From changing the way we eat to the way we think, CRISPR has the potential to change future generations - literally. ‘Designer babies’ is not the most, but probably the least that it can do.
What is CRISPR?
CRISPR stands for Clusters of Regularly Interspaced Short Palindromic Repeats. These are short stretches of nucleotide sequences crucial for the immune systems of bacteria and archaea.
It’s being touted as a cheap, efficient tool for gene editing.
CRISPR: Biology in Action
In the case of bacteria, when primarily a virus body (aka bacteriophage) attacks a bacterium, it injects its genetic material which consists of single-stranded RNA (ssRNA) into the cell. The viral genome then takes over or hijacks the bacterial machinery to make numerous copies of itself.
The CRISPR region has numerous repeats of CRISPRs, where bacteria incorporate small nucleotide sequences specific to the virus invading them known as ‘spacers.’ So the CRISPRs have these spacers between them and each viral invasion adds a spacer into the region.
The spacers are specific small sequences of the viral RNA that the bacteria keep as memories, just in case the same virus attacks again. So when the virus attacks again, the spacers are used as templates to make a CRISPR-RNA or crRNA that has complementarity to the specific sequence on the viral RNA. The crRNA goes and binds to the foreign viral RNA, and the Cas9 (CRISPR-associated) protein cleaves in a particular position, leaving the viral genome ineffective to make its copies or do anything at all.
The Cas9 protein typically binds to two RNA molecules: crRNA and another called trans-activating crRNA or tracrRNA. These two RNA molecules guide Cas9 to the target site to make its final cut. This target sequence is complementary to a 20-nucleotide long stretch of the crRNA.
It has been researched and found that the protein makes a double-stranded break, i.e. it cuts both strands of a DNA’s double helix. Now, if you’re wondering why the Cas9 doesn’t attract the bacteria’s own DNA, it is because there is another mechanism to ensure this. Short DNA sequences called protospacer adjacent motifs or PAMs, are sort of tags that sit adjacent to the target DNA sequence. And if PAM is not present, it doesn’t make a cut. This is possibly why the protein doesn’t ever attack the CRISPR region in the bacteria.
CRISPR for Human Research
Now that we’ve understood the natural phenomenon and imagined it in action, what exactly is the purpose of it? Gene editing isn’t anything new but, at the same time, isn't old enough for us to be sure of what we’re doing. It takes years and years of research to publish one result.
In fact, the first time we got to see what CRISPR looks like in action was only two years ago in 2017! A team of researchers led by Mikihiro Shibata of Kanazawa University and Hiroshi Nishimasu of the University of Tokyo made this possible. Here’s the Breathtaking New GIF Shows CRISPR Chewing Up DNA.
Genetic modification isn’t too new as we’ve been cultivating crops by selective breeding practices, to increase the quality of produce, for centuries. But the production of the first genetically modified food to be granted a license for human consumption only goes back to 1992. Researchers genetically modified tomatoes to remain firm and ripe for their short-shelf life and named them Flavr Savr. They didn’t selectively breed the tomatoes, but modified the genes specific to the ripening and firmness of tomatoes and reproduced them.
When we refer to gene-modification or editing, we mean doing so by removing a particular nucleotide (or more) from the sequence, substituting it with another, or adding a new nucleotide to the sequence.
Any changes in the gene sequence - called mutations - affect the proteins to be synthesized by them, which are responsible for the characters and features of the organism. For example, sickle-cell anemia is caused due to a point mutation, which is a change in one nucleotide of a gene sequence. As a result of the mutation, the red blood cells become sickle-shaped, and a lot of problems like general body pain, a reduced ability to fight infections, and vision issues arise. DNA profiling at the embryonic stage can tell if a baby could be born with a genetic disorder. This can then be genetically modified to reverse the mutation, and have the baby be born with no abnormality. (A side-fact: sickle-cell anemia provides a genetic resistance to malaria.)
A classic example of treating a genetic disorder by gene modification is Adenosine Deaminase or ADA Deficiency. Children born with ADA deficiency have virtually no immunity to microorganisms and are diagnosed with severe combined immunodeficiency (SCID). (These babies are kept inside bubbles free of any microorganisms to keep them alive, and are therefore called bubble babies.) Most of these babies don’t survive past the age of 2. The deficiency can be treated by enzyme replacement therapy or ERT in which they are given (through injections) the adenosine deaminase enzyme for the development and functioning of the immune system. But the problem with ERT is that the enzyme has to be introduced into the body time and again. Because of the nature of the disorder, it becomes a potential candidate for gene therapy.
