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  • Chinese scientists lead the world in editing genomes of human embryos in order to develop new therapies for intractable diseases
  • US and UK regulators have given permission to edit the genes of human embryos
  • CRISPR-Cas9 has become the most common gene editing platform, which acts like is a pair of molecular scissors
  • CRISPR technology has the potential to revolutionize medicine, but critics say it could create a two-tiered society with elite citizens, and an underclass and have called for a worldwide moratorium on gene editing
  • Roger Kornberg, professor of medicine at Stanford University and 2006 Nobel Prize winner for Chemistry explains the science, which underpins gene-editing technology
  
Gene editing positioned to revolutionise medicine
 
It is a world first for China.
 
In 2015, a group of Chinese scientists edited the genomes of human embryos in an attempt to modify the gene responsible for β-thalassemia, a potentially fatal blood disorder. Researchers, led by Junjiu Huang from Sun Yat-sen University in Guangzhou, published their findings in the journal Protein & Cell.
 
In April 2016, another team of Chinese scientists reported a second experiment, which used the same gene editing procedure to alter a gene associated with resistance to the HIV virus. The research, led by Yong Fan, from Guangzhou Medical University, was published in the Journal of Assisted Reproduction and Genetics. At least two other groups in China are pursuing gene-editing research in human embryos, and thousands of scientists throughout the world are increasingly using a gene-editing technique called CRISPR-Cas9.
 
 

CRISPR-Cas9

Almost all cells in any living organism contain DNA, a type of molecule, which is passed on from one generation to the next. The genome is the entire sequence of DNA or an organism. Gene editing is the deliberate alteration of a selected DNA sequence in a living cell. CRISPR-Cas9 is a cheap and powerful technology that makes it possible to precisely “cut and paste” DNA, and has become the most common tool to create genetically modified organisms. Using CRISPR-Cas9, scientists can target specific sections of DNA, delete them, and if necessary, insert new genetic sequences. In its most basic form, CRISPR-Cas9 consists of a small piece of RNA, a genetic molecule closely related to DNA, and an enzyme protein called Cas9. The CRISPR component is the programmable molecular machinery that aligns the gene-editing tool at exactly the correct position on the DNA molecule. Then Cas9, a bacterial enzyme, cuts through the strands of DNA like a pair of molecular scissors. Gene editing differs from gene therapy, which is the introduction of normal genes into cells in place of missing or defective ones in order to correct genetic disorders.
 
Ground-breaking discovery 

The ground-breaking discovery of how CRISPR-Cas9 could be used in genome editing was first described by Jennifer Doudna, Professor of Chemistry and Cell Biology at the University of California, Berkeley, and Emmanuelle Charpentier, a geneticist and microbiologist, now at the Max Plank Institute for Infections in Berlin, and published in the journal Science in 2012.

In 2011 Feng Zhang, a bioengineer at the Broad Institute, MIT and Harvard, learned about CRISPR and began to work adapting CRISPR for use in human cells. His findings were published in 2013, and demonstrated how CRISPR-Cas9 can be used to edit the human genome in living cells.  

Subsequently, there has been a battle, which is on-going, between the scientists and their respective institution over the actual discovery of CRISPR’s use in human embryos, and who is entitled to the technology’s patents.
 
Gene editing research gathers pace worldwide: a few western examples

In 2016 a US federal biosafety and ethics panel licensed scientists at the University of Pennsylvania’s new Parker Institute of Cancer Immunotherapy to undertake the first human study to endow T-cells with the ability to attack specific cancers. Patients in the study will become the first people in the world to be treated with T-cells that have been genetically modified.

T-cells are designed to fight disease, but puzzlingly they are almost useless at fighting cancer. Carl June, the Parker Institute’s director and his team of researchers, will alter three genes in the T-cells of 18 cancer patients, essentially transforming the cells into super fighters. The patients will then be re-infused with the cancer-fighting T-cells to see if they will seek and destroy cancerous tumors.

