Gene therapy is all the rage among researchers in several fields of medicine, and the BBC America sci-fi TV hit Orphan Black has made sure to get its own piece of the action.
As with reproductive cloning and other biotech issues hashed out over the last four years, characters in the “The Black” are making references to gene therapy with a twist that’s far-fetched, but grounded in state-of-the-art science and real-life emerging possibilities.
With the season 4 finale set to air tonight, Orphan Black fans know what’s going on with those little maggot-shaped bioelectronic cheek implants. At least for some characters, the implants are gene therapy delivery devices. The idea of an implant for gene therapy delivery is a problem scientists in the real world are working to solve, and while there’s no medical reason for using the cheek as the site of implantation, there is a location nearby the cheek where the first real-life gene therapy implants are likely to go: the ear.
Deploying Carrier Vectors
Most basic and clinical research in gene therapy uses DNA that is packaged inside carrier particles known as vectors. A vector can be a virus, a liposome (a spherical container similar to the HDL and LDL carriers that transport your “good” and “bad” cholesterol, respectively, in blood), or a variety of structures made of different chemical polymers.
Vectors have tradeoffs that differ depending on the genetic payload and the type of cells targeted. For instance, a type of viral vector called a retrovirus is good for modifying dividing cells, but not useful for diseases where non-dividing cells need to be changed.
With gene therapy today, the most commonly used vector is called the adeno-associated virus (AAV). There are various subtypes of AAV, and each subtype determines which body tissues and organs will receive the treatment. Compared with other viruses, AAV tends not to stimulate the immune system easily, particularly if the treatment is administered just once.
One more advantage of AAV is that it delivers its genetic payload into target cells as an episome – a piece of DNA that utilizes the cell’s machinery to make the needed gene product, but does not insert itself into a chromosome. This minimizes the risk of disrupting other genes, which could kill the cell or transform it into a cancer cell.
AAV can only carry a small genetic payload, however.
By injecting AAV carrying the AADC gene, a relatively small package, into a part of the brain called the putamen, neurosurgeons can restore long-term functions in Parkinson patients. It’s working, because the AADC gene just barely fits inside the AAV.
Things are different with the much larger gene that’s broken in people with Duchenne muscular dystrophy (DMD). In the latter case, advances are on the horizon because of a technology called CRISPR-Cas9, a gene editing system that does fit inside AAV, allowing for correction of the faulty gene that DMD patient’s have. But the research is still in its early stages.
Other gene therapy delivery systems rely as much on physics as they do on chemistry.
A device called a gene gun shoots tiny gold or tungsten spheres coated with the needed DNA into cells. Once inside, the genetic material detaches from the spheres.
Electroporation, using electricity to punch temporary holes in cell membranes to help naked DNA make its way into the cell, is another physical gene therapy tactic. Researchers are also studying ultrasound, hydrodynamic and magnetic methods of delivery.
DNA carries an electromagnetic charge — a negative charge, due to chemical entities called phosphate groups. This enables the molecule to be directed in an electromagnetic field, which in turn opens the possibility of merging genetic and electronic components. That’s a biophysical reality that underlies the maggot-like implants of Orphan Black, but it’s also a gene therapy implant that is emerging in the real world.
You may know someone with a cochlear implant, or you may have one yourself, and so you know that they facilitate the transference of sound waves in the air into nerve signals. But researchers have demonstrated in guinea pigs that a cochlear implant also can be used for electro-injection of DNA molecules into the nerve cells that carry impulses from the cochlea (the hearing component of the inner ear) to the brain.
These nerve cells comprise the cochlear branch of the vestibulocochlear nerve, but their degeneration leads to nerve deafness. Treating the cells with genes that make proteins called neurotrophins regenerates the nerve, so the next step is to develop similar implants for humans.
Testing of such implants has not yet begun on humans, but it may happen within a few years, certainly before you begin seeing Orphan Black style implants sending genetic payload through the body from the cheek.
The turn of the 21st century was an exciting time in the history of genetics.
The first sequencing of the human genome was completed in 2003 and it provided numerous insights to the scientific community and society in general. In 2000, during his final State of the Union Address, President Bill Clinton made a point of how all humans share 99.9 percent of our genome — it’s actually more like 99.7 percent.
