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A Rich Tradition of Patient-Focused Care — Richmond University Medical Center, New York’s Leader in Health Care and Medical Education

Posted in Cardiovascular and Vascular Systems, Diabetes Mellitus, Frontiers in Cardiology and Cardiovascular Disorders, Healthcare costs and reimbursement, Healthcare Reform, Hospital reputation, Innovations, Interviews with Scientific Leaders, Investment in Technological Breakthrough, Medicare and Medicaid, Patient Experience, Patient Outlook, Uncategorized on October 17, 2016| Leave a Comment »

A Rich Tradition of Patient-Focused Care — Richmond University Medical Center, New York’s Leader in Health Care and Medical Education 

Author: Gail S. Thornton, M.A.

WordCloud Image Produced by Adam Tubman

Co-Editor: The VOICES of Patients, Hospital CEOs, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

Richmond University Medical Center (www.RUMSCI.org), an affiliate of The Mount Sinai Hospital and the Icahn School of Medicine, is a 470+ bed health care facility and teaching institution in Staten Island, New York. The hospital is a leader in the areas of acute, medical and surgical care, including emergency care, surgery, minimally invasive laparoscopic and robotic surgery, gastroenterology, cardiology, pediatrics, podiatry, endocrinology, urology, oncology, orthopedics, neonatal intensive care and maternal health. RUMC earned The Joint Commission’s Gold Seal of Approval® for quality and patient safety.

RUMC is a designated Level 1 Trauma Center, a Level 2 Pediatric Trauma Center, a Level 3 Neonatal Intensive Care Unit (NICU), which is the highest level attainable, and a designated Stroke Center, receiving top national recognition from the American Heart Association/American Stroke Association.  Their state-of-the-art Cardiac Catheterization Lab has Percutaneous Coronary Intervention (PCI) capabilities, for elective and emergent procedures in coronary angioplasty that treats obstructive coronary artery disease, including unstable angina, acute myocardial infarction (MI), and multi-vessel coronary artery disease (CAD).

RUMC maintains a Wound Care/Hyperbaric Center and a Sleep Disorder Center on-site at its main campus.  The facility also offers behavioral health services, encompassing both inpatient and outpatient services for children, adolescents and adults, including emergent inpatient and mobile outreach units.  RUMC is the only facility that offers inpatient psychiatric services for adolescents in the community.

In April 2016, RUMC announced its intent to merge with Staten Island Mental Health Society in order to expand its footprint in Staten Island and integrate behavioral health services alongside primary care. As part of New York’s Medicaid reforms, funding is available to incentivize providers to integrate treatment for addiction, mental health issues and developmental disabilities with medical services.

With over 2,500 employees, RUMC is one of the largest employers on Staten Island, New York.

Image SOURCE: Photographs courtesy of Richmond University Medical Center, Staten Island, New York. Interior and exterior photographs of the hospital.

Below is my interview with President and Chief Executive Officer Daniel J. Messina, Ph.D., FACHE, LNHA, which occurred in September, 2016.

What has been your greatest achievement?

Dr. Messina: Professionally, my greatest achievement is my current responsibility – to be President and Chief Executive Officer of one of the greatest hospitals with a strong, solid foundation and rich history. I was born in this hospital and raised on Staten Island, so to me, there is no greater gift than to be part of a transformative organization and have the ability to advance the quality of health care on Staten Island.

My parents taught me the value of responsibility and motivation and instilled in me the drive and tenacity to be the best person I could be – for my employees and for my family. I am a highly competitive person, who is goal-oriented, hands-on and inspired by teamwork. I rarely sit behind my desk as I believe my place is alongside my team in making things happen.

As a personal goal, I recently climbed the 20,000-foot Mount Kilimanjaro in Tanzania. It was the experience of a lifetime. I could not have completed this challenge without the support of the guides and porters who helped me and my group along the way. For me, it was a challenge in proving to myself that I could be out of my comfort zone. My group and I hiked hours and hours each day, dodging rocks and scrambling along rock walls with the goal of reaching the summit. In many ways, it takes a village to climb the mountain, relying on each other in the group to get you to the next level.

In many ways, that is how I see my professional day at the hospital, working with a strong team of dedicated medical staff and employees who are focused on one goal, which is to continue our hard work, continue to improve care and continue to move forward to advance life and health care.

The mission of Richmond University Medical Center, an affiliate of The Mount Sinai Hospital and Mount Sinai School of Medicine, serves the ethnically diverse community of Staten Island, New York, by providing patients with a range of services.

How has your collaboration with the Mount Sinai network helped to expand health care delivery and services for patients of Staten Island, New York?

Dr. Messina: Being able to serve our patients year after year continues to be a top priority, so we are constantly improving upon our rich history of 100 years of exceptional patient-focused care given by our medical and surgical health care professionals as well as innovative technologies and programs created by our award-winning hospital team. We have committed medical specialists, passionate employee staff, exceptional Board of Trustees, supportive elected government officials – all who in their own way contributes to providing the highest level of patient care to the more than 500,000 residents of Staten Island, New York.

As a member of the Mount Sinai Health network, we have found ways to work collaboratively with our academic partner to ensure that our patients’ health care needs not only are fully met but also exceeded. This alliance will facilitate the development of a new, Comprehensive Breast and Women’s Healthcare Center. We have leveraged our Breast and Women’s Health Center with our RUMC general surgeons in conjunction with breast imaging, fellowship-trained physicians from Mount Sinai’s Icahn School of Medicine. The physicians who are granted this renowned fellowship interact with our patients and become an active participant in multidisciplinary breast conferences and resident and medical student education. For patients, this means that they have access to the best minds and latest research, therapies and treatment regimens throughout our network.

What makes Richmond University Medical Center and its specialty areas stand out from other hospitals?

Dr. Messina: We bring the highest level of advanced medicine to our patients. For more than 100 years, we have built a rich history of delivering patient-focused care that is unique. Our organization is recognized as a family organization with strong community spirit and family values. We are proud to be a high-technology/high-touch organization of caring professionals that go above and beyond the standard of health care. Our strengths lie in the areas of acute, medical and surgical care, including emergency care, surgery, minimally invasive laparoscopic and robotic surgery, gastroenterology, cardiology, pediatrics, podiatry, endocrinology, urology, oncology, orthopedics, neonatal intensive care and maternal health.

Each year, we embark upon a comprehensive, robust strategic planning process that involves our senior leadership team, clinical chairs, Board of Trustees as well as our medical and surgical staff and hospital employees that looks out three to five years in the future to determine what is best for the patient. We are each committed in our own way to quality patient care and building an even stronger organization.

Some of our achievements are noteworthy:

• As a New York City Department of Emergency Services designated Level 1 Trauma Center and Level 2 Pediatric Trauma Center, the only Trauma Center dually verified in New York City, we rely on sophisticated equipment so our medical and surgical specialists are prepared to treat severe conditions within minutes.
• Our Neonatal Intensive Care Unit (NICU) is a designated Level 3 facility, the highest level attainable. The unit delivers 3,000 babies annually and it was recognized as having the lowest mortality rate in the metropolitan area and a survival rate of 99 percent, that exceeds national benchmarks. Our specialists in our pediatric ambulatory services department treat over 10,000 patients annually and our children’s urgent care area records over 23,000 visits annually.
• Our state-of-the-art, 38,000-square-foot Emergency Department (ED), which will be replaced by an expanded facility and projected to open in 2018, will provide for more focused care, operational efficiency and flexibility for our staff and patient. We also will be better integrated and connected to the entire hospital campus.

Originally designed to serve 22,000 patients each year, the ED is expected to accommodate an increased volume of patients, which is estimated at 70,000 and give our medical specialists the tools they need to provide the best in care for this volume of patients. In a new patient and family-centered space with 49 treatment positions, the new ED will be connected to the existing hospital, close to surgical services, the radiology department and lab services.

Equally as important, the hospital has been strong in the face of natural disasters, especially Hurricane Sandy which occurred a few years ago, and the new ED is being designed with storm resilient and redundant design to minimize impact from severe weather conditions.

In fact, the New York City Council and the Staten Island Borough President have set aside a combined $13.5 million for this $60+ million project and believe in the transformative impact that it will have on emergency care on Staten Island. These local officials believe that Staten Island residents deserve quality, readily accessible health care.

• Heroin addiction is an epidemic on Staten Island, so we have a number of programs in place at RUMC’s Silberstein Center to provide outpatient treatment, rehabilitation and clinics, along with group therapy sessions, Alcoholics Anonymous meetings and individual therapy sessions.
• Our new primary care/walk-in facility in the heart of Staten Island borough is operational and there are no appointments required. Patients can visit with one of three physicians or a nurse practitioner. This off-site facility is not located in the hospital complex and is an expansion of our services outside of the hospital walls.
• We also maintain a Wound Care Center, Pain Management Center and a Sleep Disorder Center at our facility. In fact, we are the only local facility that offers inpatient psychiatric services for adolescents and we are expanding our capacity to meet the needs of the community.

RUMC has been awarded a top designation jointly by the American Heart Association and the American Stroke Association. What does that mean to the hospital?

Dr. Messina: This designation makes us proud as the recipient of the American Heart Association/American Stroke Association’s Quality Achievement Award for six consecutive years and its first Elite Plus recognition. This means that we have achieved 85 percent or higher adherence in indicators for two or more consecutive 12-month periods to improve quality of patient care and outcomes for stroke patients.

Our cardiac catheterization lab with Percutaneous Coronary Intervention (PCI) capabilities – the newest facility of its kind on Staten Island — now treats semi-urgent and elective coronary procedures.

For patients, this means that we have a commitment to ensure that stroke patients receive the most appropriate treatment according to nationally recognized, research-based guidelines based on the latest scientific evidence. With a stroke, when time is lost, brain is lost, and this award demonstrates our commitment to ensuring patients receive care based on evidenced-based guidelines. We are dedicated to continually improving the quality of stroke care and this recognition helps us achieve that goal.

Studies have shown that hospitals that consistently follow these quality improvement measures can reduce length of stay and 30-day readmission rates and reduce disparities in care. To qualify for the Elite Plus recognition, we met quality measures developed to reduce the time between the patient’s arrival at the hospital and treatment with the clot-buster tissue plasminogen activator, or tPA, the only drug approved by the U.S. Food and Drug Administration to treat ischemic stroke. If given intravenously in the first three hours after the start of stroke symptoms, tPA has been shown to significantly reduce the effects of stroke and lessen the chance of permanent disability. We earned the award by meeting specific quality achievement measures for the diagnosis and treatment of stroke patients at a set level for a designated period.