Gene therapy is the mechanism of introducing a gene in the body of an organism. Reproductive T-cells from ADA sufferers are taken out of the body, and modified to carry the corrected gene which can produce ADA. These are injected back into the body, which can then reproduce to make normal immune cells.
But what is the drawback? Gene therapy wasn’t so effective before CRISPR, given that anything could go wrong at any step. Incorporating the change at the right position is crucial for the gene’s function, but is also very challenging. Other gene-editing tools also come with many challenges and are time-consuming and expensive too. CRISPR on the other hand, is cheaper, more efficient and much more flexible and is consequently gaining a lot of traction.
Two 2012 research papers were pivotal in the study of using CRISPR. Published in journals Science and PNAS, the papers helped transform the bacterial defence mechanism into an efficient, programmable gene-editing tool.
Thanks to the studies, we know that Cas9 can be directed to cut any region of DNA. We can simply change the crRNA nucleotide sequence to bind to the complementary DNA target. Martin Jinek and his colleagues simplified the system further by fusing crRNA and tracrRNA, to create a single ‘guide-RNA’. And so the genome editing with CRISPR only requires the two components, guide-RNA and Cas9.
Moreover, designing a stretch of 20 nucleotide base pairs (hydrogen-bonded nucleotide pairs that form the two strands of a double-stranded DNA) matching a gene we want to edit, is achievable. The RNA with these 20 base pairs that are only found in the target gene and ‘nowhere else in the genome’ is vital.
With CRISPR cuts at very specific positions can be made. It doesn’t care about the sequence of the crRNA. We can make our own crRNA complementary to the gene we want to make changes to. Our cells have their own machinery and mechanisms to be able to join back the cut ends. The cell may join them back as it is, which may introduce mutations. However we can also give our own sequences having ends acting as templates to join the cut blunt ends and thus ‘repair’ the cut - and voila, the gene has successfully been edited, theoretically speaking.
Gene Editing Before CRISPR
Zinc Finger Nucleases and Transcription Activator-Like Effector Nucleases (TALENs) dominated the scene before CRISPR was heralded as the gene-editing tool. These tools can each cut DNA like CRISPR, but making and using them is difficult. However, they have their own applications and advantages:
ZFNs have an easier delivery process to the target gene. TALENs seem to have a higher precision rate than CRISPR but may cause less off-target mutations or unintended consequences. Research using these tools is still going on.
Biotech company Cellectis uses TALEN gene-editing technology to make CAR-T therapies for leukemia, and Sangamo BioSciences makes ZFNs that can disable a gene known to be key in the HIV infections.
Cas9 Challenges and Its Alternative: Cpf1
CRISPR-Cpf1 has several advantages over the CRISPR-Cas9 technique, with significant implications for research and therapeutics.
Cpf1 is similar to Cas9 in function, i.e. it cuts the target DNA.
Applications of CRISPR
CRISPR can very well be used in producing crops and animals that are healthier and environmentally resilient, for example BT crops.
Experiments on mice that share more than 90% of human genes have shown that CRISPR can knock-off a defective gene associated with Duchenne Muscular Dystrophy (DMD), eliminate the HIV infection and inhibit the formation of deadly proteins involved in Huntington’s disease.
Chinese scientists in 2015 created two ‘super muscular’ beagles by disabling a gene that directs normal muscle development.
Other CRISPR animal studies have ranged from genetically modifying long-haired goats for higher production of cashmere, and breeding hornless cows to eliminate the pain of shearing horns off.
Human research mostly moves the slowest due to ethical and regulatory issues. And will continue to remain slow due to the permanent nature of altering the human genome.
Pharmaceuticals and Biotechnology
This is probably where the most important ends meet, the future of medicine can be rewritten with CRISPR. The current drug discovery process is too long, given the need to ensure patient safety and gain a thorough understanding of side effects. One drug can take more than a decade to make its way to shelves, and then most likely eventually be banned because of side effects and complications. CRISPR can bring more customized therapy to the market more quickly, speeding up the traditional drug discovery process.
CRISPR allows accurate and fast identification of potential gene targets for efficient pre-clinical testing. And since it can knock-off particular genes, CRISPR gives researchers a faster and more affordable way to study more genes, in order to know which ones are affected by a disease. It can also provide more ways to treat patients and to design more efficient antibiotics.