Also in 2016, the UK’s Human Fertilisation and Embryology Authority (HFEA), which regulates fertility clinics and research, granted permission to a team of scientists led by Kathy Niakan at the Francis Crick Institute in London to edit the genes of human IVF embryos in order to investigate the causes of miscarriage. Out of every 100 fertilized eggs, fewer than 50 reach the early blastocyst stage, 25 implant into the womb, and only 13 develop beyond three months.
 
Frederick Lander, a development biologist at the Karolinska Institute Stockholm, is also using gene editing in an endeavour to discover new ways to treat infertility and prevent miscarriages. Lander is the first researcher to modify the DNA of healthy human embryos in order to learn more about how the genes regulate early embryonic development. Lander, like other scientists using gene-editing techniques on human embryos, is meticulous in not allowing them to result in a live birth. Lander only studies the modified embryos for the first seven days of their growth, and he never lets them develop past 14 days. “The potential benefits could be enormous”, he says.
 
Gene editing cures in a single treatment

Doctors at IVF clinics can already test embryos for genetic diseases, and pick the healthiest ones to implant into women. An advantage of gene editing is that potentially it could be used to correct genetic faults in embryos instead of picking those that happen to be healthy. This is why the two Chinese research papers represent a significant turning point. The gene editing technology they used has the potential to revolutionize the whole fight against devastating diseases, and to do many other things besides. The main benefit of gene editing therapy is that it provides potential cures for intractable diseases with a single treatment, rather than multiple treatments with possible side-effects.
 

The promise of gene editing for fatal and debilitating diseases
 
Among other things, gene editing holds out promise for people with fatal or debilitating inherited diseases. There are over 4,000 known inherited single gene conditions, affecting about 1% of births worldwide. These include the following:- cystic fibrosis, which each year affects about 70,000 people worldwide, 30,000 in the US, and about 10,000 in the UK; Tay-Sachs disease, which results in spasticity and death in childhood. The BRCA1 and BRCA2 inherited genes predispose women with a significantly greater chance of developing breast or ovarian cancer. Sickle-cell anaemia, in which inheriting the sickle cell gene from both parents causes the red blood cells to spontaneously “sickle” during a stress crisis; heart disease, of which many types are passed on genetically; haemophilia, a bleeding disorder caused by the absence of genetic clotting agent and. Huntington disease, a genetic condition which slowly kills victims by affecting cognitive functions and neurological status. Further, genomics play a significant role in mortality from chronic conditions such as cancer, diabetes and heart disease.
 
A world first

Huang and his colleagues set out to see if they could replace a gene in a single-cell fertilized human embryo. In principle, all cells produced as the embryo develops would then have the replaced gene. The embryos used by Huang were obtained from fertility clinics, but had an extra set of chromosomes, which prevented them from resulting in a live birth, though they did undergo the first stages of development. The technique used by Huang’s team involved injecting embryos with the enzyme complex CRISPR-Cas9, which, as described above, acts like is a pair of molecular scissors that can be designed to find and remove a specific strand of DNA inside a cell, and then replace it with a new piece of genetic material.
 
The science underpinning gene editing

In the two videos below Roger Kornberg, professor of medicine at Stanford University and 2006 Nobel Prize winner for Chemistry for his work on “transcription”, the process by which DNA is converted into RNA, explains the science, which underpins gene-editing technology:
 
How biological information, encoded in the genome, is accessed for all human activity

 
 
Impact of human genome determination on pharmaceuticals
 
An immature technology
 
Huang’s team injected 86 embryos, and then waited 48 hours; enough time for the CRISPR-Cas9 system, and the molecules that replace the missing DNA to act, and for the embryos to grow to about eight cells each. Of the 71 embryos that survived, 54 were genetically tested. Only 28 were successfully spliced, and only a fraction of those contained the replacement genetic material.
 