According to the American Heart Association/American Stroke Association, stroke is the number five cause of death and a leading cause of adult disability in the United States. On average, someone suffers a stroke every 40 seconds; someone dies of a stroke every four minutes; and 795,000 people suffer a new or recurrent stroke each year.

The values of Richmond University Medical Center are summarized in the acronym, WE CARE (Welcoming Energized Compassion Advocacy Respect Excellence). How is this part of your day-to-day life?

Dr. Messina: For more than 100 years, Richmond University Medical Center has

been building a rich history of exceptional patient-focused care for the residents of Staten Island. Each year, we carry that tradition forward by our medically innovative and patient-focused care and services we offer. It is the passion, creativity and caring of everyone who is part of our ‘hospital team’ that moves the organization to new heights.

The chart below summarizes our credo, the values that guide us every day and help us focus on the care and well-being of the people who come through our doors.

We are welcoming and gracious toward each other, and toward all who come to receive our services.

Personnel are energized for quality, creativity, commitment and teamwork.

Compassion is the way we share deep concern and care toward each person.

Advocacy is our activity that promotes the rights and responsibilities of patients, families and staff, in the hospital setting and in the community.

We show respect by recognizing the basic dignity of every person in all our interactions and in the formulation of policies and procedures.

Excellence is our way of demonstrating that we can always be more and always be better.

The Richmond University Medical Center Board is comprised of distinguished leaders of the Staten Island community who are committed to the success of the hospital and to the health of Staten Islanders.

How is this local approach revolutionizing health care for the Staten Island community?

Dr. Messina: The members of our distinguished Board of Trustees, who represent a cross-section of business professionals and community leaders, continue our goal of meeting the needs of our patients and our hospital.

Our Board remains committed to providing solutions for our patients to challenging healthcare issues they face every day and to making a difference in the lives of patients by providing the latest thinking and technology solutions. Our Board Chairperson Kathryn K. Rooney, Esq., and Vice Chairperson Ronald A. Purpora, as well as the other Board members, and even our elected government officials, have a strong connection to Staten Island and we believe it truly ‘takes a village’ to make this organization flourish.

Each year, our Board of Trustees is presented with new opportunities and possibilities for growth and development. That is why their top priority for this past year was approving the construction of a state-of-the-art Emergency Department (ED) as this undertaking will serve both the patients and staff equally. In order to serve the residents of Staten Island properly, the new ED will accommodate an increased number of patients and our medical staff will receive the tools and technology to provide the best in care for our patients.

This past year, we were provided with a $1.5 million gift from the Staten Island Foundation that will go toward the hospital’s capital campaign to construct the new $60 million Emergency Department. We decided to name the RUMC’s Allan Weissglass Pavilion Center for Ambulatory Care, in honor of our long-time community and business leader, who is a founding Board member and Board of Trustees member. Allan Weissglass devoted his time, energy and talent to the success of this hospital over many years.

We are positioning our organization for the future and we continuously build on our strengths, being responsive to the needs of the community. In the past, we saw the patient was the only ‘customer’ of the hospital. Today, that perception is evolving and our ‘customers’ are many.  With the help and support of donors, local foundations, volunteers, staff, and the community, local government officials, we are building a bright future for Richmond University Medical Center.

What is RUMC’s commitment to graduate medical education?

Dr. Messina: Our six Graduate Medical Education (GME) programs in Internal Medicine, Obstetrics and Gynecology, Pediatrics, Psychiatry, and Diagnostic Radiology and Podiatry, signify our commitment to teaching as a cornerstone of our philosophy. Our medical staff are seen as role models for our medical residents and provide quality training, medical education and research capabilities. Our existing medical staff functions as supervising physicians and gives medical residents exposure to specific responsibilities and patient care, as well as scholarly opportunities. One interesting fact is that the doctors we train come back to help treat our patients by using their knowledge and experience to work in our community.

You mentioned that ‘outreach in the community’ as a key factor in the success of the hospital’s mission to enhance the quality of life for residents of Staten Island. What types of activities are under way?

Dr. Messina: Our lifesaving work takes many forms. We are constantly finding new and different ways to engage with our community – to raise awareness and educate on a number of diseases and conditions, and, hopefully move toward better health care. We believe that our patients need to see us outside of a clinical environment, which strengthens our relationship.

For example, over the past year:

• We sponsored an annual health and wellness expo with the Staten Island Economic Development Corporation that was attended by over 2,000 people to equip the community with knowledge about their health and the local health services available to them.
• We pioneered an organ donor enrollment day by welcoming 59 visitors and guests who can potentially donate their organs to save lives.
• We partnered with the New York City Department of Transportation and our own Trauma team to demonstrate and educate the community on car seat safety.
• Our Dermatologist team took part in the Borough President’s “Back to the Beach” festival by performing skin screenings and distributing sunscreen and information on skin cancer.
• Our Obstetrics and Gynecology team hosted a baby expo to talk with new mothers and mothers-to-be about services available at the hospital.
• Our Diabetologist team partnered with the YMCA on a 16-week partnership to curb the diabetes epidemic on Staten Island through information talks and health screenings.
• We were even present at last year’s Staten Island Yankees home opening baseball game to throw out the first pitch and conduct a blood drive while distributing wellness information.

Since roughly one third of the residents on Staten Island are enrolled in Medicaid or Medicare, what steps are you taking to improve the delivery of treatment for them?

Dr. Messina: We started several initiatives last year that were funded by the federal and state governments to look at the way care is delivered to patients who are enrolled in Medicare and Medicaid. So far, we’ve reduced costs by $3.75 million and realized $1.8 million in shared savings that are re-invested in key hospital programs.

As you know, Medicare and Medicaid are two different government-run programs that were created in 1965 in response to the inability of older and low-income Americans to buy private health insurance. They were part of our government’s social commitment to meeting individual health care needs. Medicare is a federal program that provides health coverage if you are 65 or older or have a severe disability, no matter your income, while Medicaid is a state and federal program that provides health coverage if you have a very low income.

We’ve set up our own Richmond Quality Accountable Care Organization (ACO), that comprises 30 providers serving 7,500 Medicare patients. This innovative program is accountable for the quality, cost and overall care provided to people on Medicare and who are enrolled in the traditional fee-for-service program.  One program that is ongoing is one that we’ve partnered with the Visiting Nurse Service of Staten Island to prevent hospital readmissions and to identify hospitalized patients who would benefit from a higher level of care and home care services.

Another program that is under way for our Medicaid patients is teaching our staff to prevent hospital readmissions by creating an accurate list of medications that a patient takes and comparing that list against physician’s admission, transfer and discharge orders to ensure that the correct medication plan is in place.

We believe that we are transforming the underlying systems with a focus on delivering quality care and hopefully better outcomes for patients.

RUMC recently announced a merger with Staten Island Mental Health Society (SIMHS) to integrate SIMHS’ broad range of behavioral health programs into the hospital’s existing medical and behavioral program throughout Staten Island. What does this merger bring to the community?

Dr. Messina: We believe that the proposed merger between RUMC and the Staten Island Mental Health Society (SIMHS) will provide a strengthened, comprehensive network of behavioral health services across Staten Island.

This partnership will bring together two Staten Island institutions, with a combined 230 years of service to the borough, and create one strong and vibrant organization dedicated to meeting the health needs of the diverse community.

Merging the range of community-based behavioral health services provided by SIMHS with the solid foundation of primary care services provided by RUMC will create a seamless range of behavioral and medical services for our residents. We are in the unique position to transform and enhance the services of these two vital health care providers. The SIMHS will keep its name and become a division of the hospital. The merger is expected to close during calendar year 2017.

Image SOURCE: Photograph of President and Chief Executive Officer Daniel J. Messina, Ph.D., FACHE, LNHA, courtesy of Richmond University Medical Center, Staten Island, New York.

Daniel J. Messina, Ph.D., FACHE, LNHA
President & Chief Executive Officer

Daniel Messina, Ph.D., FACHE, LNHA, became President and Chief Executive Officer of Richmond University Medical Center (RUMC) – an affiliate of The Mount Sinai Hospital and Mount Sinai School of Medicine – in April 2014.

Dr. Messina, a life-long resident of Staten Island, is a seasoned executive with nearly 30 years of healthcare leadership expertise. For the previous 13 years, he served as the System Chief Operating Officer of CentraState Healthcare System in Freehold, New Jersey, where his responsibilities included all System Operations for the Medical Center, Assisted Living Facility, Skilled Nursing and Rehabilitation Center and Continuing Care Retirement Community. While in this role, Dr. Messina developed additional growth strategies that include a new Cancer Center, a Proton Therapy Center, Radio-Surgery, a new Infusion Center and programs in Robotics, Minimally Invasive Surgery, Bariatric and Neurosurgery. Other accomplishments include a new state-of-the-art 26-bed Critical Care Unit, a 49-bed Emergency Department, and the development of an 180,000 sq. ft. Ambulatory Campus and Wellness Center anchored by a 35,000 sq. ft. Medical Fitness Center. Additionally, Dr. Messina developed the Linda E. Cardinale MS Center – one of the largest and most comprehensive MS Centers in the tristate area – leading to a fundraising event that has generated over $2 million.

Dr. Messina received his B.S. in Health Science/Respiratory Therapy from Long Island University Brooklyn, and earned his M.P.A. in Healthcare Administration from LIU Post. He obtained his Ph.D. in Health Sciences and Leadership at Seton Hall University where he currently serves as an adjunct professor in the School of Health and Allied Sciences. He is active in the American College of Health Care Executives, is board certified in healthcare management as an ACHE Fellow, and recently completed a three-year term as Regent for New Jersey.

Dr. Messina serves as trustee on the National Multiple Sclerosis Society, the New Jersey Metro Chapter, and the Alumni Board of Trustees at Seton Hall University. He is a Board member of the VNA Health Group of New Jersey and a member of the Policy Development Committee of the New Jersey Hospital Association. Dr. Messina has been honored by various organizations for his service to the community, including Seton Hall University with the “Many Are One” award, the American College of Healthcare Executives with Senior, Early and Distinguished Service Awards, New Jersey Women Against MS, CentraState Auxiliary, and the Staten Island CYO.

Editor’s note:

We would like to thank William Smith, director of Public Relations, Richmond University Medical Center, for the help and support he provided during this interview.

