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Category Archives: Human Genetic Engineering

EDITORIAL Focus on what’s important

Opinion: EDITORIAL Focus on what’s important

Be vocal about the big issues

February 7, 2012

Being an MIT student gives you a voice that few other people have. Like it or not, the MIT name makes you a representative of modern science and engineering. It’s no small secret that the world turns to MIT for its understanding of science, technology and related policy — just pick up the science section of the New York Times for proof. We’re not exaggerating, then, when we say that the pulse of MIT’s campus has a substantial effect on the world beyond the Institute.

If the world turned its eye towards MIT recently, it might be a little confused. The recent “big issues” at the undergraduate level have almost purely been ones of student life policy. But dining, residence exploration, orientation, and living group culture, while all important, are not what define MIT undergraduates. MIT, and its students, are part of a much bigger and much more complex world. They should play a part in the debates that define that world.

The Institute is a nexus of important research and education with vast ethical and policy implications. Right now, MIT researchers across several fields are trying to create a new energy future for this country, but some say their efforts are misguided or misdirected. Biologists and computer scientists are developing an increasingly clear picture of genetics, simultaneously opening doors for a future of human genetic engineering and modification. MIT nuclear engineers are continuing to push for a nuclear energy future, while the rest of the world is cutting back on that technology in the wake of Japan’s recent disaster. MIT’s Lincoln Laboratories develops weapons and tactical systems, funded by the Department of Defense. The Institute has forged educational and research partnerships with Russia, China, and the United Arab Emirates — all of which have ongoing political and human rights problems.

But there are important debates to be had even closer to home. As we’ve commented or reported on in these pages, MIT (and the rest of higher education) faces major social and political challenges. A March 2011 report on women faculty in the Schools of Science and Engineering noted marked improvements in the representation of women in science and engineering here at MIT, but also pointed out that misconceptions persist. In July, The Tech’s editorial board remarked on the state of LGBT students at the Institute — and it was clear to us that more work needs to be done to make MIT a welcoming and supportive place for people of all sexual orientations, especially when it comes to faculty-student relationships. And the list doesn’t stop there.

Our purpose here is not to pass a “right” or “wrong” judgment on any of MIT’s social, educational, or research activities. Whether it’s nuclear engineering, genetics research, educational partnerships, or weapons development, there’s room for reasonable debate.

We’re asking students to engage in those debates. Some of the questions we mentioned above will be the defining issues of our time. Do MIT undergraduates want to be stuck squabbling about dorm food or orientation guides while the world changes at a breakneck pace around them?

To be sure, undergraduates are not solely concerned with student life issues like dining or orientation. Many of us have had late-night discussions with our friends about science, politics, ethics, and philosophy. But we’ve noticed in cases of public discussion a near-exclusive preponderance of student life issues. Whether through mailing lists, postering, social websites, student government, letters to The Tech, or sit-ins, undergraduates seem to be most vocal about issues with fundamentally limited scope and relevance.

This hasn’t always been the case. In the 1950s through 80s, students were regularly driven to riot or protest in response to human rights issues, wars, or political repression. Be it the establishment of Fidel Castro’s brutal regime in Cuba or the presence of recruiters for military contractors on campus, students were energized and vocal about issues with great global and national relevance. Rioting, of course, is a bad way to make a point, and we don’t support a return to that tradition.

We want MIT undergraduates to engage in more public discourse about the issues that really matter. There’s a time and a place for dining and dormitory debates, but the real focus — the real energy — should be where MIT has the most influence. The best way to preserve true MIT culture is not by butting heads with the administrations about food, it’s by having debates about the science and technology that will change the world.

Students, faculty, and administration will likely disagree on such issues. But those are the disagreements that are worth having.

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EDITORIAL Focus on what’s important

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James A. Shapiro: Purposeful, Targeted Genetic Engineering in Immune System Evolution

Your life depends on purposeful, targeted changes to cellular DNA. Although conventional thinking says directed DNA changes are impossible, the truth is that you could not survive without them. Your immune system needs to engineer certain DNA sequences in just the right way to function properly.