CRISPR is also a more efficient method of gene therapy to treat single-gene disorders such as ADA deficiency, beta-thalassemia and sickle-cell anemia.
CRISPR can also be used to successfully combat the growing problem of antibiotic-resistance, in which bacterial strains become resistant to existing antibiotics, rendering the infection untreatable.
Food & Agriculture
In the 2000s, when the ins and outs of CRISPR were still unclear, scientists at yogurt company Danisco used an early version of CRISPR, to combat a key bacterium found in milk and yogurt cultures that kept getting infected by viruses.
Now, when climate change hinders the production of food and agriculture, CRISPR will be needed in cultivation processes. For example, cacao is becoming increasingly more difficult to grow as farming regions are becoming hotter and drier. Environmental changes will also accompany the growth of new pathogens and microorganisms that are non-existent today.
Gene editing can make farming more efficient, and curb global food shortages for crops like potatoes and tomatoes. Crops can also be made resilient and resistant to droughts and pathogens.
Another interesting area is the production of learner livestock. In October 2017, researchers at the Chinese Academy of Sciences in Beijing used CRISPR to genetically engineer pig meat to have 24% less body fat.
CRISPR can be used to re-engineer microbes and create new materials. We can alter microbes to increase diversity, make more efficient biofuels and create new bio-based, environmentally friendly materials.
Limitations of CRISPR and Why It’s Being Held Back
CRISPR’s potential benefits don’t end here, the list isn’t even fully defined yet; however they don’t come without their limitations. Regulatory bodies are holding CRISPR back, and slowing down research because we still don’t understand the long-term consequence of editing genes and genomes.
When CRISPR is used for human gene therapies, safety will be the biggest concern. It is a brand new tool, and may have a wide range of side effects that we may have no knowledge of. The main concern here is the off-target activity. While, theoretically, a single-gene edit reverses a mutation that causes a disease, it can also cause an unintended activity elsewhere in the genome. Similar to side effects that happen with drugs we take for medicinal purposes. A plausible consequence is also an abnormal growth of tissue leading to cancer.
Another issue is that a mosaic generation can be formed. CRISPR can lead to a person having both edited and unedited cells - a mosaic, which can give them mixed characteristics such as having two complexions.
Moreover, immune system complications can also arise, which means that interventions and therapies may trigger an undesired response from a patient’s immune system.
Gene editing can also lead to biological activities due to a lack of precision, as with Cas9 protein that leaves blunt ends. While this can be combated by using Cpf1 instead of Cas9, other limitations may still remain.
Bringing Back The Extinct
A fantastic idea to make real-life museums - edit the genome of the embryo of the closest living relative of the extinct animal and bring them back to life. These initiatives are already being pursued by different scientific groups and organizations. But should we bring back what’s already gone? We don’t know what effects this may have on the human population and other species as we are gradually evolving to live without extinct organisms.
Pregnant couples can be told by their doctor whether their child has the possibility of having a genetic disorder, for example Down Syndrome, which is very common. Whether the couple decides to abort the child or not is their personal choice. An estimated 92 percent of women who undergo prenatal diagnosis of Down Syndrome choose to have an abortion. Is there a way you can save the baby from having the syndrome? Yes. Gene editing. And CRISPR allows a much easier and cheaper way of doing so. This can be done for multiple genetic disorders that affect humankind.
If you’ve read or heard about the Chinese scientists editing genes of an embryo, you would also have heard about the global outcry they have received for doing so. These scientists had wanted to make the baby resistant to HIV, smallpox and cholera. However in the scientific community, the use of CRISPR or any other gene-editing tool to edit human babies is considered highly unethical, and is not even legal. This is because when genetic modification is done to a germ (reproductive) cell, the change is permanent, and will follow in generations to come unless it’s modified again, but the state of natural normalcy will never be achieved.
You may want to ensure that your baby is resistant to a disease that they could get through the use of genetic modification. Others may want to ensure that their child has a specific eye color, or height and so on. It is from this concept that the term designer babies originates. There is growing concern that there will be no end to what people may choose to genetically modify in their children, and what this may mean for the future. To choose to bring a change in your baby would mean that you’re deciding the fate of a human being that hasn’t even been born yet.