By honing in on the genetic variants, or mutations, that exist for certain genes in the human population, medical geneticists achieved a capability that would have looked like science fiction to physicians of the 1970s. Deciphering the genetics that underlay our existence has so far led to measurable success in gene therapy for certain conditions, but scientists are realizing that genes do not have the final say in what happens to a cell and its owner. Read More
Elizabeth (Liz) Parrish is the CEO of BioViva, a biotechnology company that focuses on developing gene therapies, and other regenerative therapies, to intervene with human aging.
Last September, Parrish added an interesting line to her job description: patient zero for two anti-aging therapies that the company is researching.
Parrish is receiving two kinds of injections, which are administered outside the United States: a myostatin inhibitor, which is expected to prevent age-associated muscle loss; and a telomerase gene therapy, which is expected to lengthen telomeres, segments of DNA at the ends of chromosomes whose shortening is associated with aging and degenerative disease.
The study will likely continue for many years. But last week, BioViva issued a press release describing an unexpected early result, offering a clue as to what the BioViva team might publish in the weeks or months to come.
It will be unclear exactly what the BioViva researchers have found until the results do go through the rigorous process of scientific peer-review, but the un-reviewed BioViva report is raising some eyebrows. Telomeres of T-lymphocytes in blood samples taken from Parrish in September were 6.71 kilobases. That’s shorter than normal for Parrish’s age, but lymphocytes from the samples taken in March after six months of gene therapy measured 7.33 kb, according to BioViva.
The company equates the reported 620-base increase to reversing the clock on Parrish’s chromosomes by twenty years. But there are numerous caveats noted by experts in genetics and laboratory medicine that were recently published by the non-profit group Genetics Expert News Service.
For one thing, telomeres are being tested only in her T-lymphocytes, as opposed to all tissue types of her body, so even if the test result were evidence for de-aging of T-lymphocytes it doesn’t necessarily prove her entire body de-aged.
“Long-lived T cells have shorter telomere lengths than newly generated naïve cells; and cells which have reached their maximum limit of cell divisions have shorter telomeres than any other cell type,” says Rita Effros, a professor of pathology and laboratory medicine at UCLA. “Thus, a simple change in the proportion of different cell types within the peripheral blood could easily explain the data.”
Furthermore, notes Dr. Bradley Johnson, Associate Professor of Pathology and Lab Medicine at the University of Pennsylvania, “Telomere length measurements typically have low precision, with variation in measurements of around 10 percent, which is in the range of the reported telomere lengthening apparently experienced by Elizabeth Parrish.”
These criticisms notwithstanding, Parrish serving as patient zero for a brand new treatment is a milestone in medicine, one that harkens back to the medical pioneers who regularly injected themselves with various new drugs over a century ago. Before BioViva’s news broke, Discover’s Dr. David Warmflash interviewed Parrish about the therapies and her feelings about being the first test subject.
Discover: What would you say makes BioViva stand out from other biotech or gene therapy companies? Is it that you’re using yourself as a test subject?
Liz Parrish: Yes, and number two is treating biological aging as a disease. Actually, that is probably number one. We’re going at the root cause of what makes most of the population sick. And then second, of course, we’re 100 percent behind the product.
We’re using them. We are not just a research company. BioViva is about saving lives, and lessons from history suggest that the use of multiple experimental therapies at once may be the shortest route to saving lives. When AIDS research first began, we saw the use of many drugs which, when used in isolation, helped with one mechanism of the disease, but patients still died from another mechanism of the same disease. It was only when doctors combined those drugs into cocktails we saw the first real advances in combating AIDS.
Do you feel any connection, or do you see yourself as carrying on a tradition of the those early medical researchers from the late 19th and early 20th century who tested different drugs on themselves?
LP: Yes, I guess so in retrospect. We didn’t do it in the spirit of that. We did it because it had to be done, because we needed a test patient on the gene therapy, but I think it is in that spirit and I wish more people had that spirit. The U.S. is 5 percent of the world population. We take 75 percent of all prescription drugs and yet have the shortest lifespan of every industrialized country, so I wish more people would get behind their drugs and other therapies. I think it would prove that what they have is something that you would want to take.
OK, so let’s talk about the therapies that you’re taking. Is there any concern the telomerase gene therapy could led to malignancy, to cancer, in any tissue?
LP: Telomerase has never been hypothesized to be the sole cause of cancer. Not all cancers have telomerase upregulated in them. Cancer cells can develop daily in your body from a very young age. But isn’t a youthful immune system is what keeps full-blown cancer at bay?