Today's blog is a tale of how cells engineer their DNA molecules for a specific purpose. It also illustrates how an evolutionary process works within the human body.

Your immune system has to anticipate and inactivate unknown invaders. Living organisms deal with unpredictable events by evolving. They change to adapt to new circumstances. Variation comes from their capacity for self-modification. Cells have many molecular mechanisms that read, write, and reorganize the information in their genomes, the DNA molecules used for data storage.

The adaptive immune system executes basic evolutionary principles in real time. It has to recognize and combat unknown (and utterly unpredictable) invaders. Immune system cells have to produce antibody molecules that can bind to any possible molecular structure.

How do cells with finite DNA, and finite coding capacity, produce a virtually infinite variety of antibodies? The answer is that certain immune cells (B cells) become rapid evolution factories. They generate antibodies with effectively limitless diversity while preserving molecular structures needed to interact with other parts of the immune system.

Immune cells achieve both diversity and regularity in antibody structures. They accomplish this by a targeted yet flexible process of natural genetic engineering: they cut and splice DNA.

Diversity is strictly limited to a special part of the antibody molecules: a "variable" region encoded by engineered DNA. DNA encoding the "constant" region does not change in the same way. The diversity-generating process is called "VDJ recombination" because it involves cutting and splicing together different "variable" (V), "diversity" (D) and "joining" (J) coding segments. Immune cells do this by cutting DNA at defined "recombination signal sequences." There are hundreds of V segments, about a few dozen D segments, and ten J segments. The various combinations of different spliced segments makes for a tremendous amount of diversity.

Antibodies contain two paired protein chains: a longer heavy chain and a shorter light chain. The heavy chain variable coding region forms by splicing V, D, and J segments together. The light chain variable coding region forms by joining V and J segments together. There are at least 10,000 VDJ combinations and 1,000 VJ combinations. Altogether, over 10,000,000 different heavy + light chain antibodies are possible through "combinatorial diversity."

Not bad... but not good enough.

VDJ recombination generates additional diversity. Although cutting the V, D, and J segments is precise, immune cells join each pair of cleaved DNA segments at about a dozen different positions. Connection between the same two segments can have about 30 to 35 possible different sequence outcomes. This "junctional diversity" adds over 1,000 possible antibody combinations.

In addition, heavy chain D segment joining has another virtually unlimited source of variability. Immune cells have an enzyme that attaches unique new DNA sequences to either end of the D segment. These are not encoded anywhere in the genome. Such so-called "N region" sequences can add over 1,000 new variations to each existing VDJ combination.

So the total possible genetically engineered antibody diversity is something above 10,000,000 X 1,000 X 1,000 = 10,000,000,000,000 combinations. This extraordinary number appears to be large enough to generate antibodies that can protect you from virtually any invader, whatever its molecular structure may be.

The immune system is itself a rapid evolutionary process, replacing one set of immune specificities with another. The right antibody-producing cells multiply when an invader enters the body. Antibodies sit on the surface of cells that made them. When a particular variable region binds an invader, that event sends a signal inside the cell to begin dividing.

Dividing immune cells are called "activated B cells," which proliferate into distinct populations. Because the descendants of a single activated B cell share the same engineered variable region coding sequences, they produce even more invader-recognizing antibodies. By binding, these antibodies signal the rest of the immune system to begin eliminating the invaders. This is the front-line "primary" adaptive immune response.

In a future blog, I'll explain ongoing natural genetic engineering as activated immune cells mature in the "secondary" response. It is no less amazing. For now, let's draw three conclusions from the initial rapid evolution system. We see that:

Evolution has produced a system that engineers DNA with a specific purpose: encoding proteins that bind to unpredictable invaders and signal the immune system to make more antibodies and eliminate the invaders. Precise targeting of DNA cutting to variable region-coding segments allows the basic antibody structure to stay the same. At the same time, its recognition/binding capacity changes. Your B cells are able to combine several different kinds of DNA biochemistry into a functional engineering process: 1) cutting the V, D and J segments; 2) joining the cleaved segments; and 3) synthesizing and inserting the N region sequences.

