Can Genetic Testing Help Shed Light on the Autism Epidemic?
Autism cases are still on the rise, and scientists don't know why. In April, the Centers for Disease Control (CDC) reported that rates of autism had increased once again, now at an estimated 1 in 59 children up from 1 in 68 just two years ago. Rates have been climbing steadily since 2007 when the CDC initially estimated that 1 in 150 children were on the autism spectrum.
Some clinicians are concerned that the creeping expansion of autism is causing the diagnosis to lose its meaning.
The standard explanation for this increase has been the expansion of the definition of autism to include milder forms like Asperger's, as well as a heightened awareness of the condition that has improved screening efforts. For example, the most recent jump is attributed to children in minority communities being diagnosed who might have previously gone under the radar. In addition, more federally funded resources are available to children with autism than other types of developmental disorders, which may prompt families or physicians to push harder for a diagnosis.
Some clinicians are concerned that the creeping expansion of autism is causing the diagnosis to lose its meaning. William Graf, a pediatric neurologist at Connecticut Children's Medical Center, says that when a nurse tells him that a new patient has a history of autism, the term is no longer a useful description. "Even though I know this topic extremely well, I cannot picture the child anymore," he says. "Use the words mild, moderate, or severe. Just give me a couple more clues, because when you say autism today, I have no idea what people are talking about anymore."
Genetic testing has emerged as one potential way to remedy the overly broad label by narrowing down a heterogeneous diagnosis to a specific genetic disorder. According to Suma Shankar, a medical geneticist at the University of California, Davis, up to 60 percent of autism cases could be attributed to underlying genetic causes. Common examples include Fragile X Syndrome or Rett Syndrome—neurodevelopmental disorders that are caused by mutations in individual genes and are behaviorally classified as autism.
With more than 500 different mutations associated with autism, very few additional diagnoses provide meaningful information.
Having a genetic diagnosis in addition to an autism diagnosis can help families in several ways, says Shankar. Knowing the genetic origin can alert families to other potential health problems that are linked to the mutation, such as heart defects or problems with the immune system. It may also help clinicians provide more targeted behavioral therapies and could one day lead to the development of drug treatments for underlying neurochemical abnormalities. "It will pave the way to begin to tease out treatments," Shankar says.
When a doctor diagnoses a child as having a specific genetic condition, the label of autism is still kept because it is more well-known and gives the child access to more state-funded resources. Children can thus be diagnosed with multiple conditions: autism spectrum disorder and their specific gene mutation. However, with more than 500 different mutations associated with autism, very few additional diagnoses provide meaningful information. What's more, the presence or absence of a mutation doesn't necessarily indicate whether the child is on the mild or severe end of the autism spectrum.
Because of this, Graf doubts that genetic classifications are really that useful. He tells the story of a boy with epilepsy and severe intellectual disabilities who was diagnosed with autism as a young child. Years later, Graf ordered genetic testing for the boy and discovered that he had a mutation in the gene SYNGAP1. However, this knowledge didn't change the boy's autism status. "That diagnosis [SYNGAP1] turns out to be very specific for him, but it will never be a household name. Biologically it's good to know, and now it's all over his chart. But on a societal level he still needs this catch-all label [of autism]," Graf says.
"It gives some information, but to what degree does that change treatment or prognosis?"
Jennifer Singh, a sociologist at Georgia Tech who wrote the book Multiple Autisms: Spectrums of Advocacy and Genomic Science, agrees. "I don't know that the knowledge gained from just having a gene that's linked to autism," is that beneficial, she says. "It gives some information, but to what degree does that change treatment or prognosis? Because at the end of the day you have to address the issues that are at hand, whatever they might be."
As more children are diagnosed with autism, knowledge of the underlying genetic mutation causing the condition could help families better understand the diagnosis and anticipate their child's developmental trajectory. However, for the vast majority, an additional label provides little clarity or consolation.
Instead of spending money on genetic screens, Singh thinks the resources would be better used on additional services for people who don't have access to behavioral, speech, or occupational therapy. "Things that are really going to matter for this child in their future," she says.