 

 

REFERENCE/SOURCE

Richmond University Medical Center (http://rumcsi.org/Main/Home.aspx)

Other related articles:

Retrieved from http://rumcsi.org/main/annualreport.aspx

Retrieved from https://en.wikipedia.org/wiki/Richmond_University_Medical_Center

Retrieved from http://rumcsi.org/main/rumcinthenews/si-live-5202016-170.aspx

Retrieved from http://rumcsi.org/main/rumcinthenews/merger-agreement-4132016-159.aspx

Retrieved from http://blog.silive.com/gracelyns_chronicles/2016/06/rumc_receives_presitigious_bab.html

Retrieved from https://www.statnews.com/2016/10/17/vivan-lee-hospitals-utah/

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Value for Patients – Turning Advances in Science: A Case Study of a Leading Global Pharmaceutical Company – Astellas Pharma Inc.

Posted in 3D Printing for Medical Application, CANCER BIOLOGY & Innovations in Cancer Therapy, Innovations, Interviews with Scientific Leaders, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Pharmaceutical R&D Investment, Uncategorized, tagged astellas; oncology; urology; immunology nephrology; neuroscience on August 24, 2016| Leave a Comment »

Value for Patients – Turning Advances in Science: A Case Study of a Leading Global Pharmaceutical Company – Astellas Pharma Inc.

Reporter: Gail S. Thorton, M.A.

Astellas Pharma Inc. (https://www.astellas.com/en/) and Astellas Pharma U.S., Inc. (https://www.astellas.us/)

WordCloud Image Produced by Adam Tubman

UPDATED on 4/3/2017

Astellas Pharma Inc. and Ogeda SA announced today that Astellas and Ogeda shareholders have entered into a definitive agreement under which Astellas has agreed to acquire Ogeda a privately owned drug discovery company. Ogeda is a clinical-stage drug discovery company that discovers and develops small molecule drugs targeting G-protein coupled receptors (GPCRs). The lead investigational candidate, fezolinetant, is a selective NK3 receptor antagonist, and the positive data from a Phase 2a study result for the non-hormonal treatment of menopause-related vasomotor symptoms (“MR-VMS”) was announced in January 2017. This transaction expands Astellas’ late stage pipeline and is expected to contribute to its mid-to-long term growth.

SOURCE

http://www.prnewswire.com/news-releases/astellas-to-acquire-ogeda-sa-300433141.html

Astellas swoops in on a mid-stage drug for hot flashes in $860M biotech buyout deal

UPDATED on 8/24/2016

Some analysts suggested Pfizer paid too much, particularly since it will split profits from Xtandi with Japan-based Astellas Pharma, which helps market the drug. Pfizer defended the deal, saying it would add 5 cents to its earnings per share in the first full year.

“The proposed acquisition of Medivation is expected to immediately accelerate revenue growth and drive overall earnings growth potential for Pfizer,” Ian Read, chairman and chief executive of Pfizer, said in the statement on Monday.

SOURCE

http://www.nytimes.com/2016/08/23/business/dealbook/medivation-pfizer-14-billion-deal.html?_r=0

Author: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures  https://pharmaceuticalintelligence.com/biomed-e-books/series-e-titles-in-the-strategic-plan-for-2014-1015/2014-the-patients-voice-personal-experience-with-invasive-medical-procedures/

Tokyo-based Astellas Pharma Inc., a top 20 global pharmaceutical research company, has a strong, global company legacy, precision focus and patient-centric vision in creating innovative pharmaceuticals in areas of unmet medical need.

Image SOURCE: Photograph of the Astellas Pharma U.S. building. Courtesy of Astellas Pharma U.S., 5/10/2012.   

The company’s commitment to science is based on development of medicines that address high unmet medical needs in therapeutic areas that include:

• oncology,
• urology,
• immunology,
• nephrology, and
• neuroscience.

The company is also exploring advancements in new therapeutic areas and related diseases such as,

• ophthalmology—retinitis pigmentosa (RP), age-related macular degeneration (AMD), diabetic macular edema (DME) and Stargardt’s macular degeneration (SMD) and
• muscle diseases.

And they are investing in new technologies and modalities, such as,

• regenerative medicine and cell therapy, and
• next-generation vaccines.

The company is committed to improving the lives of patients through innovative science and with the highest sense of ethics and integrity. This commitment is reflected in the Astellas Group Code of Conduct, which applies to all employees across the globe and can be accessed through the link below.

Astellas Group Code of Conduct

Boosting research and development productivity remains an important issue for Astellas Pharma Inc., because innovation is vital for the company’s success in developing new therapeutic areas, technologies and modalities of treatment.

Dr. Bernhardt Zeiher, President, Development, is responsible for the more than 800-person development organization that is involved in developing these innovative therapies through cutting-edge clinical research. Dr. Zeiher’s team conducts clinical investigations of novel biological targets and new chemical entities with unique mechanisms of action and looks to determine whether the findings in preclinical testing will translate to benefit for patients.  Clinical studies are conducted globally with operational hubs in the United States, Netherlands and Japan. Astellas relocated their Development headquarters from Japan to the United States in 2008.

Building on its 120-year heritage, Astellas uses creativity and innovation to bring patients new medicines through the more than 17,000 global employees who work to improve the lives of patients and their families. Astellas was formed through the merger of Japan’s third and fifth largest pharmaceutical companies, Yamanouchi, founded in 1923, and Fujisawa, founded in 1894. Yamanouchi brought a record of developing blockbuster drugs, a pipeline full of promising new compounds and a sales and marketing culture of deeply grounded, data-driven expertise. Fujisawa brought dominance in transplantation, a soaring reputation for in-depth understanding of the disease states and treatments within its market niches, and a track record for developing high-profile, market-leading products that become new standards of care.

The company has made steady progress; they reported annual global sales of 1,372,706 million yen (approx. $13.2 billion) through the end of fiscal year 2015, with an annual research and development investment of 225,665 million yen (approx. $2.2 billion) through the end of fiscal year 2015.

Below is my interview with Astellas Dr. Bernhardt Zeiher, President, Development, which occurred in June, 2016.

What is your overall Research & Development (R&D) strategy?

Dr. Zeiher: We are focused on turning innovative science into value for patients in areas of high unmet need where we have, or can quickly acquire, expertise and where Astellas believes new scientific understanding is poised to drive significant innovation. Our commitment to R&D is based on the development of medicines that address high unmet medical needs in our main therapeutic areas of focus: oncology, urology and immunology.  We also have increased efforts to explore advancements in new therapeutic areas such as ophthalmology, nephrology, neuroscience and muscle diseases where there is a high level of unmet medical need. Building on our patient-centric vision, Astellas has been actively investing in new technologies and modalities, such as regenerative medicine and next-generation vaccines.

What are your R&D strengths?

Dr. Zeiher: Astellas is building on its legacy of bringing transformative medications to patients by investing in some of today’s most dynamic areas of scientific exploration. Innovations delivered by Astellas have helped to address and largely solve some of the most significant scientific challenges in urology and transplant. We also have built a strong presence in oncology with treatments for difficult-to-treat cancers, such as prostate and non-small cell lung cancer.

Moving forward in oncology, Astellas has made a deliberate effort to build leadership through organic efforts with a pipeline exemplifying the “follow the biology” approach that includes treatments for prostate, non-small cell lung and pancreatic cancer, and continued research in therapies for breast cancer and acute myeloid leukemia, among others. We also have forged strategic acquisitions and collaborated with industry and academic leaders to further build our portfolio.

In addition, we are leveraging what we know across conditions with similar biologies or mechanisms, building on our expertise to expand into adjacent diseases and proactively seek new opportunities. For example, leveraging our expertise in transplantation and infectious diseases, Astellas is developing the world’s first DNA vaccine for cytomegalovirus (CMV) infections. Currently in clinical trials, ASP0113 is a potential first-in-class agent for immunocompromised individuals undergoing solid organ or hematopoietic stem cell transplant who are at high risk of viral reactivation.

Describe your near-term R&D projects and pipeline activities?

Dr. Zeiher: Currently, the company is working on 35 investigational programs in Phase II and Phase III/registration development, of which half involve new molecular entities. We have a diverse pipeline with a balance of early- and later-stage assets. Later-stage programs include novel therapies/vaccines for cancer, anemia and infectious diseases.

• Our two most advanced novel oncology agents, ASP2215 and ASP8273, continue to progress through the pipeline. ASP2215 shows promise in the treatment of relapsed or refractory acute myeloid leukemia, and ASP8273 is being evaluated as a treatment for a type of non-small cell lung cancer.
• Leveraging our expertise in kidney disease, we are developing a first-in-class oral treatment for anemia associated with chronic kidney disease through our licensing agreement with FibroGen.
• Astellas is developing the world’s first DNA vaccine for cytomegalovirus (CMV) infections. Currently in clinical trials, ASP0113 is a potential first-in-class agent for immunocompromised individuals undergoing solid organ or hematopoietic stem cell transplant who are at risk of viral reactivation. We are also working on a therapeutic vaccine, ASP4070, for Japanese red cedar pollen allergy.

We are building expertise in two new therapeutic areas—ophthalmology and muscle diseases—where there is significant unmet need. Through the Astellas Institute for Regenerative Medicine (AIRM) and external collaborations, we are addressing ophthalmologic diseases with a higher risk of blindness, including age-related and Stargardt’s macular degeneration, retinitis pigmentosa (RP), and diabetic macular edema (DME). In the muscle disease area, we are collaborating with our partner, Cytokinetics, on a skeletal muscle troponin activator which is being investigated in Spinal Muscular Atrophy (SMA). In addition, Astellas and Cytokinetics have agreed to amend their collaboration agreement to enable the development of CK-2127107 for the potential treatment of ALS and to extend their joint research focused on the discovery of additional next-generation skeletal muscle activators through 2017.

The pharmaceutical industry is intensely competitive and it requires an extensive search for technological innovations. How are you positioned to be a leader in developing new medicines that address unmet medical needs in critical therapeutic areas?

Dr. Zeiher: Astellas is focused on accelerating scientific discovery with an open innovation model. The Astellas open innovation model combines in-house R&D with strategic merger and acquisition approaches to advance research in untouched and complex disease states, allowing the company to maintain steady productivity and maximize its return on R&D investment.

With open innovation, Astellas undertakes research activities in the best possible environment. In some cases, the best environment is within the Astellas research laboratories. In many other cases, we look to collaborate with top biotech and academic leaders.  By building partnerships with top researchers and companies that complement our existing expertise, Astellas is able to quickly advance into new technologies and therapeutic areas of research where there is significant unmet medical need.

This approach has helped Astellas credibly enter into, compete and lead in some segments of the most competitive therapeutic areas in the pharmaceutical industry – oncology – and is accelerating the company’s efforts to develop treatments for important emerging therapeutic categories, such as ophthalmology and musculoskeletal disease, as well as leading technologies, such as regenerative medicine and vaccines.