In the immune system, "purposeful" and "having a predestined outcome" are far from the same thing. Your immune system follows a regular process, but the end result is not fixed in advance. This is an important lesson to keep in mind as we witness ongoing public debates over evolutionary DNA change.

In biology, the alternative to randomness is not necessarily strict determinism. If the cells of the immune system can use well-defined natural genetic engineering processes to make change when change is needed, there is a scientific basis for saying that germ-line cells might do the same in the course of evolution.

 

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James A. Shapiro: Purposeful, Targeted Genetic Engineering in Immune System Evolution

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Hepatitis Research May Benefit From Stem Cells

Editor's Choice
Main Category: Liver Disease / Hepatitis
Also Included In: Stem Cell Research
Article Date: 03 Feb 2012 - 11:00 PST

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Hepatitis C is a viral disease that leads to inflammation and organ failure. However, researchers are puzzled as to why some individuals are very susceptible to the disease, while others are not.

Researchers believe they could find out how genetic variations produce these different responses by investigating liver cells from different individuals in the lab. However, liver cells are hard to obtain and extremely challenging to grow in a lab dish as they often lose their normal function and structure when removed from the body.

Now, scientists from MIT, Rockefeller University and the Medical College of Wisconsin have found a technique to generate liver-like cells from induced pluripotent stem cells (iPSCs). iPSCs are created from body tissues instead of embryos; the liver-like cells that can be infected with hepatitis C. iPSCs could allow researchers to investigate why individuals respond differently to the disease. The study is published in the Proceedings of the National Academy of Sciences.

Although many research terms have tried to established an infection in cells obtained from iPSCs, this study is the first to have done so. In addition, the new technique could eventually facilitate "personalized medicine." Using tissues obtained from the patient being treated, doctors could test the effectiveness of various medications and customize a treatment for that individual patient.

This study is a joint effort between Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science at MIT; Charles Rice, a professor of virology at Rockefeller; and Stephen Duncan, a professor of human and molecular genetics at the Medical College of Wisconsin.

In 2011, Bhatia and Rice revealed that by growing liver cells on special micropatterned plates that direct their organization, they could influence the cells to grow outside the body. Although, these cells can be infected with hepatitis C, researchers cannot proactively research the role of genetic variation in viral responses, as the cells derive from organs donated for transplantation and represent only a small population.

Bhatia and Rice collaborated with Duncan, who had demonstrated that he could transform iPSCs into liver-like cells, in order to produce cells with more genetic variation.

Often, such iPSCs are taken from skin cells. Researchers can restore these cells to an immature state - the same as embryonic stem cells - which can differentiate into any cell type by switching on specific genes in those cells. The cells can then be directed, once they become pluripotent, to become liver-like cells by switching on genes that regulate liver development.

In this study, MIT postdoc Robert Schwartz and graduate student Kartik Trehan infected those liver-like cells with hepatitis C. They created the viruses to expel a light-producing protein each time they went through their life cycle in order to confirm that infection had taken place.

The primary goal for the team is to obtain cells from individuals who had unusual reactions to hepatitis C infection and transform them into liver cells in order to research their genetics to find out why they responded the way they did.

Bhatia explains:

"Hepatitis C virus causes an unusually robust infection in some people, while others are very good at clearing it. It's not yet known why those differences exist."

One possible reason may be genetic variations in the expression of immune molecules, such as interleukin-28, a protein that has been demonstrated to play a vital role in the response to hepatitis infection. Other potential factors include, cell's susceptibility to having viruses control their replication machinery and other cellular structures, as well as cell's expression of surface proteins that allow the virus to penetrate the cells.