Your Beloved Pet Is Old. Should You Clone It?
Melvin was a special dog. A mixture of Catahoula and Doberman with black and tan markings, he was the office greeter, barking hellos to everyone who visited the Dupont Veterinary Clinic in Lafayette, Louisiana, which is owned by his human companions, Dr. Phillip Dupont and his wife, Paula. The couple say he's the best dog they ever owned.
When Melvin passed away, having two identical replicas helped ease the couple's grief.
He seemed to have an uncanny knack for understanding what they were saying, he could find lost car keys in tall grasses and the Duponts trusted him so much they felt comfortable having him babysit their grandson unattended in the backyard.
So when the 75-pound canine turned 9 and began to show signs of age, the Duponts sent off some of his skin cells to a lab in South Korea, the Sooam Biotech Research Foundation, to have him cloned. The Duponts toured the South Korean facilities and were satisfied that the animals were being treated well. While the first cloned puppy died from distemper, the second attempt produced two healthy animals—which the couple named Ken and Henry. When Melvin did pass away nearly two years later, in 2014, having two identical replicas helped ease the couple's grief. Even though it cost about $70,000 to clone Melvin, it was well worth it. "Melvin gave us a lot of pleasure," says Paula Dupont, "and this was less than the price of a new Land Cruiser."
As the technology improves, costs will tumble, making pet cloning more affordable for the mainstream.
The news has been filled recently with stories of celebrities such as Barbra Streisand or billionaire Barry Diller and his fashion icon wife, Diane von Furstenberg, spending big bucks to preserve their beloved pets—a practice New York magazine called "a laughable, extravagant waste of money." But cloning Fido isn't just for the ultra-wealthy anymore. Texas-based ViaGen now offers a domestic cloning service that will replicate Lassie for $50,000 and Garfield's kittens for a mere $25,000. While the exact number of cloned pets isn't known, the South Korean company says it has cloned about 800 pets while ViaGen has cloned about 100 cats and dogs. And as the technology improves, costs will tumble, making it more affordable for the mainstream, says Ron Gillespie, who heads PerPETuate, a Massachusetts-based outfit that collects and cryo preserves pet DNA, and works closely with ViaGen.
Even if the animals are genetic twins, biologists say, there are no guarantees their personalities will match, too.
While replicating Fido is becoming more feasible, should you? Animal rights organizations like The Humane Society and PETA are sharply critical of the practice, which is largely unregulated, and think it's outrageous to spend $50,000 or more to preserve Fluffy's genetic makeup when millions of cats and dogs are languishing in shelters and millions more are euthanized every year. And even if the animals are genetic twins, biologists say, there are no guarantees their personalities will match, too. Like humans, dogs' personalities are influenced by their environment and there are always variations in how the genes are expressed--although the Duponts say that Ken and Henry seem more like Melvin every day. "Their personalities are identical," says Paula.
Clones Ken and Henry, with Dr. Dupont and 10-year-old Melvin. Though all three dogs are genetic twins, their markings differ because the environment can influence how genes are expressed.
Still, the loss of a beloved pet can be incredibly painful, and in some cases, cloning can help deal with deep psychological wounds. When Monni Must's daughter died suddenly at age 28, the Michigan-based photographer adopted her child's black Lab, Billy Bean. As the dog got older and frailer, Must realized she couldn't handle losing her last link to her daughter—so she ponied up $50,000 to have the animal cloned. "I knew that I was falling apart," Must told Agence France-Presse. "The thought of Billy dying was just more than I could handle."
But these heated disputes miss what bioethicists believe is the real ethical dilemma—the fate of the female animals that provide the eggs and gestate the cloned puppies. "This issue tends to get framed as 'it's their personal choice, it's their money and they can do what they want with it,'" says Jessica Pierce, a bioethicist and author of Run, Spot, Run: The Ethics of Keeping Pets. "But this whole enterprise has all this collateral damage and behind-the-scenes impacts that people ignore. No one is talking about the dogs who are sacrificing themselves for this indulgence, and are suffering and being tormented just to have your clone."