For example, LAMP-vax is a next-generation DNA vaccine that utilizes the body’s natural cellular processing of Lysosomal Associated Membrane Protein (LAMP) to develop a more complete immune response to a target antigen.  The ability to activate a more complete immune response gives the LAMP-vax technology potential across a number of diseases, including allergic disease and cancer immunotherapy.  In 2015, Astellas established a licensing agreement with Immunomic Therapeutics, Inc. for the LAMP-vax products for the treatment or prevention of any and all allergic diseases in humans, including ARA-LAMP-vax for peanut allergy and other research-stage programs for food or environmental allergies.

Earlier this year, Astellas acquired Ocata Therapeutics, Inc., and established the Astellas Institute for Regenerative Medicine (AIRM) to serve as the global hub for Astellas regenerative medicine and cell therapy research. Our most advanced cellular therapy programs are in ophthalmology, but we are exploring other therapeutic areas. We are working on treatments for ophthalmologic diseases that leave patients at risk for blindness, which include retinitis pigmentosa (RP), age-related macular degeneration (AMD), and Stargardt’s macular degeneration (SMD).

Image SOURCE: Photograph of Dr. Bernhardt Zeiher, President of Development, at Astellas. Courtesy of Todd Rosenberg, 11/17/2014. 

Dr. Bernhardt Zeiher serves as President, Development, at Astellas. In this role, he is responsible for all phases of drug development.

Prior to his current role, Dr. Zeiher was executive vice president and Therapeutic Area head, Immunology, Infectious Diseases and Transplantation at Astellas. Of note, he led the development of CRESEMBA^® (isavuconazonium sulfate), which received Qualified Infectious Disease Product (QIDP) designation from the U.S. Food and Drug Administration and was approved in 2015 for the treatment of two rare invasive fungal infections. Prior to joining Astellas, he served as vice president of the Inflammation/Immunology therapeutic area at Pfizer.

Dr. Zeiher earned his Doctor of Medicine at the Case Western Reserve University School of Medicine, and completed an internal medicine residency at University Hospitals of Cleveland as well as a fellowship in Pulmonary and Critical Care Medicine at University of Iowa Hospitals and Clinics. Dr. Zeiher has received several awards, including being named a Fellow by American College of Physicians in 2004, awarded to those who demonstrate excellence and contributions to both medicine and the broader community of internists.

Editor’s note:

We would like to thank Jeff Winton, Andrew Lewis and Julie Monzo from the Astellas communications team for the tremendous help and support they provided during this interview.

REFERENCE/SOURCE

Astellas Pharma Inc. (https://www.astellas.com/en/) and Astellas Pharma U.S., Inc. (https://www.astellas.us/)

Other related articles:

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Retrieved from http://3blmedia.com/News/Astellas-and-World-Transplant-Games-Federation-Announce-Launch-Fit-Life-Promote-Physical

Retrieved from http://www.fiercepharma.com/pharma-asia/japan-s-astellas-shows-nearly-50-gain-q1-even-as-sales-drag-price-revisions

Retrieved from http://3blmedia.com/News/Astellas-Farma-Brasil-Ranked-Among-20-Greatest-Workplaces-Brazil

Other related articles were published in this Open Access Online Scientific Journal include the following: 

2016

LIVE 4:50 pm – 5:55 pm 4/25/2016 Early Detection and Prevention of Cancer & Innovation Break: Announcing the C³ Prize from Astellas Oncology and the World Medical Innovation Forum @2016 World Medical Innovation Forum: CANCER, April 25-27, 2016, Westin Hotel, Boston

LIVE 4:50 pm – 5:55 pm 4/25/2016 Early Detection and Prevention of Cancer & Innovation Break: Announcing the C³ Prize from Astellas Oncology and the World Medical Innovation Forum @2016 World Medical Innovation Forum: CANCER, April 25-27, 2016, Westin Hotel, Boston

Top Seven Big Pharma in Thomson Reuters 2015 Top 100 Global Innovators

Top Seven Big Pharma in Thomson Reuters 2015 Top 100 Global Innovators

Eye Lens Regenerated

Eye Lens Regenerated

2012

Picturing US-Trained PhDs’ Paths and Pharmaceutical Industry’s Crisis of Productivity: Partnerships between Industry and Academia

Picturing US-Trained PhDs’ Paths and Pharmaceutical Industry’s Crisis of Productivity: Partnerships between Industry and Academia

Medicines in Development for Cancer in 2012: An Excellent Response from America’s Biopharmaceutical Research Companies

Medicines in Development for Cancer in 2012: An Excellent Response from America’s Biopharmaceutical Research Companies

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A New Standard in Health Care – Farrer Park Hospital, Singapore’s First Fully Integrated Healthcare/Hospitality Complex

Posted in Innovations, Interviews with Scientific Leaders, Investment in Technological Breakthrough, Leadership, Power, Social Interlocking Connections, Patient’s Voice: Personal Experience with Invasive Medical Procedures, Uncategorized, tagged farrer park hospital; hospital innovation, health, hospital ceo, innovation in healthcare, Technology on June 22, 2016| Leave a Comment »

A New Standard in Health Care – Farrer Park Hospital, Singapore’s First Fully Integrated Healthcare/Hospitality Complex

Author: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

WordCloud Image Produced by Adam Tubman

Farrer Park Hospital, Singapore’s newest private healthcare service provider, headed by newly appointed Chief Executive Officer Timothy Low, M.D., is a private, acute tertiary institution that represents an innovation in hospital administration, incorporating the latest technology to support better decision making for better patient outcomes and shorter hospital stays along with the beauty of nature and art to enhance the patient experience. The hospital, opened in March 2016, is sited within Singapore’s first, fully integrated healthcare and hospitality complex, called Connexion, which is Asia’s first, integrated lifestyle hub for healthcare and wellness. Connexion houses the 220-bed Farrer Park Hospital with its more than 300-accredited specialists and 18 operating rooms, a 10-floor specialist Medical Center, along with a five-star hotel and spa. In 2016, Farrer Park Hospital was awarded best new hospital of the year in Asia Pacific by Global Health and Travel Awards.

Image SOURCE: Photograph courtesy of Farrer Park Hospital, Singapore. An integrated healthcare and hospitality complex, called Connexion, Asia’s first, integrated lifestyle hub for healthcare and wellness, which includes Farrer Park Hospital.  

The hospital is also a teaching site for undergraduate medical training, providing enhanced medical care, service quality and professional integrity and value. Supported by approximately 600 hospital staff, specialists at Farrer Park Hospital provide a range of services, such as cardiology, oncology, orthopedic surgery, gastroenterology and ophthalmology. A 24-hour emergency department provides attention for acute illnesses and the hospital has the most modern facilities for diagnostic imaging, nuclear medicine, radiotherapy and clinical laboratories.

Image SOURCE: Photographs courtesy of Farrer Park Hospital, Singapore. Left is a deluxe suite, top right is Farrer Park Hospital lobby, bottom right is Farrer Park Hospital building.

Medical tourism — the process of traveling outside your country of residence to receive medical care — represents a worldwide, multi-billion-dollar business that is expected to grow considerably in the next decade. Interestingly, Singapore’s medical tourism market is projected to grow by 8.3 percent annually and reach revenue of USD $1.36 billion a year by 2018.

My first question is: Why has Singapore emerged in the past few years as an international healthcare and research hub?

Dr. Low:  With Singapore’s excellent patient services and its dedication to research and wellness, the country continues to remain as the top destination for those seeking medical care. By providing convenience and trust in our medical sector, there is no doubt that it will continue to expand and grow. Our dedication is towards the patient, cutting-edge technology and personalized care. This makes Singapore a multi-faceted medical hub and a center of excellence. Patient can receive excellent standard of medical treatment, comparable to the Europe and the USA.

Currently, we are attracting foreign patients who expect five- or six-star hotel service, because we’re a private hospital. That’s why I’m strict about appearances. We have to look as groomed, and we need to be as personable, as those in hospitality and the airlines.

Please describe the concept behind Farrer Park Hospital as Singapore’s first, fully integrated healthcare and hospitality complex.

Dr. Low: The Farrer Park Hospital was designed and built to be a hospital of the future, combining innovation in medical care and medical education. The hospital was initially created by medical specialists to respond to the growing challenges of healthcare in Singapore and, more broadly, throughout the Asia Pacific region. We have ‘reimagined’ private healthcare in order to enhance medical care, service quality, professional integrity and value.

We are leading the way in healthcare innovation as we are a premier institution for medical care and education that is based upon three important tenets for the patient — comfort, fairness and value. In fact, our top accredited medical staff, along with state-of-the-art equipment and technology, contributes to increased efficiency, reduced cost, and most, importantly improved patient outcomes.

As an innovation in hospital administration, Farrer Park Hospital embraces technology and improves medical care through its state-of-the-art equipment that facilities telemedicine consulting services across the world. To create a conducive environment for medical professionals, the hospital’s 18 operating rooms are linked via fiber-optic connections to various locations through the Connexion complex, including the hospitals’ education center and lecture hall, teaching clinics and tutorial rooms as well as the hotel’s function rooms. In addition to being equipped with the latest in useful medical technology, the hospital has state-of-the-art information technology which enables seamless and rapid flow of information between the admission services, inpatient areas, operating theaters, diagnostic and therapeutic centers, clinical laboratories and medical clinics. We also are the country’s first private hospital to become a teaching site, with the medical students from Lee Kong Chian School of Medicine at Nanyang Technological University.

What is the type of environment you are creating at Farrer Park Hospital?

Dr. Low: Our care philosophy extends beyond healing and the management of disease to engaging with our patients as partners in pursuit of good health and providing an oasis for healing and relaxation. Throughout our facility, patients will find that attention has been given to every aspect and detail of our facility – from the comfort of our patients, to its impact on the environment, to the speed and ease of obtaining medical attention and to the maintenance of hygiene.

As healthcare players go, we are small and that has made us very aware of our challenges. As such, we have encouraged a culture of innovation, to grasp opportunities quickly. Healthcare is a very traditional industry, resistant to change and thus tend to be laggards in technology. Farrer Park Hospital, however, embraces technology. The seamlessness of information flow was the focus at the onset of the project. This hospital was planned technologically to be relevant for the next 20 years.

Being an institution built by healthcare practitioners has its advantages. We achieve painstaking perfection in our attention to detail. The hospital has many practical features that serve the needs of practitioners and patients while the hoteliers add details for comfort, luxury and aesthetics.

Our hospital is also supported by a hospital staff, who provide a range of specialty services, such as cardiology, oncology, orthopedic surgery, gastroenterology and ophthalmology, along with a 24-hour emergency clinic, which provides immediate care for acute illnesses. The hospital also has the most modern facilities for diagnostic imaging, nuclear medicine, radiotherapy and clinical laboratories. There is even a holistic service which focuses on screening, preventive medicine and lifestyle enhancement.

