Global Business Technology

INB 201

Dr. Lairson

Germline and Blockchain

Germline Gene Editing

"Human germline modification" means deliberately changing the genes passed on to children and future generations – in other words, creating genetically modified people. Human germline modification has for many years been widely considered off-limits, for both safety and social reasons. It is formally prohibited in more than 40 countries.

In recent years, a new generation of genetic engineering techniques, known as "gene editing" or "genome editing," has prompted speculation about their use in human embryos or gametes. In 2014, rumors intensified about researchers in the US and China working on human embryos with the inexpensive, easy-to-use gene-editing tool CRISPR. In April 2015, a research team at Sun Yat-sen University in China published a report of an experiment in which they used CRISPR to edit a gene associated with the blood disease beta- thalassemia in non-viable human embryos.

This controversy marks a new chapter of a profoundly consequential debate about the future of gene editing in humans. If perfected, somatic gene editing (or "gene therapy") holds promise for helping people who are sick, affecting only an individual consenting patient.

But editing the genes of human embryos in order to create genetically modified people is very different, and raises grave safety, social, and ethical concerns. These range from the prospect of irreversible harms to the health of future children and generations, to concerns about opening the door to new forms of social inequality, discrimination, and conflict.

What is CRISPR

The scientific story has deep roots. Scientists glimpsed the first hint of CRISPR biology in the 1980s and primitive forms of gene-editing arose in the 1990s. But a crucial leap occurred in 2012 when a group led by Jennifer Doudna of the University of California, Berkeley, and Emmanuelle Charpentier, now at the Max Planck Institute for Infection Biology in Berlin, demonstrated the possibility of simple CRISPR-based gene-editing to a broad audience of scientists with a paper in Science. The University of California and the University of Vienna filed for a patent, listing Doudna, Charpentier and other individuals. But the U.S. Patent and Trademark Office issued a patent in 2014 to Feng Zhang of the Broad Institute, which filed its application after Berkeley but requested expedited consideration. The University of California has challenged the validity of all the Broad patents (now numbering about a dozen) and the ensuing “interference” proceedings may allow another year of trash talking by scientists and bloggers alike. Meanwhile the protagonists—and their institutional proxies—continue to jockey for priority, prizes and reputation.

Within just three years since the discovery of its gene-editing potential, the new technique Crispr has become the hottest, and most controversial, development in genomics research. And now it’s more than just a science – it’s big business too.

First discovered in bacteria, Crispr (clustered regularly interspaced short palindromic repeats) is a genome-editing tool that can target specific genes in any organism based on RNA–DNA base pairing and then precisely cut the gene through the activities of the enzyme known as Crispr-associated protein 9 or Cas9. The technology can delete, repair or replace genes, and is faster, easier, cheaper and – in principle – more precise than other gene-editing techniques. With potential benefits across human health, agriculture and industrial biotechnology, it’s no surprise Crispr has entered the biological hall of fame.

But amid the surge in research and commercial opportunities, a patent battle over Crispr simmers in the background, which is casting a shadow over the technology’s future commercial potential. In 2012, Doudna and Charpentier filed a patent application after working together on Crispr, followed seven months later by a separate patent application by Zhang. Despite being second to submit, Zhang was awarded the patent based on his claimed invention date. Now Doudna and Charpentier’s team has been granted an ‘interference review of competing claims’ by the US Patent and Trademark Office to determine who invented the technology.

The biologists have done it again. Not so long ago it was cloning and embryonic stem cells that challenged moral imagination. These days all eyes are on a powerful new technique for engineering or “editing” DNA. Relatively easy to learn and to use, CRISPR has forced scientists, ethicists and policymakers to reconsider one of the few seeming red lines in experimental biology: the difference between genetically modifying an individual’s somatic cells and engineering the germline that will be transmitted to future generations. Instead of genetic engineering for one person why not eliminate that disease trait from all of her or his descendants?

This week, the U.S. National Academy of Sciences, the Chinese Academy of Sciences, and the U.K. Royal Society are trying to find ways to redraw that red line. And redraw it in a way that allows the technology to help and not to hurt humanity. Perhaps the hardest but most critical part of the ethical challenge: doing that in a way that doesn’t go down a dark path of “improvements” to the human race.

Facts (11/15)

1. Just one published study describes genome editing of human germ cells
In April, a group led by Junjiu Huang at Sun Yat-sen University in Guangzhou, China, described their use of the popularCRISPR–Cas9 technologytoedit the genomes of human embryos

2. The law on editing human germ cells varies wildly across the world
Germany strictly limits experimentation on human embryos, and violations can be a criminal offence. By contrast, in China, Japan, Ireland and India, only unenforceable guidelines restrict genome editing in human embryos.

3. You don’t have to be a pro to hack genomes
The CRISPR–Cas9 technology has made modifying DNA so cheap and easy thatamateur biologists working in converted garages or community laboratories are starting to dabble.

Ad for CRISPR:

http://www.genscript.com/

4. Cas9 is not the only enzyme in town
A key ingredient in the CRISPR–Cas9 system is the DNA-cutting enzyme Cas9. But in September, synthetic biologist Feng Zhang at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts,reported the discovery of a protein called Cpf1, which may make it even easier to edit genomes.

