Tag Archives: genetic engineering

where gene therapy is heading

The “J.P. Morgan Healthcare Conference” provided some clues on where biotechnology may be going next.

After decades of setbacks, gene therapy—a loosely defined umbrella term for any technique that uses genes to treat or prevent disease—is finally here. In December, the field got its very first FDA approval with Luxturna, which corrects a defective gene in a rare, inherited retinal disease. With a half dozen more treatments in late-stage trials and an unusually open-minded FDA commissioner in Washington, the industry is expecting a flurry of new approvals this year…

Lambert’s lobbying roadmap for 2018 includes helping insurance companies understand what to do with a new gene therapy like Luxturna, which cures blindness with a single, $850,000 injection into the eye. Ranked by sticker price, it’s the most expensive medicine in America. Spark Therapeutics, the company that makes Luxturna, argues that the six-figure price tag isn’t actually that unreasonable, if you factor in all the costs that patients with the inherited retinal disease would have racked up in a lifetime of seeking better care.

But because their clinical trial patients haven’t been followed long enough to determine if the treatment benefits are actually durable for a whole lifetime, Spark has received significant pushback from insurers. As a result, the company is already exploring a some creative new pricing models. It announced last week that it’s offering a rebate program based on the treatment’s effectiveness at 30 to 90 days and again at 30 months with one East Coast provider, and is in talks about expanding it to other insurers, Spark CEO Jeffrey Marrazzo said at JPM. He said Spark is also in discussions with the Centers for Medicare and Medicaid Services on a multi-year installment plan option. Either of these could soon serve as a model for how gene therapies might be made available to patients without cutting the legs out from under the healthcare system.

The article also mentions one study that has some potentially bad news about the effectiveness of CRISPR in humans, but it sounds like the jury is still out on that.

more on gene circuits

This is pretty dense, but what it is talking about is the idea of programming genes like circuits.

Enzyme-free nucleic acid dynamical systems

Abstract chemical reaction networks have been proposed as a programming language for complex dynamics, along with their systematic implementation using short synthetic DNA molecules. We developed this technology for dynamical systems by identifying critical design principles and codifying them into a compiler automating the design process. Using this approach, we built an oscillator containing only DNA components, establishing that Watson-Crick base-pairing interactions alone suffice for complex chemical dynamics and that autonomous molecular systems can be designed via molecular programming languages.

Gene Editing 2.0

Before CRISPR even becomes a household word (er, acronym?), it is already being replaced by newer and more precise methods, according to Wired.

Usually, when we’ve referred to Crispr, we’ve really meant Crispr/Cas9—a riboprotein complex composed of a short strand of RNA and an efficient DNA-cutting enzyme. It did for biology and medicine what the Model T did for manufacturing and transportation; democratizing access to a revolutionary technology and disrupting the status quo in the process. Crispr has already been used to treat cancer in humans, and it could be in clinical trials to cure genetic diseases like sickle cell anemia and beta thalassemia as soon as next year...

But this year, newer, flashier gene editing tools began rolling off the production line, promising to outshine their first-generation cousin. So if you were just getting your head around Crispr, buckle up. Because gene-editing 2.0 is here.


cancer and immunotherapy

The Washington Post has an article about a new cancer treatment.

When a patient is treated under the Novartis process, T cells are extracted from a patient’s blood, frozen and sent to the company’s plant in Morris Plains, N.J. There, the cells are genetically modified to attack the cancer, expanded in number, refrozen and shipped back to the patient for infusion.

Once inside the body, the cells multiply exponentially and go hunting for the CD19 protein, which appears on a kind of white blood cell that can give rise to diseases, such as leukemia and lymphoma. The turnaround time for manufacturing the therapy, called “vein-to-vein” time, will be an estimated 22 days, Novartis officials told the committee Wednesday.

From the start of Wednesday’s meeting, committee members made clear that they were not concerned about the treatment’s efficacy, which has been well established — 83 percent of patients went into remission in the pivotal Novartis trial.


interspecies chimerism, or Dr. Moreau returns

I only understand a few words of this paper in Cell, like “human”, “pig”, “embryo”, and “implantation”, but they are enough to raise both my eyebrows. I’ll quote the last paragraph of the paper rather than the abstract because it contains a little less jargon. There are some understandable, or possibly hair-raising depending on your point of view, pictures in the paper too.

Interspecies Chimerism with Mammalian Pluripotent Stem Cells. Wu, Jun et al. Cell, Volume 168 , Issue 3 , 473 – 486

The procedures and observations reported here on the capability of human pluripotent stem cells to integrate and differentiate in a ungulate embryo, albeit at a low level and efficiency, when optimized, may constitute a first step towards realizing the potential of interspecies blastocyst complementation with hPSCs. In particular, they may provide a better understanding of human embryogenesis, facilitate the development and implementation of humanized animal drug test platforms, as well as offer new insights on the onset and progression of human diseases in an in vivo setting. Ultimately, these observations also raise the possibility of xeno-generating transplantable human tissues and organs towards addressing the worldwide shortage of organ donors.