What is your perspective of engaging with patients?  

Dr. Low: The hospital’s care philosophy extends beyond healing and the management of disease to engaging patients in pursuit of good health. Healing does not end after a successful operation. It is not just about coming to the hospital for a procedure and then recuperating at home. It is about having the best and most comfortable services to get the patient on their feet. And having a family support structure close by, where relatives can stay close to the hospital, is essential in the rehabilitation process. That is why, as part of Connexion, the hospital is Asia’s first, integrated lifestyle hub for healthcare and wellness that is linked to a five-star hotel and spa.

Patients are treated by an experienced team of medical and health specialists in an environment meticulously designed to maximize comfort and efficiency while promoting well-being, rest and recovery.

How are you positioned technologically to be a leader in developing first-rate patient care? 

Dr. Low: We have taken the lead in many areas. Our facility is wired completely, any tests and treatments is automated whenever possible and the information is sent in real time to all stakeholders who require it. Our doctors can access this technology and make decisions as if they are in the hospital anywhere in the world.

What type of physician are you attempting to attract?

Dr. Low: The environment at Farrer Park Hospital is about clinical and service excellence, supported by physical and technological constructs that facilitates both these endeavors. We are building a culture of fairness and promoting decision making that is free from self-interest and toward better patient outcome. The doctors who join us must be aware that we take our code of comfort, fairness and value seriously.

What is the thinking behind the philosophy of incorporating nature and art into healthcare in Farrer Park Hospital?

Dr. Low: The architecture of Farrer Park Hospital and Connexion reflects the deep commitment to creating a true learning environment. Synergies between our hospital along with a closely linked hotel stimulate many innovations for improving the healthcare experience. The concept of a hospital near a hotel is not new, however, to integrate it to the level that we have is something novel. We followed a biophilic architecture approach throughout the facility, incorporating nature and art to enhance healing. Hospitals are traditionally not the best place for recuperation. We strive to have the restful ambiance of a hotel, in addition to proximity of doctors and family under the same roof, as well as using technology to enable seamless and speedy decision making; all this in support of better patient outcome and shorter stays.

You could say we are different in how we view private healthcare. A traditional hospital would not carve out 15 gardens at multiple levels throughout the facility so that patients and families can have places to feel the warmth of the sun and breathe fresh air whenever they like. The facility also hosts a private collection of over 700 commissioned Asian paintings meant to enhance the healing environment.

In land-scarce Singapore, a typical businessperson would not have fewer paid parking lots, making them one and a half times the size of a standard lot to allow a patient on crutches to comfortably extend the car door fully to disembark. A standard project manager would not insist that contractors construct a curved sink so that surgeons will not have water dripping down his elbows after scrubbing his or her hands, or a bath bench with a cut out that allows patients to sit while washing themselves. This may seem unnecessary but these innovative approaches translate to actual benefits to people who ‘value’ them.

Everyone has the same end goal, a good experience and better patient outcome. Our strategy is simple. We take our responsibilities to patients, their families and the clinicians seriously. Attend to their needs, anticipate their wants, and find the best way to address these concerns through innovation and technology. This ultimately brings value to patients.

How does nature and art come together at Farrer Park Hospital?

Dr. Low: The hospital, hotel and specialist center share and enjoy 15 gardens created at multiple levels in the building. One of the gardens, The Farm @ Farrer, grows fruits, vegetables and herbs for the hotel kitchens, and at the same time, is a large outdoor green space for recovering patients to stroll and sun. Uniquely, Farrer Park Hospital patients enjoy meals prepared by chefs in the hotel’s kitchens and confectionery.

Our inpatient food service, for example, is also automated, so whatever appears on the electronic screen on a patient’s personal tablet matches their dietary restrictions. The menu is a matrix of over 200 items customized by hotel chefs and our hospital nutritionist. Food that is fresh, delicious and safe for patient consumption is our primary focus.

Not only do we benchmark ourselves with hospitals, but also we take our inspiration from other industries. We believe to be at the top, you need to look beyond, break through and recreate process models and apply them for use in healthcare.

Image SOURCE: Photograph of Chief Executive Officer Timothy Low, M.D., courtesy of Farrer Park Hospital, Singapore.

Chief Executive Officer of Farrer Park Hospital, Timothy Low, M.D., brings a strong leadership background in managing award-winning hospitals. Prior to his current role, Dr. Low served as CEO of Gleneagles Hospital in Singapore. Through his leadership, the hospital established itself as a six-star private healthcare provider, clinching 14 local and regional awards including the prestigious Asian Hospital Management Award as well as the the ‘National Work Redesign Model Company’ by Spring Singapore, a governing agency for innovation in Singapore. Under his leadership, revenues exceed 42 percent to over USD $100 million.

Having also served in senior management positions for pharmaceutical and medical device industries in the Asia Pacific region, Dr. Low’s breath of exposure allowed him to pioneer the establishment of a global contract research organization, validating Singapore as its regional headquarters.

With more than 28 years of experience in the health care industry with such leading companies as Covidien, Covance and Schering-Plough, Dr. Low brings with him a strong background of leadership within the business and medical community. With his vast experience and contributions to the industry, Dr. Low is listed in the ranks of Stanford Who’s Who.

Dr. Low received his Bachelor of Medicine and Bachelor of Surgery from the National University of Singapore (NUS) and is also a graduate of the NUS Graduate School of Business, Stanford University Executive Program and the Singapore Management University Asia Pacific Hospital Management Program.

REFERENCE/SOURCE

Tan, W. (2016). Farrer Park Hospital patients can recuperate at adjoining hotel to ease ward crunch. The Straits Times. Retrieved from  http://www.straitstimes.com/singapore/health/farrer-park-hospital-patients-can-recuperate-at-adjoining-hotel-to-ease-ward-crunch

Tan, W. (2016). New Farrer Park Hospital aims to offer ‘affordable’ private care. The Straits Times. Retrieved from http://www.straitstimes.com/singapore/health/new-farrer-park-hospital-aims-to-offer-affordable-private-care

 

Anonymous (2012). Singapore Medical Tourism: Farrer Park Healthcare and Hospitality Complex Will Open in 2013. International Medical Travel Journal. Retrieved from http://www.imtj.com/news/singapore-medical-tourism-farrer-park-healthcare-and-hospitality-complex-will-open-2013/

Other related articles:

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Retrieved from http://www.farrerpark.com/hospital/Pages/Home.aspx

Retrieved from http://www.straitstimes.com/singapore/health/new-farrer-park-hospital-aims-to-offer-affordable-private-care

Retrieved from http://www.bca.gov.sg/friendlybuilding/FindBuilding/Building.aspx?id=4534

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Other related articles were published in this Open Access Online Scientific Journal include the following: 

2016

Third Annual BioPrinting and 3D Printing in the Life Sciences, 21-22 July 2016 at Academia, Singapore General Hospital Campus

Third Annual BioPrinting and 3D Printing in the Life Sciences, 21-22 July 2016 at Academia, Singapore General Hospital Campus

2015

Patient Satisfaction with Hospital Experience

Patient Satisfaction with Hospital Experience

2013

Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity 

Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity”

Risk Factor for Health Systems: High Turnover of Hospital CEOs and Visionary’s Role of Hospitals In 10 Years

Risk Factor for Health Systems: High Turnover of Hospital CEOs and Visionary’s Role of Hospitals In 10 Years

Hospitals in China

HOSPITALS in CHINA

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Point of care pulse oximetry

Posted in Curation, Diagnostics and Lab Tests, Digital HealthCare – biotech & internet joint ventures, FDA Regulatory Affairs, Innovations, Lung and pulmonology, tagged COPD, finger pulse oximetry, POCT on May 18, 2016| Leave a Comment »

Point of care pulse oximetry

Curator: Larry H. Bernstein, MD, FCAP

LPBI

 

Not All FDA-Cleared Finger Pulse Oximeters Perform Alike

http://www.mdtmag.com/news/2016/05/study-not-all-fda-cleared-finger-pulse-oximeters-perform-alike

Nonin Medical, Inc., the inventor of finger pulse oximetry, today announced the results of a new independent hypoxia lab study in humans that demonstrates that Nonin’s PureSAT pulse oximetry technology captures and reports worsening patient conditions better than other Food and Drug Administration (FDA)-cleared oximeter brands.¹Nonin made the results available in a white paper at the American Thoracic Society (ATS) and American Telemedicine Association (ATA) conferences this week.

Not all FDA-cleared finger pulse oximeters perform alike, says a new study. Nonin Medical’s pulse oximetry technology was found to be more accurate in patients with challenging conditions, such as COPD.

In the study, conducted independently by Clinimark Laboratories in Boulder, Colo., three finger pulse oximeters were tested; one from Nonin Medical and two from large, private-labeled manufacturers. All oximeters had FDA 510(k) clearance as “medical devices,” but two of them did not provide the clinical accuracy required to track desaturations in patients with low blood circulation and labored breathing. Only the Nonin Medical oximeter was able to accurately track the desaturation events as compared to an independent hospital tabletop oximeter control device.

Not all FDA-cleared finger pulse oximeters perform alike, says a new study. Nonin Medical’s pulse oximetry technology was found to be more accurate in patients with challenging conditions, such as COPD. (Credit: PRNewsFoto/Nonin Medical, Inc.)

“Over the years, a number of inexpensive, imported FDA-cleared oximeters have flooded the market, all claiming to be accurate,” said Jim Russell, vice president of quality, regulatory and clinical affairs for Nonin Medical. “This study dispels the myth that all pulse oximeters perform alike, especially on challenging patients such as those with chronic obstructive pulmonary disease (COPD).

“Clinicians, hospitals and telemedicine providers can better manage COPD patients and potentially reduce readmission rates by choosing pulse oximeters that provide early and accurate data on all patients, including the sickest patients. Nonin Medical’s oximeter performance is proven,” Russell said.

References
¹Batchelder, P.B., Fingertip Pulse Oximeter Performance in Dyspnea and Low Perfusion During Hypoxic Events. Clinimark Laboratories, Boulder, Colorado. 2016. White Paper.

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Antibody drug conjugates (ADCs)

Posted in Cancer and Current Therapeutics, Clinical & Translational, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Immuno-Oncology & Genomics, Immunology, Innovations, tagged antibody-drug conjugates, Constructing, Homogeneous, Processes on May 5, 2016| Leave a Comment »

Antibody drug conjugates (ADCs)

Larry H. Bernstein, MD, FCAP: Curator

LPBI

UPDATED 6/01/2024

Below are a curation of reports highlighting both clinical trial failures and serious adverse events reported from clinical trials of various antibody drug or antibody radioligand conjugates.  As see below, there have been mutliple failures of these types of biological entitites in oncology clinical trials, either displaying issues related to efficacy and/or safety.