Therapy to cure HIV
 
Fan, the Chinese scientist who used CRISPR in an endeavor to discover a therapy for HIV/Aids, collected 213 fertilized human eggs, donated by 87 patients, which like embryos used by Huang, were unsuitable for implantation, as part of in vitro fertility therapy. Fan used CRISPR–Cas9 to introduce into some of the embryos a mutation that cripples an immune-cell gene called CCR5. Some humans who naturally carry this mutation are resistant to HIV, because the mutation alters the CCR5 protein in a way that prevents the virus from entering the T-cells it tries to infect. Fan’s analysis showed that only 4 of the 26 human embryos targeted were successfully modified.
 
Deleting and altering genes not targeted
 
In 2012, soon after scientists reported that CRISPR could edit DNA, experts raised concerns about “off-target effects,” where CRISPR inadvertently deletes or alters genes not targeted by the scientists. This can happen because one molecule in CRISPR acts like a bloodhound, and sniffs around the genome until it finds a match to its own specific sequence. Unfortunately, the human genome has billions of potential matches, which raises the possibility that the procedure might result in more than one match. 
 
Huang is considering ways to decrease the number of “off-target” mutations by tweaking the enzymes to guide them more precisely to a desired spot, introducing the enzymes in a different format in order to try to regulate their lifespans, allowing enzymes to be shut down before mutations accumulate; and varying the concentrations of the introduced enzymes and repair molecules. He is also, considering using other gene-editing techniques, such as LATENT.

 
The slippery slope to eugenics

Despite the potential therapeutic benefits from gene editing, critics suggest that genetic changes to embryos, known as germline modifications, are the start of a “slippery slope” that could eventually lead to the creation of a two-tiered society, with elite citizens, genetically engineered to be smarter, healthier and to live longer, and an underclass of biologically run-of-the-mill humans.
 
Some people believe that the work of Huang, Fan and others crosses a significant ethical line: because germline modifications are heritable, they therefore could have an unpredictable effect on future generations. Few people would argue against using CRISPR to treat terminal cancer patients, but what about treating chronic diseases or disabilities? If cystic fibrosis can be corrected with CRISPR, should obesity, which is associated with many life-threatening conditions? Who decides where the line is drawn?
 
40 countries have banned CRISPR in human embryos. Two prominent journals, Nature and Science, rejected Huang’s 2012 research paper on ethical grounds, and subsequently, Nature published a note calling for a global moratorium on the genetic modification of human embryos, suggesting that there are “grave concerns” about the ethics and safety of the technology.
 
A 2016 report from the Nuffield Council on Bioethics suggests that because of the steep rise in genetic technology, and the general availability of cheap, simple-to-use gene-editing kits, which make it relatively straightforward for enthusiasts outside laboratories to perform experiments, there needs to be internationally agreed ethical codes before the technology develops further.
 
Recently, the novelist Kazuo Ishiguro, among others, joined the debate, arguing that social changes unleashed by gene editing technologies could undermine core human values. “We’re coming close to the point where we can, objectively in some sense, create people who are superior to others,” says Ishiguro.
 
Takeaways

CRISPR has been described as the “Model T of genetics”.  Just as the Model T was the first motor vehicle to be successfully mass-produced, and made driving cheap and accessible to the masses, so CRISPR has made a complex process to alter any piece of DNA in any species easy, cheap and reliable, and accessible to scientists throughout the world. Although CRISPR still faces some technical challenges, and notwithstanding that it has ignited significant protests on ethical grounds, there is now a global race to push the boundaries of its capabilities well beyond its present limits.
 