Of course rich people are going to have copies of all their vital organs cloned in pigs as soon as this technology is available. And some mad dictator or Bond villain on an island somewhere is going to be breeding pig people. Now speaking of madmen on islands, there was a story about a certain Dr. Moreau…but it was only a story, right?

 “Monsters manufactured!” said I. “Then you mean to tell me—”

“Yes. These creatures you have seen are animals carven and wrought into new shapes. To that, to the study of the plasticity of living forms, my life has been devoted. I have studied for years, gaining in knowledge as I go. I see you look horrified, and yet I am telling you nothing new. It all lay in the surface of practical anatomy years ago, but no one had the temerity to touch it. It is not simply the outward form of an animal which I can change. The physiology, the chemical rhythm of the creature, may also be made to undergo an enduring modification,—of which vaccination and other methods of inoculation with living or dead matter are examples that will, no doubt, be familiar to you. A similar operation is the transfusion of blood,—with which subject, indeed, I began. These are all familiar cases. Less so, and probably far more extensive, were the operations of those mediaeval practitioners who made dwarfs and beggar-cripples, show-monsters,—some vestiges of whose art still remain in the preliminary manipulation of the young mountebank or contortionist. Victor Hugo gives an account of them in ‘L’Homme qui Rit.’—But perhaps my meaning grows plain now. You begin to see that it is a possible thing to transplant tissue from one part of an animal to another, or from one animal to another; to alter its chemical reactions and methods of growth; to modify the articulations of its limbs; and, indeed, to change it in its most intimate structure.

“And yet this extraordinary branch of knowledge has never been sought as an end, and systematically, by modern investigators until I took it up! Some of such things have been hit upon in the last resort of surgery; most of the kindred evidence that will recur to your mind has been demonstrated as it were by accident,—by tyrants, by criminals, by the breeders of horses and dogs, by all kinds of untrained clumsy-handed men working for their own immediate ends. I was the first man to take up this question armed with antiseptic surgery, and with a really scientific knowledge of the laws of growth. Yet one would imagine it must have been practised in secret before. Such creatures as the Siamese Twins—And in the vaults of the Inquisition. No doubt their chief aim was artistic torture, but some at least of the inquisitors must have had a touch of scientific curiosity.”

“But,” said I, “these things—these animals talk!”

He said that was so, and proceeded to point out that the possibility of vivisection does not stop at a mere physical metamorphosis. A pig may be educated. The mental structure is even less determinate than the bodily. In our growing science of hypnotism we find the promise of a possibility of superseding old inherent instincts by new suggestions, grafting upon or replacing the inherited fixed ideas. Very much indeed of what we call moral education, he said, is such an artificial modification and perversion of instinct; pugnacity is trained into courageous self-sacrifice, and suppressed sexuality into religious emotion. And the great difference between man and monkey is in the larynx, he continued,—in the incapacity to frame delicately different sound-symbols by which thought could be sustained. In this I failed to agree with him, but with a certain incivility he declined to notice my objection. He repeated that the thing was so, and continued his account of his work.

I asked him why he had taken the human form as a model. There seemed to me then, and there still seems to me now, a strange wickedness for that choice.

He confessed that he had chosen that form by chance. “I might just as well have worked to form sheep into llamas and llamas into sheep. I suppose there is something in the human form that appeals to the artistic turn more powerfully than any animal shape can.

NAS study on genetically modified crops

The National Academy of Sciences has released a massive study of genetically modified crops. This has been a tough issue to discern the facts because there has been a lot of corporate propaganda coming from one side, and a lot of emotion from well-meaning but not-all-that-scientific activists from the other side. I would consider the NAS to be pretty close to an impartial, science-based source, although you could argue that the academics involved probably do a lot of research funded by the agriculture industry. Still, it is a very large number of academics involved and is very thoroughly peer-reviewed, so I think you could regard this as the academic consensus.

First, on human health effects, they offer some reassuring news:

There have been claims that GE crops have had adverse effects on human health. Many reviews have indicated that foods from GE crops are as safe as foods from non-GE crops, but the committee reexamined the original studies of this subject. The design and analysis of many animal-feeding studies were not optimal, but the large number of experimental studies provided reasonable evidence that animals were not harmed by eating food derived from GE crops. Additionally, long-term data on livestock health before and after the introduction of GE crops showed no adverse effects associated with GE crops. The committee also examined epidemiological data on incidence of cancers and other human-health problems over time and found no substantiated evidence that foods from GE crops were less safe than foods from non-GE crops.