CRISPR is a breakthrough technology which will ultimately change the world, who we are, how we live and possibly even bring extinct species back to life. It will change our eating habits as well the food that we eat. It will help us optimize modern medicines so we can fight infections, diseases and genetic disorders more efficiently. CRISPR allows us to edit genes and work with biology in a way which was never before possible.
Quadratic Voting is a method of collective decision-making in which a participant votes not just for or against an issue, but also expresses how strongly they feel about it. It can help protect the interests of small groups of voters that care deeply about particular issues. Quadratic Voting can be used in democratic institutions, in corporate governance, and blockchain-enabled collective decision-making.
In Quadratic Voting, each participant is given a number of credits that can be used to vote for an issue. However, the cost of casting more than one vote for an issue is quadratic, not linear. So, the marginal cost of each additional vote is far higher than of the previous vote.
Here is the Quadratic Voting formula: Cost to the voter = (Number of votes) to the power of 2.
Imagine that a vote generally costs $1 to put toward an issue, and you have $100 of voting credits. You want to cast your vote toward protecting endangered species. Casting one vote will cost you $1. However, casting two votes for the same issue will cost you $4, casting three votes for the same issue will cost you $9 and casting 10 votes for the same issue will cost you your entire $100 of credits.
So, while you are increasing the chances of victory for your issue with each additional vote, the quadratic nature of the voting ensures that only those who care deeply about issues will cast additional votes for them.
Use in Colorado
After Democrats won Colorado’s Governorship and both of the state’s houses in 2018, they used Quadratic Voting to decide which appropriations bills to fund first. Since legislators were likely to sponsor their own bills and vote for them, the Democratic caucus sought a method to gauge which bills had everyone’s support.
Initially, the Colorado Democrats assigned 15 tokens for each legislator to use on their preferred 15 bills. After this didn’t work well, they talked to Microsoft economist Glen Weyl, who explained how Quadratic Voting could provide a solution.
Weyl saw Quadratic Voting as a solution to the ‘tyranny of the majority’ issue. Regular voting assumes that everyone cares for an issue equally, which is rarely the case. The reality is that some legislators do not care about certain issues, care moderately about others and care deeply about a few.
So, instead, each legislator was given 100 tokens. If a legislator cast one vote each for several issues, it would cost them one token each. However, a legislator could cast more than one vote for an issue, at the following cost in tokens:
Colorado’s experiment with Quadratic Voting was largely successful.
How is quadratic voting different from traditional voting systems?
First-Past-the-Post: In the first-past-the-post system used in most democracies, a candidate can win without getting the votes of a majority of people. Let’s say Candidate A gets 35% of votes, B, 30%, C, 24%, and D, 11%. A wins, but we know that a majority of people voted for someone other than A.
Proportional Voting: To address this, some jurisdictions have adopted proportional voting systems. Here, if 35% of the electorate votes for a given party, then 35% of seats in the legislature given to that party, and so on. Though these systems can be seen as an ‘evolved’ version of the first-past-the-post system, they do not work when a binary (yes or no) decision has to be made.
Ranked Choice Voting: In Ranked Choice Voting (which is used by several jurisdictions in California), each voter ranks their favorite candidates. The candidate with the lowest number of votes is eliminated in each round, and that candidate’s votes are redistributed to the candidates next in each vote’s preference order ahead of the next round. Though Ranked Choice Voting has its strengths, it is a complex and time-consuming system.
Quadratic Voting: Though Quadratic Voting is also complex, it arguably better protects the interests of small groups of voters that care deeply about particular issues. By increasing the cost of each additional vote, it disincentivizes voters that don’t care about issues from casting several votes for them. It also allows voters to show the intensity of their support for a given issue by casting several votes for it – at the expense of their ability to vote on other issues.
Modern democracies have generally used one person, one vote in their elections and legislative processes. Corporations have often adopted more sophisticated voting mechanisms (for example, allowing a shareholder to designate someone else to vote on their behalf). Complicated but arguably more democratic voting systems, such as Proportional Voting and Ranked Choice Voting, have not found widespread acceptance due to their complexity.
Now that blockchain-enabled collective decision making allows votes to be tracked in a transparent, public way, more complicated voting systems can be adopted. By allowing voters to express not just their preferences but also the intensity of these preferences, Quadratic Voting protects the interests of small groups of voters that care deeply about certain issues.
The Internet of Things (IoT) is a network of physical objects, including vehicles, medical devices and home appliances, that use sensors and APIs to connect to one another and exchange data over the internet.