5. Pigs are on the front line of genome-editing experiments
Dogs, goats and monkeys areall part of the growing CRISPR zoo. But pigs in particular have been at the heart of several eye-catching announcements—frommicropigs that weigh about six times less than many farm pigs, to super-muscly pigs, to apig whose genome has been edited in 62 places(the aim being to produce a suitable non-human organ donor).

6. Gates, Google and DuPont want a piece of the genome-editing action
In August, several high-profile investors, including the Bill & Melinda Gates Foundation and Google Ventures, pumped US$120 million into the genome-editing firm Editas Medicine of Cambridge, Massachusetts. Big Agriculture is following suit: DuPont forged an alliance with the genome-editing firm Caribou Biosciences of Berkeley, California, in October, and announced its intention to use CRISPR–Cas9 technology to engineer crops.

The gene-editing technology called CRISPR is probablythe fastest-spreading technology in the history of biology.

Here’s one reason why: each weekday at 8 a.m. at the offices of AddGene in Cambridge, Massachusetts, interns start loading UPS packages containing the raw DNA material needed for gene-editing, sending it as far away as Zimbabwe and Croatia.

AddGene is a nonprofit that exists to help scientists share their DNA inventions. Think of it as an Amazon.com for biological parts. Anyone can submit one—or order someone else’s part for $65.

Easy access to gene-editing technology is what has allowed labs everywhere to get into the game. Last year, there were more than 1,300 scientific papers on CRISPR, and it’s been used to do everything from curing muscular dystrophy in mice to making super-muscled beagles.

And remember those Chinese scientists who set off an ethical firestorm by editing human embryos? They got their ingredients by mail order from AddGene, too.

AddGene was started in 2004 by a graduate student, Melina Fan, who got tired of trying to beg and barter for key materials she needed. Why not create a central repository to which everyone can contribute?

Here’s how it works: the language of DNA is a code, but it’s physical. It’s made up of strings of chemical bases labelled A, G, C, and T. To ship it, AddGene mails out vials of E. coli bacteria with the valuable bits of DNA spliced into mini-chromosomes, known as plasmids.

There are about 45,000 plasmids to choose from. Want to make a mouse’s brain cells react to light? That’s plasmid number 20298, deposited by Karl Deisseroth, the famed co-inventor of optogenetics at Stanford. Need to turn off every gene in a fruit fly, one by one? That’s number 64750.

The idea of synthetic biology—mixing and matching biological parts to make stuff —has led to a lot of heavy breathing in the media. “Biological Legos” we’re told, will turn life into mere “plug-and-play.” A well-known annual synthetic biology competition, iGEM, asks students to build things like flashing bacteria using defined DNA parts that come in a kit.

In reality, biology isn’t as tidy as an Ikea kit. Researchers say AddGene became biology’s de facto parts store by solving practical problems. “[It’s] for practicing scientists,” says Bruce Shay, a genetic engineer at Carnegie Mellon University, who submitted DNA this year so others can use a technique he created to make cells glow. “They love the chaos. They are about collecting disorder.”

What is Blockchain?

Napster and bitcoin – peer to peer

Distributed ledger technology

The blockchain is an even more potent technology. In essence it is a shared, trusted, public ledger that everyone can inspect, but which no single user controls. The participants in a blockchain system collectively keep the ledger up to date: it can be amended only according to strict rules and by general agreement. Bitcoin’s blockchain ledger prevents double-spending and keeps track of transactions continuously. It is what makes possible a currency without a central bank.

blockchain is a self-sustaining, peer-to-peer database technology for managing and recording transactions with no central bank or clearinghouse involvement. Because blockchain verification is handled through algorithms and consensus among multiple computers, the system is presumed immune to tampering, fraud, or political control. It is designed to protect against domination of the network by any single computer or group of computers. Participants are relatively anonymous, identified only by pseudonyms, and every transaction can be relied upon. Moreover, because every core transaction is processed just once, in one shared electronic ledger, blockchain reduces the redundancy and delays that exist in today’s banking system.

Blockchains are also the latest example of the unexpected fruits of cryptography. Mathematical scrambling is used to boil down an original piece of information into a code, known as a hash. Any attempt to tamper with any part of the blockchain is apparent immediately—because the new hash will not match the old ones. In this way a science that keeps information secret (vital for encrypting messages and online shopping and banking) is, paradoxically, also a tool for open dealing.

However blockchains have a host of other uses because they meet the need for a trustworthy record, something vital for transactions of every sort. Dozens of startups now hope to capitalise on the blockchain technology, either by doing clever things with the bitcoin blockchain or by creating new blockchains of their own.

tamper-proof public databases—land registries, say, (Honduras and Greece are interested);

or registers of the ownership of luxury goods or works of art.

Documents can be notarised by embedding information about them into a public blockchain—and you will no longer need a notary to vouch for them.

Financial-services firms are contemplating using blockchains as a record of who owns what instead of having a series of internal ledgers. A trusted private ledger removes the need for reconciling each transaction with a counterparty, it is fast and it minimises errors.

blockchain technology could become a game-changing force in any venue where trading occurs, where trust is at a premium, and where people need protection from identity theft — including the public sector (managing public records and elections), healthcare (keeping records anonymous but easily available), retail (handling large-ticket purchases such as auto leasing and real estate), and, of course, all forms of financial services. Indeed, some farsighted banks are already exploring how blockchain might transform their approaches to trading and settling, back-office operations, and investment and capital assets management.