Giant leap against diabetes

By B. D. Colen, Harvard Staff Writer

Harvard stem cell researchers announced today that they have made a giant leap forward in the quest to find a truly effective treatment fortype 1 diabetes, a disease that affects an estimated 3 million Americans at a cost of about $15 billion annually.With human embryonic stem cells as a starting point, the scientists were for the first time able to produce, in the kind of massive quantities needed for cell transplantation and pharmaceutical purposes, human insulin-producing beta cells equivalent in most every way to normally functioning beta cells.

Doug Melton, who led the work, said he hopes to have human transplantation trials using the cells under way within a few years. Twenty-three years ago, when his infant son Sam was diagnosed with type 1 diabetes, Melton dedicated his career to finding a cure for the disease.

“We are now just one preclinical step away from the finish line,” said Melton, whose daughter Emma also has type 1 diabetes.A report on the new work is being published today by the journal Cell.

((A spinner flask — containing red culture media, cells and a magnetic stir bar — is placed on top of a magnetic stirrer. Magnified images show how single cells quickly grow into clusters. Credit: Mikey Segel))

Felicia W. Pagliuca, Jeff Millman, and Mads Gurtler of Melton’s lab are co-first authors on the Cell paper. The research group and paper authors include a Harvard undergraduate.

“You never know for sure that something like this is going to work until you’ve tested it numerous ways,” said Melton, Harvard’s Xander University Professor and a Howard Hughes Medical Instituteinvestigator. “We’ve given these cells three separate challenges with glucose in mice, and they’ve responded appropriately; that was really exciting.

“It was gratifying to know that we could do something that we always thought was possible,” he continued, “but many people felt it wouldn’t work. If we had shown this was not possible, then I would have had to give up on this whole approach. Now I’m really energized.”

The stem cell-derived beta cells are undergoing trials in animal models, including non-human primates, Melton said.

Elaine Fuchs, the Rebecca C. Lancefield Professor atRockefeller University, and a Howard Hughes Medical Institute investigator who is not involved in the work, hailed it as “one of the most important advances to date in the stem cell field, and I join the many people throughout the world in applauding my colleague for this remarkable achievement.

“For decades, researchers have tried to generate human pancreatic beta cells that could be cultured and passaged long-term under conditions where they produce insulin. Melton and his colleagues have now overcome this hurdle and opened the door for drug discovery and transplantation therapy in diabetes,” Fuchs said.

Jose Oberholzer, associate professor of surgery, endocrinology, and diabetes, as well as bioengineering, at the University of Illinois at Chicago and director of the islet and pancreas transplant program and the chief of the Division of Transplantation, said the work “will leave a dent in the history of diabetes. Doug Melton has put in a lifetime of hard work in finding a way of generating human islet cells in vitro. He made it. This is a phenomenal accomplishment.”

Melton, who also is co-scientific director of the Harvard Stem Cell Institute and the University’sDepartment of Stem Cell and Regenerative Biology — both of which were created more than a decade after he began his quest — said that when he told his son and daughter, they were surprisingly calm. “I think like all kids, they always assumed that if I said I’d do this, I’d do it,” he said with a self-deprecating grin.

Type 1 diabetes is an autoimmune metabolic condition in which the body kills off all the pancreatic beta cells that produce the insulin needed for glucose regulation in the body. Thus the final preclinical step in the development of a treatment involves protecting from immune system attack the approximately 150 million cells that would have to be transplanted into each patient being treated. Melton is collaborating to develop an implantation device to protect the cells with Daniel G. Anderson, the Samuel A. Goldblith Professor of Applied Biology, associate professor in the department of chemical engineering, the Institute of Medical Engineering and Science, and theKoch Institute at MIT.

Melton said that the device Anderson and his colleagues at Massachusetts Institute of Technology are testing has thus far protected beta cells implanted in mice from immune attack for many months. “They are still producing insulin,” Melton said.

Cell transplantation as a treatment for diabetes is still essentially experimental, uses cells from cadavers, requires the use of powerful immunosuppressive drugs, and has been available to only a very small number of patients.

Anderson said the new work by Melton’s lab is “an incredibly important advance for diabetes. There is no question that ability to generate glucose-responsive, human beta cells through controlled differentiation of stem cells will accelerate the development of new therapeutics. In particular, this advance opens the doors to an essentially limitless supply of tissue for diabetic patients awaiting cell therapy.”

Richard A. Insel, chief scientific officer at JDRF (Juvenile Diabetes Research Foundation), which helps fund Melton’s work, said “JDRF is thrilled with this advancement toward large-scale production of mature, functional human beta cells by Dr. Melton and his team. This significant accomplishment has the potential to serve as a cell source for islet replacement in people with type 1 diabetes and may provide a resource for discovery of beta cell therapies that promote survival or regeneration of beta cells and development of screening biomarkers to monitor beta cell health and survival to guide therapeutic strategies for all stages of the disease.”

Eliot Brenner, program director of the Helmsley Charitable Trust’s type 1 diabetes program, said, “The trust is pleased to have supported Dr. Melton and his team in this breakthrough. The ability to create insulin-producing cells not only has significant clinical potential, but it opens an important new path for researchers to understand and develop novel treatments for type 1 diabetes.”

Melton expressed gratitude to both JDRF and the Helmsley Charitable Trust, saying, “Their support has been, and continues to be, essential. I also need to thank [research supporters] Howard and Stella Heffron, whose faith in our vision got this work under way, and helped to get us where we are today.”

While diabetics can keep their glucose metabolism largely under control by injecting insulin multiple times a day, that does not provide the kind of exquisite fine-tuning necessary to properly control metabolism, and that lack of control can lead to devastating complications from blindness to loss of limbs.