Source: https://www.fiercebiotech.com/biotech/asco-jjs-radioligand-spurs-responses-4-deaths-mar-early-results

ASCO: J&J’s radioligand spurs responses, but 4 deaths mar early results
By Annalee Armstrong May 24, 2024

Johnson & Johnson’s radiopharmaceutical spurred “profound and durable” responses, however, four patient deaths in the early-stage trial marred the results.

JNJ-6420 is an anti-hK2 antibody-based targeted radioligand therapy that’s designed to deliver a high-energy, short-range alpha-particle emitter to prostate cancer cells. The first-in-human study tested the radiopharmaceutical in patients with metastatic castration-resistant prostate cancer who have previously received at least one prior androgen receptor pathway inhibitor. The results are to be presented next week at the American Society of Clinical Oncology conference. The goal of the phase 1 dose-escalation study was to demonstrate the drug’s safety and to find a dose to move into phase 2. In one trial group, 37 patients were on a fixed dosing starting schedule, receiving between 50 μCi and up to 300 μCi. Twenty-nine patients in the other trial group were capped at a cumulative 500-μCi dose. As of the Jan. 5 data cutoff, 64 patients had received at least one dose of JNJ-6420, with safety data being recorded for 57 patients who had received 150 μCi. Of these patients, 35, or 61%, experienced grade 3 or higher treatment-emergent adverse events (TEAEs), and 21, or 37%, had a serious TEAE. Almost all patients experienced some sort of TEAE. There were four deaths due to TEAEs, which were associated with repeated dosing of JNJ-6420. The full data set linked two of the deaths to interstitial lung disease (ILD), one to respiratory failure related to COVID-19 and one to decreased appetite/hypotension. ILD is a common adverse event in oncology treatment, particularly for antibody-drug conjugates. The condition causes progressive scarring of lung tissue. The deaths related to ILD occurred in patients who had received cumulative doses greater than or equal to 750 μCi. To address the risk of ILD and thrombocytopenia, the study investigators are recommending a cumulative dose cap and an adaptive dose schedule. Evaluation of adaptive dosing is ongoing.  Other common TEAEs in the study included anemia and two conditions related to low white blood cells, lymphopenia and leukopenia. Nine patients discontinued treatment. As for the responses, the data showed a reported PSA50 rate of 45.6%. This is a measure of prostatic-specific antigen, which is a key biomarker in prostate cancer. A PSA response is associated with prolonged overall survival.

ADC puts Zynlonta study on hold after 7 patient deaths, 5 other severe adverse events (2023)

Source: https://www.fiercepharma.com/pharma/adc-therapeutics-puts-zynlonta-study-enrollment-pause-after-seven-patient-deaths-five-other

By Zoey Becker  Jul 11, 2023

DC Therapeutics has slammed the brakes on enrollment in a phase 2 combination trial for Zynlonta as it investigates seven patient deaths and five other severe respiratory events among patients who received the drug.

For the study in unfit or frail patients with previously untreated diffuse large B-cell lymphoma (DLBCL), investigators had enrolled 40 participants. After receiving the ADC drug, 12 of them experienced respiratory-related, treatment-emergent adverse events, ADC said in a Tuesday release.

The investigators concluded that 11 of the events, including six of the deaths, were “unrelated” to the Zynlonta treatment or unlikely to be related to the drug, ADC said.  All of the patients who died suffered from at least one “significant” comorbidity, including obstructive pulmonary disease, pulmonary edema, chronic bronchiectasis, idiopathic pulmonary fibrosis or recent COVID-19 infection. All of the patients who passed away were at least 80 years of age, according to the company. ADC said it put a “voluntary pause” on the trial to gain more time to “evaluate data … and determine next steps.” The study was testing ADC’s medicine in combination with Roche’s Rituxan. “Our top priority is the safety of every patient who participates in our clinical trials,” CEO Ameet Mallik said in the company’s statement. “This trial includes a very difficult-to-treat patient population with limited treatment options, and we will provide an update on next steps when available.” ADC has notified the FDA and the European Medicines Agency (EMA) and doesn’t expect to report any additional trial data by the end of the year.

However in 2024 from ADC Therapeutics site

ZYNLONTA^® 1 4Q 2023 net sales expected to be ~$16.5 million, a double-digit percentage increase as compared to 3Q 2023

LOTIS-7: Study of ZYNLONTA in combination with bispecifics cleared first dosing cohort​ with no DLT and with early signs of efficacy

ADCT-601 (targeting AXL): Reached MTD and currently in dose optimization; Early signs of antitumor activity in both monotherapy and in combination

Multiple data catalysts expected in 2024 and with a cash runway now expected into 4Q 2025

LAUSANNE, Switzerland, Jan. 04, 2024 (GLOBE NEWSWIRE) — ADC Therapeutics SA (NYSE: ADCT) today provided business updates.

“During 2023, we took a number of decisive actions to help position the Company for success in 2024 and beyond. We prioritized our pipeline, strengthened our organization and implemented a disciplined capital allocation model to generate cost efficiencies,” said Ameet Mallik, Chief Executive Officer of ADC Therapeutics. “We believe we are starting to see signs of the commercial turnaround. We are also encouraged to see positive initial signals in the LOTIS-7 trial of ZYNLONTA in combination with bispecifics as well as early signs of antitumor activity in the Phase 1b trial of ADCT-601. We now expect our cash runway to extend into the fourth quarter of 2025 and believe we are on a path to unlock the substantial value in the Company.”

Source: ADC Therapeutics Press Release at https://ir.adctherapeutics.com/press-releases/press-release-details/2024/ADC-Therapeutics-Provides-Business-Updates/default.aspx

 

Processes for Constructing Homogeneous Antibody Drug Conjugates

by DR ANTHONY MELVIN CRASTO Ph.D

Processes for Constructing Homogeneous Antibody Drug Conjugates

David Y. Jackson^*†

^† Igenica Biotherapeutics, 863A Mitten Road, Suite 100B, Burlingame, California 94010, United States

Org. Process Res. Dev., Article ASAP

http://dx.doi.org:/10.1021/acs.oprd.6b00067       http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00067#    Publication Date (Web): April 14, 2016

Antibody drug conjugates (ADCs) are synthesized by conjugating a cytotoxic drug or “payload” to a monoclonal antibody. The payloads are conjugated using amino or sulfhydryl specific linkers that react with lysines or cysteines on the antibody surface. A typical antibody contains over 60 lysines and up to 12 cysteines as potential conjugation sites. The desired DAR (drugs/antibody ratio) depends on a number of different factors and ranges from two to eight drugs/antibody. The discrepancy between the number of potential conjugation sites and the desired DAR, combined with use of conventional conjugation methods that are not site-specific, results in heterogeneous ADCs that vary in both DAR and conjugation sites. Heterogeneous ADCs contain significant fractions with suboptimal DARs that are known to possess undesired pharmacological properties. As a result, new methods for synthesizing homogeneous ADCs have been developed in order to increase their potential as therapeutic agents. This article will review recently reported processes for preparing ADCs with improved homogeneity. The advantages and potential limitations of each process are discussed, with emphasis on efficiency, quality, and in vivo efficacy relative to similar heterogeneous ADCs.

Antibody drug conjugates (ADCs) are a rapidly growing class of targeted therapeutic agents for treatment of cancer.(1-8) Although the number of ADCs in clinical trials has steadily increased since 2005, many have failed to reach the later stages of clinical development; one has been withdrawn from the market (Mylotarg in 2002), and only two (Adcetris and Kadcyla) are currently approved by the FDA for cancer indications (Figure 1A).(9-11) Thus, far, the approval rate for ADCs has not met early expectations and is lagging behind other antibody-based therapeutics. Based on the number of approved ADCs versus those that have failed to progress into later stage clinical trials, the success rate is reminiscent of that for small molecule drugs. The reasons for the clinical failures of ADCs are often not known or they are still under investigation. More commonly, when the reasons for clinical failure are clear, the information is not made available to the public domain. Emerging preclinical data suggests that heterogeneity, a property shared by most ADCs currently in clinical development (Table 1), may ultimately limit their potential as therapeutic agents.(12, 13)

Table 1. Examples of Heterogeneous ADCs Currently in Clinical Trials for Cancer Indications^a

a Source: www.clinicaltrials.gov.

 

 

http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/0/oprdfk.ahead-of-print/acs.oprd.6b00067/20160428/images/large/op-2016-00067k_0001.jpeg

Figure 1. (A) Number of ADCs in different stages of clinical development from 2006 to 2014. (B) Structure of a typical IgG antibody showing lysines (red), cysteines (yellow), and glycans (green) as potential conjugation sites.(16)

ADCs are composed of a cytotoxic drug or “payload” conjugated to a tumor selective monoclonal antibody. The heterogeneity of conventional ADCs arises from the synthetic processes currently used for conjugation.(14) Payloads are typically conjugated to the antibody using amino or thiol specific linkers that react with lysines or cysteines on the antibody surface.(15) A typical antibody contains more than 50 lysines and up to 12 cysteines as potential conjugation sites (Figure 1B).(16) The optimal DAR (drugs/antibody ratio) for most ADCs, however, ranges from 2 to 8 drugs/antibody and is dependent upon a variety of different factors. The discrepancy between the number of potential conjugation sites and the desired DAR, combined with the use of conjugation methods that are not site-specific, result in heterogeneous ADCs that vary in both DAR and conjugation sites. Consequently, conventional heterogeneous ADCs often contain significant amounts of unconjugated antibody in addition to fractions with suboptimal DARs. Unconjugated antibodies can compete for antigen binding and inhibit ADC activity, while fractions with suboptimal DARs are frequently prone to aggregation, poor solubility, and/or instability that ultimately result in a poor therapeutic window.(17, 18)

The relative degree of ADC heterogeneity depends on the methods used for conjugation. For example, Kadcyla, an ADC approved in 2013 for breast cancer, is synthesized using a two-step process in which the linker and payload are conjugated in separate steps (Scheme 1A).(19-21)The linker contains an amino-specific NHS ester that reacts with antibody lysines in the first step and a thiol-specific maleimide group that reacts with a maytansinoid payload in the second step. The process affords a highly heterogeneous mixture of ADC molecules containing from 0 to 10 payloads/antibody with an average DAR of 3.5 drugs/antibody.(22, 23) Additional heterogeneity arises due to distribution of the payloads across dozens of potential conjugation sites. As a result, Kadcyla contains hundreds of different ADC molecules, each with its own unique pharmacological properties.(24)