The confusion of longevity research with cancer research is a recurring misconception and implies correlations that have not been proven. There are two lines of research into telomerase: longevity and cancer. The two never intersect.
In longevity research we do not find ourselves looking at increases in cancerous cells from telomerase induction, but rather a protection against cancer.
In previous interviews with other people, you’ve alluded to the tragic story of Jesse Gelsinger, the 18-year-old boy who died in an early gene therapy clinical trial at the University of Pennsylvania in the 1990s.
Ethically, of course there’s a difference between Gelsinger and you; I’ve heard you say that this is worth risking your life for. But on top of the tragedy of Gelsinger losing his life, didn’t it also set the whole field of gene therapy back several years?
From that perspective, in the unlikely event that something goes terribly wrong in the experiment on you, do you worry what might happen to gene therapy research? Have you considered this a possible rationale for slowing down, maybe taking a more conservative approach?
LP: Gene therapy has come a long way since the 1999 tragedy of Jesse Gelsinger.
The relevant research did not stop [after the event], only the applications, and even then only temporarily. But the big game-changer now is that we have better delivery methods.
Hundreds of people are partaking in gene therapies today and none have the issues we saw 16 years ago in Jesse Gelsinger. We also need to put this in perspective: almost 100,000 people already die of adverse drug reactions (ADEs) every year in the USA alone, while nobody has ever died from this latest generation of gene therapies.
That being said, we at BioViva are very careful to ensure the safest possible outcome while still testing every limit. I would not have taken a gene therapy that would have likely killed the patient and nor would anybody at BioViva. I simply stated that all data are equally important, and that to that end I would accept any outcome, up to and including my own death, in order to move the science forward.
We as a company, and I as a person did take a risk, but a risk we believe will change the world for the better and kick-start an industry with the best approach to curing disease and increasing healthy lifespan.
What do you think about the idea that, the potential of the studies on you notwithstanding, you’re just one datum, so what will we really know?
LP: Yes, absolutely. That’s true, but N=1 from one human is worth 10,000 mice, but of course every human’s body is different and people are going to respond differently.
And of course the FDA since the 1970s has passed almost 50 drugs through the system to the market that it pulled later, despite going through gold standard testing. So that’s why we have to start now and see what happens. No matter what safety and efficacy you have, if you can have N=10,000, you’re probably going to have some adverse effects down the road.
Whether it’s directly related to the gene therapy or to something else in the patient’s life, it may take years to determine, so it’s very important to start now with gene therapy. Currently, over 100,000 people die of aging related diseases, so at what point do we realize that life is risky and that taking a chance may be our best bet?
Which tissues are they using to monitor your telomere length, given that telomeres vary between tissues? Generally, in telomere studies, lymphocytes are used, because they’re easy to access, but what factors went into deciding which tissues to use in you both for monitoring and targeting the therapy.
LP: We are using lymphocyte testing at this time, as it is the most advanced and well understood way to test telomere length today.
I also understand that to carry the therapeutic gene through your blood and into your cells, BioViva is using what’s called an AAV vector, which has the advantage of delivering the genetic payload so that it ends up as an episome (free floating gene), rather than being integrated into a chromosome.
Is this a safety measure, to minimize the risk of mutagenesis and oncogenic transformation? Is there any possible negative to that, such as decreased duration of the effects?
LP: We are not necessarily trying to integrate the gene, as studies have not proven the benefit of doing so.
We are trying to create an episome in the nucleus, which will code for the target protein. Integration is still an important discussion because past delivery methods, which we avoid due to them creating integrational mutagenesis (integrating into the chromosome in random areas that caused the cell to become unstable).
We want to separate our method from that older method. Our delivery method does not cause integrational mutagenesis, and when it does integrate, it does so into a safe harbor site on chromosome 19 where cancer is not an outcome.
Are there concerns among your team that treatment for slowing or reversing aging of healthy tissues could also prevent elimination of malignant or premalignant cells?
LP: Cancer cells can appear in people of any age, but the proliferation of cancer cells owes more to a decrease in immune system capability than an increase in telomerase activity. Not all cancers involve telomerase production, and a peer-reviewed paper in 2012 showed that old mice saw no increase in cancer with telomerase induction.