About 10 percent of the more than 26 million Americans living with type 2 diabetes are dependent on insulin injections, and presumably would be candidates for beta cell transplants, Melton said.

“There have been previous reports of other labs deriving beta cell types from stem cells. No other group has produced mature beta cells as suitable for use in patients,” he said. “The biggest hurdle has been to get to glucose sensing, insulin-secreting beta cells, and that’s what our group has done.”

Harvard President Drew Faust noted, “When the Harvard Stem Cell Institute was created in 2004, the University ventured into uncharted and, some thought, untenable terrain. Today, the possibility of growing in knowledge and in wisdom has given way to the promise of improving health and changing lives. Doug Melton and his colleagues continue to push stem cell science forward with their extraordinary work. This accomplishment is something none of us could have predicted 10 years ago, and I am excited to see where it all leads.”

In addition to the institutions and individual cited above, the work was funded by the Harvard Stem Cell Institute, the National Institutes of Health, and theJPB Foundation.

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Launch of the Global Health Research Process Map

            On the 8th of July 2014 The Global Health Network launched the Global Health Research Process Map, the first digital toolkit designed to enable researchers anywhere in the world to conduct rigorous global health research. It has the potential to revolutionise the current process, speeding new research and therapies to the patient and saving lives in the process. The event was a great success, with over 100 researchers, media and other interested people attending at the Wellcome Trust, Euston Road, London. Videos from the event appear at the end of this article. In a globally networked age, health and scientific research is drastically lacking in the regions where evidence to improve health is needed most and it is surprisingly disjointed and inefficient. Crucial evidence is not being generated because doctors and nurses lack research skills and support. Effort is also regularly duplicated or conducted using different criteria in different territories and studies, and sometimes it falls by the wayside from lack of simple resources and guidance on best practice. Researchers wanting to develop treatments of the future are hindered by the lack of access to a global network. The Global Health Research Process Map is set to change all that. It’s an open-access internationally-available online resource that guides every process and method needed to initiate a health research study. For each step researchers and their staff are provided with the information, support and training that they need to successfully run a health study. Researchers will also gain the opportunity to engage with their peers along the way, aiding collaboration and the spread of ideas. The sharing of research methods allows researchers to learn from the experiences of previous studies and saves time and raises standards - this is possible because many steps and processes are similar, regardless of the design or disease area. The Global Health Research Process Map is the product of four years of best practice gathered and refined by the research community who use the pioneering Global Health Network to guide and support their effort to conduct research in challenging settings. The launch coincided with an article in Nature Medicine (20, 694 (2014)) entitled "Website pools clinical trial forms for use in developing countries", published on the 7th of July 2014. Dr Trudie Lang also published on the Huffington Post, in "Harnessing the Digital Sharing Revolution to Save Lives". News of the launch was also picked up by the British Medical Journal (BMJ 2014;349:g4498) in a note titled "Digital map for global health researchers". A blog was also posted to The Lancet, "A 21st century upgrade for global health" by Gemma Bowsher, Nathan Post and Emelia Martin of Medsin-UK. Launch Event Videos: Dr Trudie Lang, Director of The Global Health Network - Introduction and 

Overview of The Global Health Research Process Map, Introduction of the panel

   

  Dr Egeruan Babatunde Imoukhuede – Jenner Institute, University of Oxford - Realities of conducting Research in African Countries 

  Ken Awundo - Laboratory Manager at KEMRI-Wellcome Trust, Kilifi Kenya - The challenges of setting up research laboratories in Africa and the impact of The Global Health Network

  Roger Gorman, CEO, ProFinda.com - a digital platform perspective on sharing and breaking down silos. He discusses 7 themes, or 'digi-trends'

  Dr Abha Saxena – Coordinator, Global Health Ethics, World Health Organization - Why research in low- and middle-income countries and what the WHO is doing to address the challenges to get more and better research done

  Dr Ben Goldacre, doctor, academic, campaigner and writer - How we can embed research activity as seemlessly and unobtrusively as possible into everyday clinical activity

 The launch also included a Questions and Answers session, wherein firstly Professor Rosanna Peeling, the Chair, asked questions of the panel: - Scientists do not share, as they are set up to be competitive for shrinking funding. How do you resolve the conflict between competition and sharing? - If we do share, and we encourage more people to take on research, why should people in low income settings take up health research? - Why now for the process map? Is it something we could not do before? - 

Trudie, what can we all do tomorrow to make this work?

 And was wrapped up with questions from the floor, and a thanks and closure by Dr Trudie Lang: Questions from the floor: - How do you engage with the people who need these tools? The role of recognition. - How are you engaging with the hard to reach regions in low- and middle-income countries, rather than just the resourced organisations. How does South-South partnership and mentorship get incorporated - how have southern partners played a role in developing the tools? - One of the barriers to embedding research in everyday clinical practise is the ethics of this. How do we overcome this as it is a danger to see ethics as a barrier rather than as a protection? - There are many nongovernmental organisations (NGOs) that are working in difficult and hard to reach areas where it is difficult to even get qualified staff. How can this platform support the NGOs and the staff who work for them but have limited skills and knowledge to further generate and disseminate evidence? - What is the role of youth in The Global Health Network, and how can they get more involved in Global Health? - Is there a quality control process to the process map? - How do we attract young people into research, who will be the future "customers" of this tool? What can we go around the world and use to sell to young people so that they can come and join us on this crusade? - Some people go through years of training to become researchers, and you have come up with a tool where you say to research naive workers that all you have to do is go through this process map and 

you can do research. How do you balance these two 'types' of research worker?

  Thanks to everyone who took part, everyone who attended and to all the users on The Global Health Network that contribute so much of their time, energy and resources to the success of these tools.

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