Bhatia explains the liver-like cells generated in this investigation are similar to "late fetal" liver cells. The team is currently working on producing more mature liver cells.

The long-term goal for the team is personalized treatments for individuals with hepatitis. According to Bhatia one could imagine obtaining cells from an individual, making iPSCs, reprogramming them into liver cells and infecting them with the same strain of hepatitis that the individual has. This would allow doctors to test various medications on the cells to find out which ones are better at clearing the infection.

Written by Grace Rattue
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

Visit our liver disease / hepatitis section for the latest news on this subject.

Source: MIT

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Plant Physiologist Helen Stafford leaves Reed College Biology Dept. $1M [Tomorrow's Table]

Applause for Plant Physiologist Helen Stafford who left the Reed College Biology Department $1M. As a woman scientist in the 1950s, Stafford was ineligible for many jobs. Reed College, not deterred by her sex, offered her a position. She went on to establish a successful career and inspired many young scientists. Here is a short story of how she influenced my career.

The windowless room, dank an dark, was not an obvious place for inspiration. I took notes, wondering if I would be able to glean anything meaningful from Professor Helen Stafford's (1922-2011) meandering lecture. I was skeptical. After all, this was the same teacher who, annoyed with our choice of vegetarianism, had told us that "plants have feelings, too".

But what I learned that day, 33 years ago, would trigger a grand curiosity about the natural world and draw me into the greatest scientific puzzle of my career.

Helen informed us that human language is not the only way that species communicate. Plants form intimate associations with fungi and bacteria, which allow them to thrive in stressful environments. Establishment and maintenance of the relationship depends on the passing and receiving of coded information between partners. She also told us that plants can only defend themselves against microbes that they can sense.

This interspecies communication is not restricted to plants and microbes. The human intestine is home to diverse bacteria, allowing us to harvest nutrients that would otherwise be inaccessible. The human immunodeficiency virus chooses for its target only those of us that carry a specific receptor, decorated in a particular way.

All these interactions dramatically affect human health and farm productivity.

I was hooked.

To read the rest of the story on the Tree of Life blog, click here.

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Plant Physiologist Helen Stafford leaves Reed College Biology Dept. $1M [Tomorrow's Table]

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Cellectis Plant Sciences Announces the Signature of a Strategic Partnership with SESVanderHave in Sugar Beet

Regulatory News:

Cellectis (Paris:ALCLS) plant sciences, the plant genome engineering company and subsidiary of Cellectis (Alternext: ALCLS), announces today the signature of a research and commercial agreement with SESVanderHave, a world leader in the sugar beet seed industry, on the use of Cellectis technologies in sugar beet.

The agreement aims at developing commercial varieties for the sugar beet seed market using new breeding techniques and targeted genetic modifications. Cellectis plant sciences will provide SESVanderHave with custom-designed meganucleases for the Sugar Beet genome, to expedite the development of new targeted traits in sugar beet.

 

" We believe SESVanderHave is the ideal partner to bring innovative sugar beet products to the market to address the needs of the sugar industry and the sugar beet farmers. This partnership is a new step in the implementation of our technologies ? said Luc Mathis, CEO of Cellectis plant sciences.

" SESVanderHave is very enthusiast about the agreement ?, said SESVanderHave CEO Rob Van Tetering. " As the innovative leader in the sugar beet seed industry, SESVanderHave is continuously seeking for new opportunities to improve its sugar beets with the objective of supplying more competitive varieties to the farmers and the sugar industry in all markets. The agreement with Cellectis will help us in finding innovative solutions for the industry in the near future ?.

Financial terms of the agreement have not been disclosed.

About Cellectis plant sciences

Established in March 2010, Cellectis plant sciences is a subsidiary of Cellectis dedicated to the applications of meganucleases in plants. Its main mission is to increase and accelerate usage of Cellectis? proprietary technology in agricultural biology, broaden the company?s platform to attract new and expanded licensing opportunities and explore the development of proprietary traits for selected applications. Cellectis plant sciences is located in Saint Paul, Minnesota, USA. Professor Daniel Voytas, Chief Scientific Officer of Cellectis plant sciences, is also Director of the University of Minnesota Center for Genome Engineering.