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  • 16% of Mexico’s population has type-2 diabetes (T2DM) and each year it kills 70,000
  • Mexican mothers feed their children sugary beverages from birth and create soda addicts
  • In 2014 a national sugar tax on fizzy drinks was introduced, but sales on untaxed sugary beverages increased
  • The Carlos Slim Foundation (CSF) takes fundamental action to dent Mexico’s T2DM epidemic
  • The CSF collaborates with MIT’s Broad Institute to conduct the largest and most comprehensive genomic study on T2DM in Mexican populations
  • Three years later CSF announces the discovery of the first common genetic variant shown to predispose Mexicans to T2DM
  • Findings could lead to improved diagnostics and new therapies for T2DM, say experts
  • The Broad Institute and the CSF make their genomic studies and other data freely available to scientists worldwide
  • Organizations with bureaucratic walls that restrict the free-flow and sharing of knowhow and information significantly impede the advancement of our understanding and management of globally important chronic conditions such as T2DM
 
Slim lessons in diabetes understanding and management

What can a self-made 77-year-old son of Catholic Lebanese immigrants to Mexico contribute to our understanding and management of T2DM?
 
77-year-old Carlos Slim built a business empire, which today is worth the equivalent to 6% of Mexico’s GDP. His company Grupo Carso is influential in every sector of the Mexican economy, and he is currently the chairman and CEO of telecom giants Telmex and América Móvil. Slim believes that businessmen should do more than just give‍ money, and says they "should participate in solving problems".

An important aspect of reducing the significant burden of chronic health conditions such as T2DM, is to reduce the bureaucracies of key organizations, which impede the sharing of important knowhow that help our understanding and management of these globally important disease.
 
Slim has turned his attention to Mexico’s vast and escalating diabetes epidemic, which devastates the lives of millions, and significantly dents the Mexican economy. Recently, the Carlos Slim Foundation (CSF) started applying the knowhow and skills used to build world-class companies to tackle the Mexican diabetes burden, and in less than three years, discovered a gene, which contributes to the significantly higher incidence rate of T2DM in Latin Americans. The CSF intends to build on this to develop new treatments.
 


Diabetes in Mexico

Each year, T2DM related complications kill 70,000 Mexicans. In 2015, there were 11m people with diabetes in Mexico - almost 12% of its adult population - projected to rise to some 16m by 2035. Mexico has one of the world’s highest rates of childhood obesity, a significant contributory risk factor of T2DM. The prevalence of overweight or obese children and adolescents between 5 and 19 years is 35%. This is believed to be the result of mother’s feeding their babies sugary drinks: partly because of the lack of clean water, and partly cultural since many Mexicans consider chubby babies to be good. According to Dr. Salvador Villalpando, a childhood obesity specialist at the Federico Gomez Children's Hospital in Mexico City, “about 10% of Mexican children are fed soda from birth to six months, and by the time they reach two it's about 80%." Mexico has become the No. 1 per capita consumer of sugary beverages, with the average person drinking more than 46 gallons per year: nearly 50% more than the average American.
 
Over the last 20 years, the prevalence of T2DM in Mexico, a country with a population of 122 million, has increased rapidly. The Mexican health system is struggling to effectively adapt to the diabetes burden facing the nation. Healthcare spending represents approximately 6% of GDP and is divided near equally between the public and private sectors. The former, supports mostly low-income non-salaried workers, accounting for about 60% of those in work: some 30m. The latter, is an employer-based scheme linked to salaried workers.


Sugar tax

So acute is the problem of T2DM in Mexico that in January 2014, the government introduced a 10% tax on sugar-sweetened beverages. Research published in the British Medical Journal in 2016 suggests that the tax resulted in a 6% reduction in the purchases of taxed beverages in the first year, increasing to 12% by the end of the second year. The study also reported increases in purchases of untaxed beverages. Findings are disputed by the drinks industry. “Fizzy drinks only account for 5.6% of Mexico's average calorie consumption so can only be a small part of the solution to obesity and diabetes,” says Jorge Terrazas of Anprac; Mexico's bottled drinks industry body.
  
