This past April, an alleged serial rapist and murderer, who had remained unidentified for over 40 years, was located by comparing a crime scene DNA profile to a public genetic genealogy database designed to identify biological relatives and reconstruct family trees. The so-called "Golden State Killer" had not placed his own profile in the database.
Forensic use of genetic genealogy data is possible thanks to widening public participation in direct-to-consumer recreational genetic testing.
Instead, a number of his distant genetic cousins had, resulting in partial matches between themselves and the forensic profile. Investigators then traced the shared heritage of the relatives to great-great-great-grandparents and using these connections, as well as other public records, narrowed their search to just a handful of individuals, one of whom was found to be an exact genetic match to the crime scene sample.
Forensic use of genetic genealogy data is possible thanks to widening public participation in direct-to-consumer recreational genetic testing. The Federal Bureau of Investigation maintains a national forensic genetic database (which currently contains over 16 million unique profiles, over-representing individuals of non-European ancestry); each profile holds genetic information from only 13 to 20 variable gene regions, just enough to identify a suspect. However, since this database and related forensic databases were established, the nature of genetic profiling has significantly changed: direct-to-consumer genetic tests routinely use whole genome scans involving simultaneous analysis of hundreds of thousands of variants.
With such comprehensive genetic information, it becomes possible to discern more distant genetic relatives. Thus, even though public DNA collections are smaller than most law enforcement databases, the potential to connect a crime scene sample to biological relatives is enhanced. The successful use of one genealogy database (GEDMatch) in the GSK case demonstrates the power of the approach, so much so that the genetic profiles of over 100 similar cold cases are now being run through the same resource. Indeed, in the two months since the GSK case was first reported, 5 other cold cases have been solved using similar methods.
Autonomy in the Genomic Age
While few would disagree with the importance of finally bringing to justice those who commit serious violent offenses, this new forensic genetic application has sparked broad discussion of privacy-related and ethical concerns. Before, the main genetic databases accessible to the police were those containing the profiles of accused or convicted criminals, but now the DNA of many more "innocent bystanders," across multiple generations, are in play.
The genetic services that provide a venue for data sharing typically warn participants that their information can be used for purposes beyond those they intend, but there is no legal prohibition on the use of crowd-sourced public collections for forensic investigation. Some services, such as GEDMatch, now explicitly welcome possible law enforcement use.
The decisions of individuals to contribute their own genetic information inadvertently exposes many others across their family tree.
The implication is that consumers must choose for themselves whether they are willing to bring their genetic information into the public sphere. Many have no problem doing so, seeing value in law enforcement access to such data. But the decisions of individuals to contribute their own genetic information inadvertently exposes many others across their family tree who may not be aware of or interested in their genetic relationships going public.
As one well-known statistical geneticist who predicted forensic uses of public genetic data noted: "You are a beacon who illuminates 300 people around you." By the same token, 300 people, most of whom you do not know and have probably never met, can illuminate your genetic information; indeed a recent analysis has suggested that most in the U.S. are identifiable in this way. There is nothing that you can do about it, no way to opt out. Thus, police interaction with such databases must be addressed as a public policy issue, not left to the informed consent of individual consumers.
When Consent Will Not Suffice
For those concerned by the broader implications of such practices, the simplest solution might be to discourage open access sharing of detailed genetic information. But let's say that we are willing to continue to allow those with an interest in genealogy to make their data readily searchable. What safeguards should we implement to ensure that the family members who don't want to opt in, or who don't have the ability to make that choice, remain unharmed? Their autonomy counts, too.
We might consider regulation similar to the kind that limit law enforcement use of forensic genetic databases of convicted and arrested individuals. For example, in California, familial searches can only be performed using the database of convicted individuals in cases of serious crimes with public safety implications where all other investigatory methods have been exhausted, and where single-source high-quality DNA is available for analysis. Further, California policy separates the genealogical investigative team from local detectives, so as to minimize the impact of incidental findings (such as unexpected non-paternity).
Importantly, the individual apprehended was not the first, or even second, but the third person subjected to enhanced police scrutiny.
No such regulations currently govern law enforcement searches of public genealogical databases, and we know relatively little about the specifics of the GSK investigation. We do not know the methods used to infer genetic relationships, or their likelihood of mistakenly suggesting a relationship where none exists. Nor do we know the level of genetic identity considered relevant for subsequent follow-up. It is also unclear how law enforcement investigators combined the genetic information they received with other public records data. Together, this leaves room for an unknown degree of investigation into an unknown number of individuals.