Telomerase induction may actually be our first line of defense against cancer, because a youthful immune system regularly rids the body of cancerous cells. The mechanism of telomerase could restore cells epigenetically to a youthful state exhibiting fewer aging gene biomarkers. An example would be turning off the genes that turn on as we age such as P53, a tumor-associated gene.
If you were to develop a common type of cancer, how would we know if it’s from the gene therapy, or because you would have gotten it anyway?
LP: If I was to be diagnosed with cancer, we could have that cancer sequenced to see if it had an extra copy of the target gene [from the gene therapy].
So, you’re getting telomerase gene therapy as well as a myostatin inhibitor. Was there any discussion about the merits of giving you two experimental therapies at the same time? Imagine it’s the year 2096, you’re 120 plus, looking and feeling exactly as you do today and you have the blood chemistry of a 25 year-old. How would we know which therapy did it?
LP: Such an amazing outcome, if it happened, would necessarily be due to both those two therapies or more.
We believe that these two types of therapy are synergistic, and will benefit each other in ways that will maximize outcome. One gene therapy is hypothesized to create better signaling with stem cells. The other creates stem cells that can potentially divide indefinitely, as stem cell depletion is a risk for older people.
These benefits, combined with the protection against frailty or sarcopenia (loss of muscle tissue) with a myostatin inhibitor, and the more youthful epigenetics of a cell with telomerase induction, makes this combined therapy very powerful.
The Columbia River basin, stretching from Idaho down through Washington and Oregon, is dotted with more than 200 hatcheries in which salmon and steelhead trout are raised before being released to supplement wild populations.
Those wild fish have struggled on their own, due to fishing, dams that block migration routes and other human-related pressures. Hatcheries can help stabilize populations, allowing fishing operations to continue, but only if they produce fish whose offspring can thrive in the wild.
Michael Blouin, a biology professor at Oregon State University, has long known that fish raised in the concrete troughs of a hatchery are different than wild fish. Blouin and his fellow researchers discovered this back in 2011. Their 19-year examination of steelhead trout — an anadromous fish in the same genus as Pacific salmon — found that steelhead raised in captivity were adapting to the evolutionary pressures of the hatcheries within a single generation. The steelhead that best adapted to hatcheries did worst, in terms of reproductive success, once they were released into the wild. Read More
The Nicoya peninsula in northwestern Costa Rica is one of the most beautiful places on the planet. This 75-mile sliver of land, just south of the Nicaraguan border, is covered with cattle pastures and tropical rain forests that stretch down to the crashing waves of the Pacific Ocean. The coastline is dotted with enclaves of expats who fill their time surfing, learning yoga and meditating on the beach.
For the locals, life is not so idyllic. They live in small, rural villages with limited access to basics such as electricity, linked by rough tracks that are dusty in the dry season and often impassable when it rains. The men earn a living by fishing and farming, or work as laborers or sabaneros (cowboys on huge cattle ranches), while the women cook on wood-burning stoves. Yet Nicoyans have a surprising claim to fame that is attracting the attention of scientists from around the world.
Their secret was uncovered in 2005 by Luis Rosero-Bixby, a demographer at the University of Costa Rica in San José. He used electoral records to work out how long Costa Ricans were living, and found that their life expectancy is surprisingly high. In general, people live longest in the world’s richest countries, where they have the most comfortable lives, the best health care and the lowest risk of infection. But that wasn’t the case here. Read More
It might not just be expectant mothers who have to pay attention to their lifestyle. Now a new study published in Science could be relevant to a growing body of research looking at ways in which the lifestyle and environment of men before they become fathers could influence the lives of their children and grandchildren.
We know that many human traits, such as weight, height, susceptibility to disease, longevity or intelligence, can be partly inherited, but researchers have so far struggled to identify the precise genetic basis for this. This may partly be due to limitations in our understanding of how genetics works, but now there is growing interest in the potential for something called “epigenetics” to explain this heritability. Read More
Human genetic engineering is not new; it has been going on for a long, long time — naturally. Ancient viruses are really good at inserting themselves and modifying human gene code. Over millennia, constant infections would come to mean that 8 percent of the entire human genome is made up of inserted virus code. All this gene recoding of our bodies occurred under Darwin’s rules, natural selection and random mutation. But nonrandom, deliberate human genetic engineering is new, and it is a big deal.