"Even in the best-case scenarios, the cloned pet may go through several rounds of failed reproductive attempts—failed pregnancies, still births, and deformities."
Animal cloning, of course, is not new. Dolly, the sheep, made her debut in 1996 as the first cloned mammal. In 2005, Korea's Sooam Biotech cloned the first dog, and cloning horses and cows has become almost routine. Typically, the cloning process for dogs is fairly uncomplicated. It entails the use of a group of female dogs whose hormones are artificially manipulated with drugs to promote them to produce eggs. The eggs are then surgically harvested from donor dogs' ovaries. The immature eggs are stripped of their genetic information and then the pet's DNA is fused with the egg. When the embryo begins to develop, it is then transplanted to the womb of a surrogate dog.
However, cloning can have a high failure rate. When South Korea's Sooam Biotech lab cloned the first dog in 2005, there were 1000 failures—which means that number of eggs were fertilized and began to gestate, but at some point their development failed. And this figure doesn't include the number of dogs born with deformities serious enough that they are incompatible with life and need to be euthanized. "Even in the best-case scenarios, the cloned pet may go through several rounds of failed reproductive attempts—failed pregnancies, still births, and deformities," says Insoo Hyun, a bioethicist at Case Western Reserve University in Cleveland. "You can't do just one egg and one transfer. That won't happen. There is no guarantee that the very first time you will have a healthy animal. They're not miracle workers and you can't fight biology."
"You just have to let your pet go. It's all part of the experience."
But Ron Gillespie, who's been in the animal breeding business for decades, thinks these fears are overblown and that cloning is similar to the selective breeding that goes on all the time with cattle and even with champion racehorses. "We're really the victim of a lot of misinformation and misunderstanding," he says. "Right now, on average, we're dealing with three dogs: two that supply eggs and one to carry the embryo to term."
Still, this debate skirts the hard realities: dogs and cats simply have shorter lifespans than humans, and ethicists and animal rights activists believe there are better ways to deal with that grief. "You just have to let your pet go," says Hyun. "It's all part of the experience."
Genome Reading and Editing Tools for All
In 2006, the cover of Scientific American was "Know Your DNA" and the inside story was "Genomes for All." Today, we are closer to that goal than ever. Making it affordable for everyone to understand and change their DNA will fundamentally alter how we manage diseases, how we conduct clinical research, and even how we select a mate.
A frequent line of questions on the topic of making genome reading affordable is: Do we need to read the whole genome in order to accurately predict disease risk?
Since 2006, we have driven the cost of reading a human genome down from $3 billion to $600. To aid interpretation and research to produce new diagnostics and therapeutics, my research team at Harvard initiated the Personal Genome Project and later, Openhumans.org. This has demonstrated international informed consent for human genomes, and diverse environmental and trait data can be distributed freely. This is done with no strings attached in a manner analogous to Wikipedia. Cell lines from that project are similarly freely available for experiments on synthetic biology, gene therapy and human developmental biology. DNA from those cells have been chosen by the US National Institute of Standards and Technology and the Food and Drug Administration to be the key federal standards for the human genome.
A frequent line of questions on the topic of making genome reading affordable is: Do we need to read the whole genome in order to accurately predict disease risk? Can we just do most commonly varying parts of the genome, which constitute only a tiny fraction of a percent? Or just the most important parts encoding the proteins or 'exome,' which constitute about one percent of the genome? The commonly varying parts of the genome are poor predictors of serious genetic diseases and the exomes don't detect DNA rearrangements which often wipe out gene function when they occur in non-coding regions within genes. Since the cost of the exome is not one percent of the whole genome cost, but nearly identical ($600), missing an impactful category of mutants is really not worth it. So the answer is yes, we should read the whole genome to glean comprehensively meaningful information.
In parallel to the reading revolution, we have dropped the price of DNA synthesis by a similar million-fold and made genome editing tools close to free.