Why This Matters
What has been revealed is that the GSK search resulted in the identification of 10 to 20 potential distant genetic relatives, which led to the investigation of 25 different family trees, 24 of which did not contain the alleged serial rapist and murderer. While some sources described a pool of 100 possible male suspects identified from this exercise, others imply that the total number of relatives encompassed by the investigation was far larger. One account, for example, suggests that there were roughly 1000 family members in just the one branch of the genealogy that included the alleged perpetrator. Importantly, the individual apprehended was not the first, or even second, but the third person subjected to enhanced police scrutiny: reports describe at least two false leads, including one where a warrant was issued to obtain a DNA sample.
These details, many of which only came to light after intense press coverage, raise a host of concerns about the methods employed and the degree to which they exposed otherwise innocent individuals to harms associated with unjustified privacy intrusions. Only with greater transparency and oversight will we be able to ensure that the interests of people curious about their family tree do not unfairly impinge on those of their mostly law-abiding near and distant genetic relatives.
In November 2020, messenger RNA catapulted into the public consciousness when the first COVID-19 vaccines were authorized for emergency use. Around the same time, an equally groundbreaking yet relatively unheralded application of mRNA technology was taking place at a London hospital.
Over the past two decades, there's been increasing interest in harnessing mRNA — molecules present in all of our cells that act like digital tape recorders, copying instructions from DNA in the cell nucleus and carrying them to the protein-making structures — to create a whole new class of therapeutics.
Scientists realized that artificial mRNA, designed in the lab, could be used to instruct our cells to produce certain antibodies, turning our bodies into vaccine-making factories, or to recognize and attack tumors. More recently, researchers recognized that mRNA could also be used to make another groundbreaking technology far more accessible to more patients: gene editing. The gene-editing tool CRISPR has generated plenty of hype for its potential to cure inherited diseases. But delivering CRISPR to the body is complicated and costly.
"Most gene editing involves taking cells out of the patient, treating them and then giving them back, which is an extremely expensive process," explains Drew Weissman, professor of medicine at the University of Pennsylvania, who was involved in developing the mRNA technology behind the COVID-19 vaccines.
But last November, a Massachusetts-based biotech company called Intellia Therapeutics showed it was possible to use mRNA to make the CRISPR system inside the body, eliminating the need to extract cells out of the body and edit them in a lab. Just as mRNA can instruct our cells to produce antibodies against a viral infection, it can also teach them to produce the two molecular components that make up CRISPR — a guide molecule and a cutting protein — to snip out a problem gene.
"The pandemic has really shown that not only are mRNA approaches viable, they could in certain circumstances be vastly superior to more traditional technologies."
In Intellia's London-based clinical trial, the company applied this for the first time in a patient with a rare inherited liver disease known as hereditary transthyretin amyloidosis with polyneuropathy. The disease causes a toxic protein to build up in a person's organs and is typically fatal. In a company press release, Intellia's president and CEO John Leonard swiftly declared that its mRNA-based CRISPR therapy could usher in a "new era of potential genome editing cures."
Weissman predicts that turning CRISPR into an affordable therapy will become the next major frontier for mRNA over the coming decade. His lab is currently working on an mRNA-based CRISPR treatment for sickle cell disease. More than 300,000 babies are born with sickle cell every year, mainly in lower income nations.
"There is a FDA-approved cure, but it involves taking the bone marrow out of the person, and then giving it back which is prohibitively expensive," he says. It also requires a patient to have a matched bone marrow done. "We give an intravenous injection of mRNA lipid nanoparticles that target CRISPR to the bone marrow stem cells in the patient, which is easy, and much less expensive."
Meanwhile, the overwhelming success of the COVID-19 vaccines has focused attention on other ways of using mRNA to bolster the immune system against threats ranging from other infectious diseases to cancer.
The practicality of mRNA vaccines – relatively small quantities are required to induce an antibody response – coupled with their adaptable design, mean companies like Moderna are now targeting pathogens like Zika, chikungunya and cytomegalovirus, or CMV, which previously considered commercially unviable for vaccine developers. This is because outbreaks have been relatively sporadic, and these viruses mainly affect people in low-income nations who can't afford to pay premium prices for a vaccine. But mRNA technology means that jabs could be produced on a flexible basis, when required, at relatively low cost.