About Cellectis

Cellectis improves life by applying its genome engineering expertise to a broad range of applications, including agriculture, bioresearch and human therapeutics. Cellectis is listed on the NYSE-Euronext Alternext market (code: ALCLS) in Paris.

For further information about Cellectis, visit our website at: http://www.cellectis.com

Follow Cellectis on twitter?: http://twitter.com/cellectis

About SESVanderHave

SESVanderHave is an international market leader in the sugar beet seed industry, specialized in every aspect of the research, breeding, production, processing and marketing of sugar beet seed. Worldwide, SESVanderHave sells sugar beet varieties resulting from the continuous research and breeding process with its proprietary germplasm. Each variety represents a customized solution to the needs of a specific sugar beet market. SESVanderHave pursues a proactive policy of investments in biotechnology, modern breeding technologies and improved seed technologies to improve the performance of the sugar beet crop.

Wherever sugar beets grow, SESVanderHave is present.

Disclaimer

This press release and the information contained herein do not constitute an offer to sell or subscribe, or a solicitation of an offer to buy or subscribe, for shares in Cellectis in any country. This press release contains forward-looking statements that relate to the Company?s objectives based on the current expectations and assumptions of the Company?s management only and involve risk and uncertainties that could cause the Company to fail to achieve the objectives expressed by the forward-looking statements.

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Cellectis Plant Sciences Announces the Signature of a Strategic Partnership with SESVanderHave in Sugar Beet

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Experts Weigh in on Bird Flu Research

By: David Pelcyger

Pigeons are seen eating on a street in Hong Kong on January 6, 2012. Photo by Aaron Tam/AFP/Getty Images.

Earlier this month, the scientists who altered the H5N1 virus to create a more contagious strain that's transmissible between ferrets, agreed to a temporary moratorium, due to safety concerns. The NewsHour reported the story here and here.

That decision has, if anything, intensified the debate. What began as a question on whether scientific journals should publish the complete research has grown into an argument on whether to conduct these studies, and others like them, at all.

The Newshour asked three experts to weigh in on the matter: Richard H. Ebright, a molecular biologist at Rutgers, Vincent Racaniello, a microbiologist at Columbia, and Carl Zimmer, a journalist who has authored ten books about science, specializing in biology and evolution.

Answers have been edited for length.

What were the goals of either the Wisconsin or Dutch bird flu studies?

Zimmer: We know that sooner or later, new kinds of diseases hit our species. You just have to look at history--the way SARS appeared out of nowhere in 2003, for example. HIV crossed over from chimps to humans in the early 1900s, but no one even knew about it until the 1980s. That head start allowed HIV to become one of the most horrific killers of the twentieth century.

The only way to prepare for new outbreaks is to study dangerous viruses in the lab--and, in some cases, even make them from scratch.

There's been a lively debate about just how big of a risk H5N1 poses to humanity. It normally passes from bird to bird. When it manages to infect humans, it seems to be quite deadly. Flu viruses are continually evolving, adapting to their hosts, and yet H5N1 has not managed to spill over into our species for years now. That might mean that there are too many obstacles in the evolutionary landscape for H5N1 to reach a form that would allow it to become a human-to-human pathogen. The studies in Wisconsin and the Netherlands were designed to address that question.

Racaniello: The goal was to determine if H5N1 aerosol transmission could be achieved in ferrets in the laboratory, and if so, what mutations accompany this process. Avian H5N1 viruses do not transmit among mammals, and therefore such experiments provide invaluable insight into this process.