Carlos Slim Foundation and diabetes

The obesity epidemic, aging population and escalating health costs have increasingly strained resources and exacerbated Mexico’s diabetes burden, which the CSF is intent to reduce. In 2010 the Foundation formed an association with MIT’s Broad Institute. With an investment of US$74m it formed the Slim Initiative in Genomic Medicine for the Americas (SIGMA). It was a natural fit because Slim knows just how big data strategies transformed retail businesses and also cancer research and therapies; and the Broad Institute specialises in developing big genomic data sets and making them available to molecular scientists in premier research centres throughout world in order to transform medicine. From its inception SIGMA set out to systematically identify genes underlying diabetes.
 
The development of T2DM depends on complex inheritance-environment interactions along with certain lifestyle behaviors. Previous HealthPad Commentaries have described such complexities. One described the lifetime research endeavors of Professor Sir Steve Bloom, Head of Diabetes, Endocrinology and Metabolism at Imperial College London, on obesity and the gut-brain relationship.
 
SIGMA believed that having access to genomic research undertaken by a network of world class scientists holds out the possibility of discovering fundamental aspects of the biological mechanisms linked to T2DM. And this could form the basis for more effective diagnostics and new and improved therapies for the condition. Until recently, only a select group of specialists had full access to such data. The CSF was also mindful that their relationship with the Broad Institute would help build Mexico’s capacity in genomic medicine.
 
T2DM risk gene found in Latin Americans

A major focus of SIGMA’s 2010 research agenda was to identify the genetic risk factors that contribute to the significantly higher incidence rate of T2DM in Mexico compared with the rest of the world. SIGMA conducted the largest and most comprehensive genomic study to date on T2DM in Mexican populations, which involved scientists at 125 institutions in 40 countries, and resulted in the discovery of the first common genetic variant shown to predispose Latin American’s to T2DM.

Findings show that people who carry the higher risk version of the gene are 25% more likely to have diabetes than those who do not. People who inherit copies of the gene from both parents are 50% more likely to have diabetes. The higher risk-form of the gene is present in half of the people with recent Native American ancestry, including Latin Americans. The elevated frequency of this risk gene in Latin Americans could account for, as much as 20% of the populations’ increased prevalence of T2DM. The gene variant also is found in about 20% of East Asians, but is rare in populations from Europe and Africa.

 
Doing science with one eye closed

"Most genomic research has focused on European or European-derived populations, which is like doing science with one eye closed,” says Eric Lander, Professor of Biology at MIT and President and Founding Director of the Broad Institute, who went on to say, “There are many discoveries that can only be made by studying non-European populations." José Florez, a principal investigator of the SIGMA study adds, “By expanding our search to include samples from Mexico and Latin America, we’ve found one of the strongest genetic risk factors discovered to date, which could illuminate new pathways to target with drugs and a deeper understanding of T2DM.”
 
The impact of evolutionary science on healthcare systems

Roger Kornberg, Professor of Medicine at Stanford University who won the 2006 Nobel Prize in chemistry, "for his studies of the molecular basis of eukaryotic transcription", describes how human genome sequencing and genomic research fundamentally changed the way healthcare is organized and delivered. “Genomic sequencing enables us to identify every component of the body responsible for all life processes. In particular, it enables the identification of components, which are either defective or whose activity we may wish to edit in order to improve a medical condition,” says Kornberg.
 
 
Website helps translating genomic discoveries into therapies

Three years following their discoveries; the CSF launched SIGMA 2 with a mandate to complete its genetic analysis of T2DM, improve diagnostics, and develop therapeutic roadmaps to guide the development of new treatments. SIGMA 2 also planned to ramp up scientific capabilities in both the US, and Mexico by developing a unique resource. In 2016 SIGMA 2 created a website of open-access genetic data on T2DM. The site contains data available from all the SIGMA studies, plus information on major international data networks, including more than 100,000 DNA samples, and the complete results of 28 large genome association studies. Scientists throughout the world have free access to these data.
 