As of 1990, increasingly genetically modified humans walk among us. More and more gene therapies carry new instructions into our bodies and place them in the right spots; in so doing, they modify our most fundamental selves, our core, heretofore slow-evolving DNA. We are still in the very early stages of effectively hijacking viruses for human-driven purposes; just a few years ago it took a long time to identify and isolate a single faulty gene and figure out what was wrong, never mind finding a way to replace it with a properly functioning alternative. Early gene therapy focused on obscure, deadly orphan diseases like ADA-SCID (the immune disease that “Bubble Boy” had), adrenoleukodystrophy (say that five times fast), Wiskott-Aldrich syndrome, various leukemias, and hemophilia.
In theory the technique is relatively simple: Take a neutered virus, one that is engineered to not harm you but that readily infects human cells to ferry in new DNA instructions, write a new set of genetic instructions into the virus, and let it loose to infect a patient’s cells. And ta‑da! You have a genetically modified human. (Think of this as deliberately sneezing on someone but instead of giving them a cold, you give them a benign infection that enters their body, recodes their cells, and fixes a faulty gene.)
Mixed breed. Mongrel. Roadside setter. A something-something. Dogs of uncertain provenance get called a lot of things. When the animal arrives at a shelter, staff usually can make only an educated guess about the dog’s parentage.
Most of the dogs at my local animal control are assessed as “pit mixes” upon arrival — including the three I’ve adopted over the past 2 years. But a pit bull isn’t a breed: it’s just a type of dog characterized by a short coat, muscular frame and broad, oversized head.
All three of my dogs clearly — at least to my eyes — showed signs of specific breeds somewhere in their heritage: Tall and snow white Pullo looks like the breed standard for an American Bulldog. Tyche’s body is svelte like a boxer’s and inky black like some Labs. And lanky, long-limbed Waldo sometimes bays like a hound, especially when treeing squirrels.
Guessing my dogs’ breeds was a fun parlor game, but I wanted more definitive answers. So I turned to science. And, well, let’s just say it’s a good thing I didn’t place any bets on what was in my dogs’ family trees.
A version of this article originally appeared at The Conversation.
There could be a way of predicting – and preventing – which children will go on to have low intelligence, according to the findings of a study researchers at Cardiff University presented on Monday. They discovered that children with two copies of a common gene (Thr92Ala), together with low levels of thyroid hormone are four times more likely to have a low IQ. This combination occurs in about 4% of the UK population.
Importantly, if you had just one of these factors, but not both, there did not appear to be an increased risk of low intelligence. These are early results, but suggest that it might be possible to treat children early with thyroid hormone supplementation to enhance their intelligence. This raises many ethical issues.
A common objection is that being smarter does not make your life better. In this study, researchers were concerned with those with an IQ between 70-85. Below 70 is classified as intellectual disability but an IQ of 70 to 75 is similar to mild intellectual disability.
Even for individuals with an IQ between 75 and 90 there are still significant disadvantages. Job opportunities tend to be the least desirable and least financially rewarding, requiring significant oversight. More than half the people with this IQ level fail to reach the minimum recruitment standards for the US military. Individuals with this lower level of intelligence are at significant risk of living in poverty (16%), being a chronic welfare dependent (17%) and dropping out of school (35%) compared to individuals with average intelligence. Studies show that they also face an increased risk of incarceration and being murdered.
Linda Gottfredson, who’s undertaken much of this research, concludes that at the very least, “an IQ of 75 is perhaps the most important threshold in modern life”. So it is clear that those of low-normal intelligence, although not classified as disabled, are significantly disadvantaged.
If we could enhance their intelligence, say with thyroid hormone supplementation, we should.
By Eliza Strickland
What can you learn from getting your genome sequenced? If you’re a relatively healthy person like me, the answer is, not much… at least not yet.
I embarked on a mission to get myself sequenced for my recent article “The Gene Machine and Me.” The article focused on the sequencing technology that will soon enable a full scan of a human genome for $1000, and to make the story come alive, I decided to go through the process myself. I got my DNA run through the hottest new sequencing machine, the Ion Proton, and had it analyzed by some of the top experts on genome sequencing, a team at Houston’s Baylor College of Medicine.
The Baylor team has been intimately involved in many of the most important advances of genome sequencing over the last decade. And their accomplishments reveal both the astoundingly rapid progress of the technology, and how far we have yet to go. Here’s a synopsis: the story of five genomes.