You could still argue, as the Europeans do, that the precautionary principle means new technologies must be treated as guilty until proven innocent. It is somewhat the opposite here in the big-business-friendly U.S. Still, there is no smoking gun here.

Nor is there a smoking gun on the ability of genetic engineering to deliver yield increases. Some are arguing that the smoking gun is evidence showing it has not really done this yet. That is somewhat disappointing, but with biotechnology continuing to accelerate I don’t think you can point to progress so far as evidence that no further progress will be made. That is like saying we have not cured cancer to date, so it is time to give up.

There is disagreement among researchers about how much GE traits can increase yields compared with conventional breeding. In addition to assessing detailed surveys and experiments comparing GE with non-GE crop yields, the committee examined changes over time in overall yield per hectare of maize, soybean, and cotton reported by the U.S. Department of Agriculture (USDA) before, during, and after the switch from conventional to GE varieties of these crops. No significant change in the rate at which crop yields increase could be discerned from the data. Although the sum of experimental evidence indicates that GE traits are contributing to actual yield increases, there is no evidence from USDA data that they have substantially increased the rate at which U.S. agriculture is increasing yields…

One of the critical questions about the new traits that may be produced with emerging genetic engineering technologies is the extent to which these traits will contribute to feeding the world in the future. Some crop traits, such as insect and disease resistance, are likely to be introduced into more crop species and the number of pests targeted will also likely increase. If deployed appropriately, those traits will almost certainly increase harvestable yields and decrease the probability of losing crop plantings to major insect or disease outbreaks. However, there is great uncertainty regarding whether traits developed with emerging genetic-engineering technologies will increase crop potential yield by improving photosynthesis and increasing nutrient use. Including such GE traits in policy planning as major contributors to feeding the world must be accompanied by strong caveats.

The don’t talk too much about one of my questions, the extent to which corporate profit-driven genetic engineering reduces genetic diversity, potentially making the global food system less resilient in the face of future shocks. They don’t seem concerned about the possibility of genetically engineered crops escaping and wreaking havoc in our remaining natural ecosystems.

I’ll reproduce one graphic I found interesting, distinguishing between the concepts of potential and actual yield. One point they seem to be making is that the focus of genetic engineering to date has been on reducing crop losses to weeds, pests, and diseases. This does not increase the plant’s ability to make full use of water, nutrients, and ultimately sunlight more efficiently than the naturally-derived crop has in the past. So this is why there is still the potential for a lot of progress, as well as the potential for risks to diversity, resilience, human health and ecosystems. This also reinforces my general sense that medical biotech is farther along than agricultural biotech.

National Academies of Sciences, Engineering, and Medicine. 2016. Genetically Engineered Crops: Experiences and Prospects. Washington, DC: The National Academies Press. doi: 10.17226/23395.

National Academies of Sciences, Engineering, and Medicine. 2016. Genetically
Engineered Crops: Experiences and Prospects. Washington, DC: The National Academies Press. doi:


This is the story of Theranos, a biotech startup that was supposed to have a revolutionary blood-testing technology but ultimately turned out to be a scam. It turned out the technology didn’t work. It probably didn’t start out as a scam. They probably thought they were close to getting it to work, sold investors and consumers on the idea, thought if they could hide the problems for awhile they could buy some time to make it work and get away with it. But, it never worked and they eventually couldn’t hide the problems.

The most interesting part of the story, to me, is whether the tech startup model will translate to the biotech sector. The article has a little bit to say about that:

Holmes had indeed mastered the Silicon Valley game. Revered venture capitalists, such as Tim Draper and Steve Jurvetson, invested in her; Marc Andreessen called her the next Steve Jobs. She was plastered on the covers of magazines, featured on TV shows, and offered keynote-speaker slots at tech conferences. (Holmes spoke at Vanity Fair’s 2015 New Establishment Summit less than two weeks before Carreyrou’s first story appeared in theJournal.) In some ways, the near-universal adoration of Holmes reflected her extraordinary comportment. In others, however, it reflected the Valley’s own narcissism. Finally, it seemed, there was a female innovator who was indeed able to personify the Valley’s vision of itself—someone who was endeavoring to make the world a better place…

Holmes subsequently raised $6 million in funding, the first of almost $700 million that would follow. Money often comes with strings attached in Silicon Valley, but even by its byzantine terms, Holmes’s were unusual. She took the money on the condition that she would not divulge to investors how her technology actually worked, and that she had final say and control over every aspect of her company. This surreptitiousness scared off some investors. When Google Ventures, which focuses more than 40 percent of its investments on medical technology, tried to perform due diligence on Theranos to weigh an investment, Theranos never responded. Eventually, Google Ventures sent a venture capitalist to a Theranos Walgreens Wellness Center to take the revolutionary pinprick blood test. As the V.C. sat in a chair and had several large vials of blood drawn from his arm, far more than a pinprick, it became apparent that something was amiss with Theranos’s promise…

Silicon Valley, once so taken by Holmes, has turned its back, too. Countless investors have been quick to point out that they did not invest in the company—that much of its money came from the relatively somnolent worlds of mutual funds, which often accrue the savings of pensioners and retirees; private equity; and smaller venture-capital operations on the East Coast. In the end, one of the only Valley V.C. shops that actually invested in Theranos was Draper Fisher Jurvetson. Many may have liked what Holmes represented about their industry, but they didn’t seem to trust her with their money.