Ferrets were used because they are a good model for influenza virus infection. When ferret-to-ferret transmission was achieved, the amino acid changes involved can provide information on the mechanisms that regulate airborne transmission of viruses, a topic that is poorly understood. Furthermore, it makes it possible to look for these mutations in H5N1 viruses circulating in the wild, to provide an early warning of the emergence of viruses that might transmit among humans. It is important to point out that ferrets are not humans, and the viruses selected in ferrets are not likely to transmit among humans.

What are your concerns about the research?

Ebright: The primary risks are accidental release through accidental infection of a lab worker who then infects others -- for which there are many precedents -- and deliberate release by a disturbed or disgruntled lab worker, for which the 2001 US anthrax mailings provide a precedent. Bioterrorism and biowarfare also are risks.

Zimmer: I am concerned about the ad hoc way in which scientists are figuring out how to do this research. The possibility that the Wisconsin and Dutch researchers would produce mammal-ready H5N1 flu was baked into their grant applications. Surely the debate about the potential danger should have been conducted back then, rather than now, when the scientists are ready to publish their results. If scientists have to worry that they won't be able to publish their work after years of research, fewer people will address the pressing issue of dangerous new viruses.

Is there a way to safely conduct this study, or studies with similar risks, and achieve the goals of the research? If yes, how? If no, does shutting down this type of research raise concerns about scientific freedom?

Ebright: Future work with lab-generated transmissible avian influenza viruses should be performed only at the highest biosafety level, only at the highest biosecurity standard, and only after approval by, and under the oversight of, a national or international review process that identifies risks and benefits, weighs risks and benefits, mitigates risks, and manages risks.

The same should be the case for all other research directed at increasing a potential pandemic pathogen's virulence, transmissibility, or ability to evade vaccines and treatments.

Racaniello: Shutting down H5N1 transmission research is an overreaction proposed by individuals who do not understand the science or the reasons for doing the experiments.

This work can be safely conducted under Biosafety level 3* containment. Scientists have been conducting dangerous experiments for years under these conditions, and there have been no disasters. On the contrary, the only two bioterror attacks in history originated in government laboratories.

The [National Science Advisory Board for Biosecurity**] is selecting the wrong set of experiments with which to flex their regulatory muscles. There is little chance that the ferret-passaged H5N1 virus will infect and transmit among humans.

This is not the first time scientists have disagreed about conducting research in specific areas. Human genetic engineering is another example. Why has this debate been so intense?

Racaniello: Most virologists agree that the experiments should proceed and are not exceptionally dangerous. The exceptions are those who don't understand the science, and the bioterror community. These individuals have proliferated since 9/11 and the anthrax attacks. They are paid large sums of money to sit in offices and decree what scientists can or cannot do. They are not practicing scientists and they don't appear to understand the underlying science.

Entire academic departments and corporations have been funded by the U.S. government to ponder potential dangers and tell scientists what to do. We now have a bioterror-industrial complex that rivals the military-industrial complex that Dwight Eisenhower warned us about. It is a scam, and I hope one day the nature and extent of the wasted money will be revealed to the public.

Ebright: Decisions not to perform specific proposed research projects, or to perform them only after modifications to mitigate risk, are routine. However, no such mandatory review process occurs for research projects that involve the enhancement of a pathogens's virulence, transmissibility, or ability to evade countermeasures--even though such projects potentially place at risk tens, hundreds, or millions of humans.

In 2004, a National Academy of Sciences panel called for a mandatory review process to be implemented for projects that involve the enhancement of a pathogens's virulence, transmissibility, or ability to evade countermeasures. Unfortunately, the panel's recommendations were rejected by the National Science Advisory Board for Biosecurity, the panel's recommendations were not implemented by National Institutes of Health extramural research programs, and projects creating new potential pandemic pathogens were funded and performed with absolutely no risk-benefit review. We are now reaping the harvest of these poor decisions.

*Under federal law, bird flu must be investigated within a "Biosafety Level 3" lab, on a scale of 4.

*The National Science Advisory Board for Biosecurity recommended that the journals Science and Nature withhold some details of the bird flu research from publication.

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Experts Weigh in on Bird Flu Research

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