The importance of the open exchange of information

The new web portal represents a breakthrough, because it allows scientists throughout the world access to genetic information, and this is expected to accelerate progress of our understanding and treating diabetes. “The open exchange of information is essential for scientific progress, but it is not always easily achievable. This site not only helps us to overcome this barrier – by allowing access to patient data from around the world – but also will allow directing scientists to the most prevalent genetic risk factors among the populations of Latin America and others who have been underrepresented in large-scale genomic studies,” says Lander who believes that, "It is essential that the benefits of the genomic revolution are accessible to people throughout the Americas and the world."

The SIGMA project has been a story of total success. Our extraordinary partners, both in Mexico and the US, have made it possible to make historic advances in the understanding of the basic causes of T2DM. We hope that through our contributions we will be able to improve the ways in which the disease is detected, prevented and treated,” says Roberto Tapia-Conyer, CEO of the CSF.

 
Takeaways
 
So, for an investment of US$25m a year for three years SIGMA made a significant discovery, which could beneficially affect the diagnostics and treatment of T2DM, and it also enhanced Mexico’s capacity for genomic research. Such success was due, in part, to the leadership of a 77-year-old Mexican businessman intent on solving problems, who thought globally, partnered with world-class institutions, understood and supported the potential of big data strategies and genomic research, and stood shoulder-to-shoulder with Eric Lander against healthcare organizations, which build and defend bureaucratic walls that significantly restrict the open access of knowhow and data.
 
 
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Roger Kornberg

Winzer Professor in Medicine, Stanford University School of Medicine; Nobel Laureate 2006; Chairman of the Board at Sensor-Kinesis Corporation

Dr. Roger Kornberg was awarded the 2006 Nobel Prize in Chemistry “for his studies of the molecular basis of eukaryotic transcription.” He determined how DNA’s genetic blueprint is read and used to direct the process for protein manufacture.

Dr. Kornberg carried out a significant part of the research leading to this prize at the Stanford Synchrotron Radiation Laboratory (SSRL), a Department of Energy (DOE)-supported research facility located at the Stanford Linear Accelerator Center (SLAC). Dr. Kornberg also carried out research at the Advanced Light Source, another DOE-funded synchrotron light source located at the Lawrence Berkeley National Laboratory.

Dr. Kornberg was the first to create an actual picture of how transcription works at a molecular level in the important group of organisms called eukaryotes (organisms whose cells have a well-defined nucleus). Humans and other mammals are included in this group, as is ordinary yeast. For cells to produce working proteins—a process necessary for life—information stored in DNA must first be transcribed into a form readable by the cell’s internal machinery.

Dr. Kornberg’s studies have provided an understanding at the atomic level of how the process of transcription occurs and also how it is controlled. Because the regulation of transcription underlies all aspects of cellular metabolism,

Dr. Kornberg’s research also helps explain how the process sometimes goes awry, leading to birth defects, cancer and other diseases.


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The Cancer Genome Atlas is a landmark research program supported by the National Cancer Institute and National Human Genome Research Institute at the National Institutes of Health. TCGA researchers will identify the genomic changes in more than 20 different types of human cancer.

By comparing the DNA in samples of normal tissue and cancer tissue taken from the same patient, researchers can identify changes specific to that particular cancer.

TCGA is analyzing hundreds of samples for each type of cancer. By looking at many samples from many different patients, researchers will gain a better understanding of what makes one cancer different from another cancer. This is important because even two patients with the same type of cancer may experience very different outcomes or respond very differently to treatments. By connecting specific genomic changes with specific outcomes, researchers will be able to develop more effective, individualized ways of helping each cancer patient.

What is TCGA Trying to Find?

TCGA will help us to understand what turns a normal cell into a cancer cell. By comparing DNA from normal and cancer tissue, we have already learned that:

  • There are certain areas of the genome commonly affected in several types of cancers. Often, these changes affect genes that control pathways in cells that cause cells to divide and survive when they normally would die.

  • Specific changes – also called signatures – allow us to tell one type of cancer from another. These signatures help doctors identify specific types
    of cancer, which may respond differently to various treatments or have a different prognosis. 

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