I think we are on the cusp of some kind of biotech boom. The question is, what will it look like, who exactly will it benefit, and who will want it? The health care and agricultural sectors are the most obvious fields. In fact, I think it is already pervasive in those fields. We are starting to here about biotech methods of fighting mosquitoes, and I suspect we will pull out all the stops when diseases like dengue and Zika start to affect people in the rich world. Agricultural pests won’t be far behind. Maybe stingless, pesticide resistant bees to replace our lost pollinators. Food science may weigh in with yeast vats that produce food without photosynthesis and animal protein without animals, although consumers are going to be very wary of these products at first. Viruses targeting specific bacteria might be the answer to antibiotic resistance. We may see cures for diseases that have alluded us until now, and a steady uptick in total life span and healthy life span at least among the moderately affluent. New fertility treatments, ways to preserve egg and sperm cells for long periods of time or even across generations, organ and whole organism cloning, ways for same-sex couples to have biological children, children carried by surrogate mothers, etc.

But these technologies all seem like they will benefit a few big corporate players, not the kind of broad-based startup ecosystem we have seen with information technology. Maybe that is okay. The idea of dorm room and garage genetic engineering labs is a little scary after all. But if there was a kind of broad-based, consumer-focused biotech innovation ecosystem, what would it look like? Maybe novel pets and houseplants. Maybe novel bioelectrical devices like radios, batteries, chargers, night lights, phones, computers, watches and other things that glow in the dark. Maybe energy-related devices like solar cells, fuel cells, oil-producing algae and bacteria that produce methane, methanol or other useful organic products from garbage. Maybe new forms of water and wastewater treatment that can work at many scales. Maybe new forms of biodegradable packaging. Maybe building materials and machines that can grow and heal. New forms of manufacturing. Maybe somebody will figure out how to put DNA in a computer or a computer in DNA.

This all sounds like nutty stuff now, when we are just starting to yawn at the wonders of the infotech age that seemed nutty a decade or two ago. They are such a part of our lives now that we have already forgotten life without them, and we think we saw them coming all along. I think biotech is already here behind the scenes, much as infotech was in the 80s and early 90s, and at some point it is going to seem to burst into the public consciousness just as infotech did in the mid-90s with the advent of the internet. I just don’t know what the biotech equivalent of the internet is going to be.

RNA interference

Monsanto is trying to use genetic technology to kill honeybee pests.

RNA can also “silence” specific genes, preventing an organism from using them to make proteins. In 1998 scientists discovered that they could engineer stretches of double-stranded RNA to do the same thing. As a lab technique, RNA interference—or RNAi—turned out to be useful for learning about genes by turning them off. It also showed promise in fighting viruses, cancers, and even harmful pests and parasites. The researchers at the seminar were talking about using RNAi to prevent mosquitoes from spreading malaria, but that gave Hayes another idea. “I thought, could this be adapted to honeybee predator control?” In other words: to kill mites…

Traditional pesticides act like chemical backhoes, killing their targets (beetles, weeds, viruses) but harming good things along the way (beneficial insects, birds, fish, humans). RNAi, in theory, works instead like a set of tweezers, plucking its victims with exquisite specificity by clicking into sequences of genetic code unique to that organism. “If you could design an ideal pesticide, this is the stuff you’re looking for,” says Pamela Bachman, a toxicologist at Monsanto.


gene circuits

Here’s another article on the idea of designed biological circuits.

Synthetic mixed-signal computation in living cells

Living cells implement complex computations on the continuous environmental signals that they encounter. These computations involve both analogue- and digital-like processing of signals to give rise to complex developmental programs, context-dependent behaviours and homeostatic activities. In contrast to natural biological systems, synthetic biological systems have largely focused on either digital or analogue computation separately. Here we integrate analogue and digital computation to implement complex hybrid synthetic genetic programs in living cells. We present a framework for building comparator gene circuits to digitize analogue inputs based on different thresholds. We then demonstrate that comparators can be predictably composed together to build band-pass filters, ternary logic systems and multi-level analogue-to-digital converters. In addition, we interface these analogue-to-digital circuits with other digital gene circuits to enable concentration-dependent logic. We expect that this hybrid computational paradigm will enable new industrial, diagnostic and therapeutic applications with engineered cells.