WRITING
In parallel to the reading revolution, we have dropped the price of DNA synthesis by a similar million-fold and made genome editing tools like CRISPR, TALE and MAGE close to free by distributing them through the non-profit Addgene.org. Gene therapies are already curing blindness in children and cancer in adults, and hopefully soon infectious diseases and hemoglobin diseases like sickle cell anemia. Nevertheless, gene therapies are (so far) the most expensive class of drugs in history (about $1 million dollars per dose).
This is in large part because the costs of proving safety and efficacy in a randomized clinical trial are high and that cost is spread out only over the people that benefit (aka the denominator). Striking growth is evident in such expensive hyper-personalized therapies ever since the "Orphan Drug Act of 1983." For the most common disease, aging (which kills 90 percent of people in wealthy regions of the world), the denominator is maximal and the cost of the drugs should be low as genetic interventions to combat aging become available in the next ten years. But what can we do about rarer diseases with cheap access to genome reading and editing tools? Try to prevent them in the first place.
A huge fraction of these births is preventable if unaffected carriers of such diseases do not mate.
ARITHMETIC
While the cost of reading has plummeted, the value of knowing your genome is higher than ever. About 5 percent of births result in extreme medical trauma over a person's lifetime due to rare genetic diseases. Even without gene therapy, these cost the family and society more than a million dollars in drugs, diagnostics and instruments, extra general care, loss of income for the affected individual and other family members, plus pain and anxiety of the "medical odyssey" often via dozens of mystified physicians. A huge fraction of these births is preventable if unaffected carriers of such diseases do not mate.
The non-profit genetic screening organization, Dor Yeshorim (established in 1983), has shown that this is feasible by testing for Tay–Sachs disease, Familial dysautonomia, Cystic fibrosis, Canavan disease, Glycogen storage disease (type 1), Fanconi anemia (type C), Bloom syndrome, Niemann–Pick disease, Mucolipidosis type IV. This is often done at the pre-marital, matchmaking phase, which can reduce the frequency of natural or induced abortions. Such matchmaking can be done in such a way that no one knows the carrier status of any individual in the system. In addition to those nine tests, many additional diseases can be picked up by whole genome sequencing. No person can know in advance that they are exempt from these risks.
Furthermore, concerns about rare "false positives" is far less at the stage of matchmaking than at the stage of prenatal testing, since the latter could involve termination of a healthy fetus, while the former just means that you restrict your dating to 90 percent of the population. In order to scale this up from 13 million Ashkenazim and Sephardim to billions in diverse cultures, we will likely see new computer security, encryption, blockchain and matchmaking tools.
Once the diseases are eradicated from our population, the interventions can be said to impact not only the current population, but all subsequent generations.
THE FUTURE
As reading and writing become exponentially more affordable and reliable, we can tackle equitable distribution, but there remain issues of education and security. Society, broadly (insurers, health care providers, governments) should be able to see a roughly 12-fold return on their investment of $1800 per person ($600 each for raw data, interpretation and incentivizing the participant) by saving $1 million per diseased child per 20 families. Everyone will have free access to their genome information and software to guide their choices in precision medicines, mates and participation in biomedical research studies.
In terms of writing and editing, if delivery efficiency and accuracy keep improving, then pill or aerosol formulations of gene therapies -- even non-prescription, veterinary or home-made versions -- are not inconceivable. Preventions tends to be more affordable and more humane than cures. If gene therapies provide prevention of diseases of aging, cancer and cognitive decline, they might be considered "enhancement," but not necessarily more remarkable than past preventative strategies, like vaccines against HPV-cancer, smallpox and polio. Whether we're overcoming an internal genetic flaw or an external infectious disease, the purpose is the same: to minimize human suffering. Once the diseases are eradicated from our population, the interventions can be said to impact not only the current population, but all subsequent generations. This reminds us that we need to listen carefully, educate each other and proactively imagine and deflect likely, and even unlikely, unintended consequences, including stigmatization of the last few unprotected individuals.