Other scientists suggest that mRNA could even provide a means of developing a universal influenza vaccine, a goal that's long been the Holy Grail for vaccinologists around the world.
"The mRNA technology allows you to pick out bits of the virus that you want to induce immunity to," says Michael Mulqueen, vice president of business development at eTheRNA, a Belgium-based biotech that's developing mRNA-based vaccines for malaria and HIV, as well as various forms of cancer. "This means you can get the immune system primed to the bits of the virus that don't vary so much between strains. So you could actually have a single vaccine that protects against a whole raft of different variants of the same virus, offering more universal coverage."
Before mRNA became synonymous with vaccines, its biggest potential was for cancer treatments. BioNTech, the German biotech company that collaborated with Pfizer to develop the first authorized COVID-19 vaccine, was initially founded to utilize mRNA for personalized cancer treatments, and the company remains interested in cancers ranging from melanoma to breast cancer.
One of the major hurdles in treating cancer has been the fact that tumors can look very different from one person to the next. It's why conventional approaches, such as chemotherapy or radiation, don't work for every patient. But weaponizing mRNA against cancer primes the immune cells with the tumor's specific genetic sequence, training the patient's body to attack their own unique type of cancer.
"It means you're able to think about personalizing cancer treatments down to specific subgroups of patients," says Mulqueen. "For example, eTheRNA are developing a renal cell carcinoma treatment which will be targeted at around 20% of these patients, who have specific tumor types. We're hoping to take that to human trials next year, but the challenge is trying to identify the right patients for the treatment at an early stage."
Repairing Damaged mRNA
While hopes are high that mRNA could usher in new cancer treatments and make CRISPR more accessible, a growing number of companies are also exploring an alternative to gene editing, known as RNA editing.
In genetic disorders, the mRNA in certain cells is impaired due to a rogue gene defect, and so the body ceases to produce a particular vital protein. Instead of permanently deleting the problem gene with CRISPR, the idea behind RNA editing is to inject small pieces of synthetic mRNA to repair the existing mRNA. Scientists think this approach will allow normal protein production to resume.
Over the past few years, this approach has gathered momentum, as some researchers have recognized that it holds certain key advantages over CRISPR. Companies from Belgium to Japan are now looking at RNA editing to treat all kinds of disorders, from Huntingdon's disease, to amyotrophic lateral sclerosis, or ALS, and certain types of cancer.
"With RNA editing, you don't need to make any changes to the DNA," explains Daniel de Boer, CEO of Dutch biotech ProQR, which is looking to treat rare genetic disorders that cause blindness. "Changes to the DNA are permanent, so if something goes wrong, that may not be desirable. With RNA editing, it's a temporary change, so we dose patients with our drugs once or twice a year."
Last month, ProQR reported a landmark case study, in which a patient with a rare form of blindness called Leber congenital amaurosis, which affects the retina at the back of the eye, recovered vision after three months of treatment.
"We have seen that this RNA therapy restores vision in people that were completely blind for a year or so," says de Boer. "They were able to see again, to read again. We think there are a large number of other genetic diseases we could go after with this technology. There are thousands of different mutations that can lead to blindness, and we think this technology can target approximately 25% of them."
Ultimately, there's likely to be a role for both RNA editing and CRISPR, depending on the disease. "I think CRISPR is ideally suited for illnesses where you would like to permanently correct a genetic defect," says Joshua Rosenthal of the Marine Biology Laboratory in Chicago. "Whereas RNA editing could be used to treat things like pain, where you might want to reset a neural circuit temporarily over a shorter period of time."
Much of this research has been accelerated by the COVID-19 pandemic, which has played a major role in bringing mRNA to the forefront of people's minds as a therapeutic.
"The pandemic has really shown that not only are mRNA approaches viable, they could in certain circumstances be vastly superior to more traditional technologies," says Mulqueen. "In the future, I would not be surprised if many of the top pharma products are mRNA derived."
"Making Sense of Science" is a monthly podcast that features interviews with leading medical and scientific experts about the latest developments and the big ethical and societal questions they raise. This episode is hosted by science and biotech journalist Emily Mullin, summer editor of the award-winning science outlet Leaps.org.