Scheme 1. (A) General Process for Synthesizing ADCs such as Kadcyla via Lysine Conjugation; (B) General Process for Synthesizing ADCs, such as Adcetris, via Cysteine Conjugation

Conjugation of payloads to antibodies through interchain cysteines reduces ADC heterogeneity relative to lysine conjugation because there are fewer potential conjugation sites. Adcetris, an ADC approved in 2011 for treatment of Hodgkin’s lymphoma, is an example of a cysteine conjugated ADC.(25-27) The process for cysteine conjugation involves partial reduction of four antibody interchain disulfide bonds to generate up to eight reactive thiol groups. The partially reduced antibody is subsequently conjugated to a payload containing a thiol-specific maleimide linker. The payload used for Adcetris is monomethyl auristatin E (MMAE) and contains a protease cleavable maleimide linker (Scheme 1B). Although Adcetris is less heterogeneous than Kadcyla, it is composed of dozens of different ADC molecules containing 0 to 8 payloads with an average DAR of 3.6 drugs/antibody.(28) Like most cysteine conjugated ADCs, Adcetris has a reduced half-life in vivo compared to the parent antibody, cAC10. The diminished half-life has been attributed to rapid clearance of high DAR species (>4 drugs/antibody) and to partial loss of interchain disulfide bonds during the conjugation process.(29, 30)

Although different processes for lysine and cysteine conjugation are used to synthesize Adcetris and Kadcyla, both ADCs contain thio-succinimide bonds between the payload and the antibody, which originate from the use of maleimide linkers in the conjugation processes. Kadcyla contains a thio-succinimide between the linker and the payload (Scheme 1A), while Adcetris contains a thio-succinimide bond between the linker and the antibody (Scheme 1B). Thio-succinimide groups are known to undergo undesired side reactions such as elimination or thiol exchange that can result in premature release of the payloads from the ADC and lead to reduced potency and/or increased systemic toxicity.(31, 32)

Despite the known limitations of conventional heterogeneous ADCs, most ADCs currently in clinical development utilize similar conjugation methods to those described in Scheme 1. As a result, they are likely to possess similar pharmacological properties to Adcetris and Kadcyla, in addition to other less successful ADCs that may have performed poorly in clinical trials. In order to improve the pharmacological properties of current and future ADCs, new site-specific conjugation processes for synthesizing homogeneous ADCs are now being developed.(33-36)

Site-specific conjugation processes for constructing homogeneous ADCs can be divided into three different categories. Two are focused on antibody modification (engineered amino acids and enzyme mediated), while the third category is focused on linker modification. The categories can be subdivided further based on the specific processes that are used (Table 2). Examples from each process were selected based on availability of sufficient preclinical data to enable comparison with similar conventional heterogeneous ADCs. Homogeneous ADCs derived from these processes have only just begun to enter clinical trials. Whether they will outperform their heterogeneous counterparts in clinical trials remains uncertain, but preclinical data suggest that homogeneous ADCs are likely to dominate future clinical trials and will lead to improved clinical results.

Table 2. Summary of Different Processes for Constructing Homogeneous ADCs

…….

All of the processes reviewed here were successfully used to construct ADCs with improved homogeneity over ADCs synthesized using conventional methods. A majority of approaches utilize recombinant antibody engineering to introduce unique functional groups for site-specific conjugation. The unique functional groups were introduced either as point mutations for cysteine and non-natural amino acids or as enzyme recognition tags. These recombinant engineering approaches offer several potential advantages over nonrecombinant approaches. For example, engineered cysteines can be incorporated into dozens of different sites with minimal impact on the functional properties of the antibody. This enables ADCs to be optimized for conjugation efficiency, linker stability, and potency. Engineered non-natural amino acids offer additional advantages due to the diverse array of different functional groups that can be introduced. Furthermore, non-natural amino acids enable a variety of new linker chemistries to be investigated that are not possible with conventional conjugation processes.

The flexibility offered by recombinant processes may also represent their greatest challenge. The importance of the conjugation site for ADC activity is well-established, but additional factors should be considered before selecting a development candidate. Potential effects on antibody expression, conjugation efficiency, linker stability, aggregation, and other factors need to be considered before selecting a specific conjugation site. These factors can ultimately determine the success or failure of an ADC development program. Since antibodies share many of the same properties, it seems likely that optimal conjugation sites will be identified that are broadly effective when used with different antibodies. Other potential challenges for processes involving antibody engineering include increased development time and costs, immunogenicity of engineered sequence tags, scalability, and use of novel linkers and payloads that are not yet clinically validated.

In addition to homogeneity, improvements in other ADC properties such as potency, stability and half-life were observed. In fact, many of the homogeneous ADCs derived from these processes out-performed conventional heterogeneous ADCs in efficacy and safety studies. Much of their success has been attributed to elimination of high DAR species present in conventional ADCs. In general, experimental results are consistent with this conclusion, and many would agree that substantial progress has resulted from these efforts to improve ADC homogeneity. Ironically, the relative contribution of homogeneity to the improved properties of the engineered ADCs could not be determined from most studies because other factors known to effect ADC activity could not be ruled out.

For instance, recombinant approaches for making homogeneous ADCs were designed to introduce conjugation sites in different locations from those used in conventional methods. Since it is now well-established that “location matters”, the observed differences in activity between TDCs (or NDCs) and the conventional ADC controls could result from different conjugation sites, rather than from elimination of high DAR species. Enzyme mediated approaches face similar challenges when comparing homogeneous and heterogeneous ADCs because the conjugation sites are different. Other variables such as linker type (cleavable or noncleavable) and payload (maytansine or PBD) need to be carefully controlled before reaching conclusions about the benefits of homogeneity.

Linker based processes are more suitable for comparing homogeneous ADCs with conventional heterogeneous ADCs because they utilize the same conjugation sites. Once other variables that might impact ADC activity were carefully controlled, the relative benefits of homogeneity were revealed for the first time and the results confirmed that efforts to improve ADC homogeneity have been a worthwhile endeavor.

Most of the processes reviewed here are still in early phases of clinical development. All of the methods have advantages and limitations that will ultimately decide which approach will become the preferred process for manufacturing homogeneous ADCs. It is not yet clear which process will rise above the others as a preferred method, but all of these approaches have contributed valuable information to our knowledge base and resulted in ADCs with improved pharmacological properties over conventional heterogeneous ADCs. Our future challenge will be to apply this knowledge to develop ADCs that will be more effective as therapeutic agents. Our ability to synthesize homogeneous ADCs provides another reason to be optimistic about the future of ADCs.

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00067

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Gene Editing with CRISPR gets Crisper

Posted in Artificial Intelligence - Breakthroughs in Theories and Technologies, Artificial Intelligence - General, BioIT: BioInformatics, Biological Networks, Gene Regulation and Evolution, BioTechnology - Venture Creation, Cancer and Current Therapeutics, Cancer Informatics, Cancer Screening, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Clinical & Translational, Clinical Diagnostics, Clinical Genomics, CRISPR/Cas9 & Gene Editing, Diagnostics and Lab Tests, Disease Biology, Small Molecules in Development of Therapeutic Drugs, DNA repair, FDA Regulatory Affairs, Gene Regulation, Genetics & Pharmaceutical, Genomic Expression, Genomic Testing: Methodology for Diagnosis, Genomics Pharmacy, Innovations, Loss of function gene, Mutant Gene Expression, Nanotechnology for Drug Delivery, Next Generation Sequencing (NGS), Oligonucleotide Therapeutics & Delivery, tagged causal variants underlying trait differences, CRISPR-based gene editing, Drug discovery, gene mapping and CRISPR/Cas, genetic markers, mapping, mapping panels, phenotype, sgRNA, systems biology, targeted recombination events, yeast on May 3, 2016| Leave a Comment »

Gene Editing with CRISPR gets Crisper

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

 

CRISPR Moves from Butchery to Surgery   

More Genomes Are Going Under the CRISPR Knife, So Surgical Standards Are Rising

• Meghaan M. Ferreira, Ph.D.

http://www.genengnews.com/gen-articles/crispr-moves-from-butchery-to-surgery/5759/

• http://www.genengnews.com/Media/images/Article/thumb_GE_Dharmacon_cas9tracrrna1332182551.jpg

  The Dharmacon subsidary of GE Healthcare provides the Edit-R Lentiviral Gene Engineering platform. It is based on the natural S. pyrogenes system, but unlike that system, which uses a single guide RNA (sgRNA), the platform uses two component RNAs, a gene-specific CRISPR RNA (crRNA) and a universal trans-activating crRNA (tracrRNA). Once hybridized to the universal tracrRNA (blue), the crRNA (green) directs the Cas9 nuclease to a specific genomic region to induce a double- strand break.

  Scientists recently convened at the CRISPR Precision Gene Editing Congress, held in Boston, to discuss the new technology. As with any new technique, scientists have discovered that CRISPR comes with its own set of challenges, and the Congress focused its discussion around improving specificity, efficiency, and delivery.

  In the naturally occurring system, CRISPR-Cas9 works like a self-vaccination in the bacterial immune system by targeting and cleaving viral DNA sequences stored from previous encounters with invading phages. The endogenous system uses two RNA elements, CRISPR RNA (crRNA) and trans-activating RNA (tracrRNA), which come together and guide the Cas9 nuclease to the target DNA.

  Early publications that demonstrated CRISPR gene editing in mammalian cells combined the crRNA and tracrRNA sequences to form one long transcript called asingle-guide RNA (sgRNA). However, an alternative approach is being explored by scientists at the Dharmacon subsidiary of GE Healthcare. These scientists have a system that mimics the endogenous system through a synthetic two-component approach thatpreserves individual crRNA and tracrRNA. The tracrRNA is universal to any gene target or species; the crRNA contains the information needed to target the gene of interest.

  Predesigned Guide RNAs

  In contrast to sgRNAs, which are generated through either in vitro transcription of a DNA template or a plasmid-based expression system, synthetic crRNA and tracrRNA eliminate the need for additional cloning and purification steps. The efficacy of guide RNA (gRNA), whether delivered as a sgRNA or individual crRNA and tracrRNA, depends not only on DNA binding, but also on the generation of an indel that will deliver the coup de grâce to gene function.

  “Almost all of the gRNAs were able to create a break in genomic DNA,” said Louise Baskin, senior product manager at Dharmacon. “But there was a very wide range in efficiency and in creating functional protein knock-outs.”