Cheap processors, sensors and wireless networks have made it possible to turn anything from a pill to a plane into an internet-connected ‘thing’ that is more useful to its customer. For example, the Orenda coffee maker
can monitor when you wake up and heat coffee accordingly.
Such ‘smart’ devices communicate directly with one another without human intermediaries (engaging in Machine to Machine communication, or M2M). This digital intelligence attempts to merge the digital and the physical.
The term ‘IoT device’ generally refers to objects that previously were not expected to connect to the internet. So, computers, tablets and smartphones are not considered IoT devices.
Connectivity Enables IoT
IoT is rapidly becoming a reality, as manufacturing companies adopt private 5G networks and major phone carriers roll out 5G wireless coverage.
Tiny sensors in IoT devices send data to one another and to the cloud using wireless internet networks (Wi-Fi or 5G) and can increasingly compute and store data locally (edge computing). The principle behind an IoT-enabled smart home full of devices engaging in M2M communication can be extended to smart campuses and smart cities.
7 Major IoT Applications
1 Smart Homes
Smart homes are the first major consumer application of IoT. For example, Google’s Nest Hub can control cameras, doorbells and thermostats around the house. AlertMe, Haier, Philips and Belkin are also market leaders in this space. The global smart home market is already valued at over $80 billion and this figure is expected to rise to $150 billion by 2024.
2 Smart Agriculture
IoT-enabled smart agriculture seeks to use sensors to track light, humidity, temperature, soil moisture and other relevant characteristics to better manage agricultural systems remotely. Such smart farming is significantly more efficient than conventional farming, since it optimizes agricultural inputs (including through irrigation) and outputs (including through targeted harvesting).
3 Livestock Monitoring
Farm use of IoT devices also extends to better monitoring of the location, health and size of livestock. It can also help prevent the spread of disease by enabling the quick identification of sick animals, so they can be removed from the group.
4 Connected Cars and Remote Fleet Management
Automated vehicles require a complex network of sensors, software and connections to navigate roads. Eventually, connected cars will use Vehicle-to-Vehicle (V2V) communication to enhance safety and ease congestion. Though driverless cars are a reality, we will likely not see a fully interconnected system of exclusively driverless cars using V2V communications for at least a decade.
IoT is also enabling remote fleet management. For example, a trucking company can remotely view each truck’s speed, acceleration, location, route, fuel, load weight, performance and driver attention.
5 Smart Cities
Smart cities use IoT sensors to measure and optimize water use, energy use, waste management, traffic, air quality and other important city processes. We are only part of the way through a strong urbanization trend. The United Nations expects 68% of the world’s population to live in urban areas by 2050. Smart cities will help mitigate the resulting strain on infrastructure and resources.
6 Health Care and Fitness
By enabling more granular measurements of health indicators, remote monitoring and more timely data analysis, IoT devices can save lives and improve health. Their applications will also benefit physicians, hospitals and insurers, for example by providing more comprehensive health information, reducing health care costs and improving treatment outcomes.
The Apple Watch and other IoT-connected wearables (from LookSee, Myo, Fitbit, Sony, Samsung and others) help track and improve fitness. Soon, we will see smart clothes with embedded IoT sensors.
In manufacturing, IoT processes can improve the productivity of each worker, by automating routine tasks, providing workers with better data, allowing remote monitoring of processes, optimizing supply chains and improving operational efficiency. The automobile industry has already achieved great productivity and efficiency gains through IoT-enabled manufacturing. A potential downside of improved productivity is that fewer workers may be needed.
Security, Privacy and Compliance Concerns
As IoT technology improves, it faces three major challenges. First, interconnectedness may increase vulnerability to bad actors, including in sensitive areas like health and traffic. Second, there are valid concerns that smart homes and smart cities are highly surveilled environments, harming everyone’s privacy. Third, IoT systems will have to comply with a complex patchwork of privacy, security and consumer protection laws that may vary by country, state and city.
The Future of IoT
Globally, there has been significant public and private investment in improving wireless internet speed and reducing latency. Therefore, despite challenges, the IoT applications described above are becoming a reality.
In San Francisco, a new Target store in California sells only IoT devices. In Minneapolis, McKinsey is opening a retail store as a ‘stage’ for technology solutions. Interestingly, the rise of IoT is creating a new emphasis on physical ‘things’ and blurring the line between products and services.