, we'll know enough about someone from a sample of their DNA that we could make a specific poison. That's the danger, not those of us who want to encode DNA for storage."
In the end, the reality of and risks surrounding encoding on DNA are the same as any scientific advancement: It's another system that is vulnerable to people with bad intentions but not one that is inherently unethical.
"Every human action has some ethical implications," Zhirnov says. "I can use a hammer to build a house or I can use it to harm another person. I don't see why DNA is in any way more or less ethical."
If that house can store all the knowledge in human history, it's worth learning how to build it.
Editor's Note: In response to readers' comments that silicon is one of the earth's most abundant materials, we reached back out to our source, Dr. Victor Zhirnov. He stands by his statement about a coming shortage of silicon, citing this research. The silicon oxide found in beach sand is unsuitable for semiconductors, he says, because the cost of purifying it would be prohibitive. For use in circuit-making, silicon must be refined to a purity of 99.9999999 percent. So the process begins by mining for pure quartz, which can only be found in relatively few places around the world.
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.”