  To remove the guesswork from gRNA design, Dharmacon developed an algorithm to predict gene knockout efficiency using wet-lab data. They also incorporated specificity as a component of their algorithm, using a much more comprehensive alignment tool to predict potential off-target effects caused by mismatches and bulges often missed by other alignment tools. Customers can enter their target gene to access predesigned gRNAs as either two-component RNAs or lentiviral sgRNA vectors for multiple applications.

  “We put time and effort into our algorithm to ensure that our guide RNAs are not only functional but also highly specific,” asserts Baskin. “As a result, customers don’t have to do any design work.”

  Donor DNA Formats

  http://www.genengnews.com/Media/images/Article/thumb_MilliporeSigma_CRISPR3120824917.jpg

  MilliporeSigma’s CRISPR Epigenetic Activator is based on fusion of a nuclease-deficient Cas9 (dCas9) to the catalytic histone acetyltransferase (HAT) core domain of the human E1A-associated protein p300. This technology allows researchers to target specific DNA regions or gene sequences. Researchers can localize epigenetic changes to their target of interest and see the effects of those changes in gene expression.

  Knockout experiments are a powerful tool for analyzing gene function. However, for researchers who want to introduce DNA into the genome, guide design, donor DNA selection, and Cas9 activity are paramount to successful DNA integration.MilliporeSigma offers two formats for donor DNA: double-stranded DNA (dsDNA) plasmids and single-stranded DNA (ssDNA) oligonucleotides. The most appropriate format depends on cell type and length of the donor DNA. “There are some cell types that have immune responses to dsDNA,” said Gregory Davis, Ph.D., R&D manager, MilliporeSigma.

• The ssDNA format can save researchers time and money, but it has a limited carrying capacity of approximately 120 base pairs.In addition to selecting an appropriate donor DNA format, controlling where, how, and when the Cas9 enzyme cuts can affect gene-editing efficiency. Scientists are playing tug-of-war, trying to pull cells toward the preferred homology-directed repair (HDR) and away from the less favored nonhomologous end joining (NHEJ) repair mechanism.One method to achieve this modifies the Cas9 enzyme to generate a nickase that cuts only one DNA strand instead of creating a double-strand break. Accordingly, MilliporeSigma has created a Cas9 paired-nickase system that promotes HDR, while also limiting off-target effects and increasing the number of sequences available for site-dependent gene modifications, such as disease-associated single nucleotide polymorphisms (SNPs).“The best thing you can do is to cut as close to the SNP as possible,” advised Dr. Davis. “As you move the double-stranded break away from the site of mutation you get an exponential drop in the frequency of recombination.”

 

• Ribonucleo-protein Complexes

  Another strategy to improve gene-editing efficiency, developed by Thermo Fisher, involves combining purified Cas9 protein with gRNA to generate a stable ribonucleoprotein (RNP) complex. In contrast to plasmid- or mRNA-based formats, which require transcription and/or translation, the Cas9 RNP complex cuts DNA immediately after entering the cell. Rapid clearance of the complex from the cell helps to minimize off-target effects, and, unlike a viral vector, the transient complex does not introduce foreign DNA sequences into the genome.

  To deliver their Cas9 RNP complex to cells, Thermo Fisher has developed a lipofectamine transfection reagent called CRISPRMAX. “We went back to the drawing board with our delivery, screened a bunch of components, and got a brand-new, fully  optimized lipid nanoparticle formulation,” explained Jon Chesnut, Ph.D., the company’s senior director of synthetic biology R&D. “The formulation is specifically designed for delivering the RNP to cells more efficiently.”

  Besides the reagent and the formulation, Thermo Fisher has also developed a range of gene-editing tools. For example, it has introduced the Neon^® transfection system for delivering DNA, RNA, or protein into cells via electroporation. Dr. Chesnut emphasized the company’s focus on simplifying complex workflows by optimizing protocols and pairing everything with the appropriate up- and downstream reagents.

From Mammalian Cells to Microbes

One of the first sources of CRISPR technology was the Feng Zhang laboratory at the Broad Institute, which counted among its first licensees a company called GenScript. This company offers a gene-editing service called GenCRISPR™ to establish mammalian cell lines with CRISPR-derived gene knockouts.

“There are a lot of challenges with mammalian cells, and each cell line has its own set of issues,” said Laura Geuss, a marketing specialist at GenScript. “We try to offer a variety of packages that can help customers who have difficult-to-work-with cells.” These packages include both viral-based and transient transfection techniques.

However, the most distinctive service offered by GenScript is its microbial genome-editing service for bacteria (Escherichia coli) and yeast (Saccharomyces cerevisiae). The company’s strategy for gene editing in bacteria can enable seamless knockins, knockouts, or gene replacements by combining CRISPR with lambda red recombineering. Traditionally one of the most effective methods for gene editing in microbes, recombineering allows editing without restriction enzymes through in vivo homologous recombination mediated by a phage-based recombination system such as lambda red.

On its own, lambda red technology cannot target multiple genes, but when paired with CRISPR, it allows the editing of multiple genes with greater efficiency than is possible with CRISPR alone, as the lambda red proteins help repair double-strand breaks in E. coli. The ability to knockout different gene combinations makes Genscript’s microbial editing service particularly well suited for the optimization of metabolic pathways.

Pooled and Arrayed Library Strategies

Scientists are using CRISPR technology for applications such as metabolic engineering and drug development. Yet another application area benefitting from CRISPR technology is cancer research. Here, the use of pooled CRISPR libraries is becoming commonplace. Pooled CRISPR libraries can help detect mutations that affect drug resistance, and they can aid in patient stratification and clinical trial design.

Pooled screening uses proliferation or viability as a phenotype to assess how genetic alterations, resulting from the application of a pooled CRISPR library, affect cell growth and death in the presence of a therapeutic compound. The enrichment or depletion of different gRNA populations is quantified using deep sequencing to identify the genomic edits that result in changes to cell viability.

MilliporeSigma provides pooled CRISPR libraries ranging from the whole human genome to smaller custom pools for these gene-function experiments. For pharmaceutical and biotech companies, Horizon Discovery offers a pooled screening service, ResponderSCREEN, which provides a whole-genome pooled screen to identify genes that confer sensitivity or resistance to a compound. This service is comprehensive, taking clients from experimental design all the way through to suggestions for follow-up studies.

Horizon Discovery maintains a Research Biotech business unit that is focused on target discovery and enabling translational medicine in oncology. “Our internal backbone gives us the ability to provide expert advice demonstrated by results,” said Jon Moore, Ph.D., the company’s CSO.

In contrast to a pooled screen, where thousands of gRNA are combined in one tube, an arrayed screen applies one gRNA per well, removing the need for deep sequencing and broadening the options for different endpoint assays. To establish and distribute a whole-genome arrayed lentiviral CRISPR library, MilliporeSigma partnered with the Wellcome Trust Sanger Institute. “This is the first and only arrayed CRISPR library in the world,” declared Shawn Shafer, Ph.D., functional genomics market segment manager, MilliporeSigma. “We were really proud to partner with Sanger on this.”

Pooled and arrayed screens are powerful tools for studying gene function. The appropriate platform for an experiment, however, will be determined by the desired endpoint assay.

Detection and Quantification of Edits

 

http://www.genengnews.com/Media/images/Article/BioRad_QX200_System4276117210.jpg

The QX200 Droplet Digital PCR System from Bio-Rad Laboratories can provide researchers with an absolute measure of target DNA molecules for EvaGreen or probe-based digital PCR applications. The system, which can provide rapid, low-cost, ultra-sensitive quantification of both NHEJ- and HDR-editing events, consists of two instruments, the QX200 Droplet Generator and the QX200 Droplet Reader, and their associated consumables.

Finally, one last challenge for CRISPR lies in the detection and quantification of changes made to the genome post-editing. Conventional methods for detecting these alterations include gel methods and next-generation sequencing. While gel methods lack sensitivity and scalability, next-generation sequencing is costly and requires intensive bioinformatics.

To address this gap, Bio-Rad Laboratories developed a set of assay strategies to enable sensitive and precise edit detection with its Droplet Digital PCR (ddPCR) technology. The platform is designed to enable absolute quantification of nucleic acids with high sensitivity, high precision, and short turnaround time through massive droplet partitioning of samples.

Using a validated assay, a typical ddPCR experiment takes about five to six hours to complete. The ddPCR platform enables detection of rare mutations, and publications have reported detection of precise edits at a frequency of <0.05%, and of NHEJ-derived indels at a frequency as low as 0.1%. In addition to quantifying precise edits, indels, and computationally predicted off-target mutations, ddPCR can also be used to characterize the consequences of edits at the RNA level.

According to a recently published Science paper, the laboratory of Charles A. Gersbach, Ph.D., at Duke University used ddPCR in a study of muscle function in a mouse model of Duchenne muscular dystrophy. Specifically, ddPCR was used to assess the efficiency of CRISPR-Cas9 in removing the mutated exon 23 from the dystrophin gene. (Exon 23 deletion by CRISPR-Cas9 resulted in expression of the modified dystrophin gene and significant enhancement of muscle force.)

Quantitative ddPCR showed that exon 23 was deleted in ~2% of all alleles from the whole-muscle lysate. Further ddPCR studies found that 59% of mRNA transcripts reflected the deletion.

“There’s an overarching idea that the genome-editing field is moving extremely quickly, and for good reason,” asserted Jennifer Berman, Ph.D., staff scientist, Bio-Rad Laboratories. “There’s a lot of exciting work to be done, but detection and quantification of edits can be a bottleneck for researchers.”

The gene-editing field is moving quickly, and new innovations are finding their way into the laboratory as researchers lay the foundation for precise, well-controlled gene editing with CRISPR.

 

Are Current Cancer Drug Discovery Methods Flawed?

GEN May 3, 2016   http://www.genengnews.com/gen-news-highlights/are-current-cancer-drug-discovery-methods-flawed/81252682/

 

Researchers utilized a systems biology approach to develop new methods to assess drug sensitivity in cells. [The Institute for Systems Biology]

Understanding how cells respond and proliferate in the presence of anticancer compounds has been the foundation of drug discovery ideology for decades. Now, a new study from scientists at Vanderbilt University casts significant suspicion on the primary method used to test compounds for anticancer activity in cells—instilling doubt on methods employed by the entire scientific enterprise and pharmaceutical industry to discover new cancer drugs.

“More than 90% of candidate cancer drugs fail in late-stage clinical trials, costing hundreds of millions of dollars,” explained co-senior author Vito Quaranta, M.D., director of the Quantitative Systems Biology Center at Vanderbilt. “The flawed in vitro drug discovery metric may not be the only responsible factor, but it may be worth pursuing an estimate of its impact.”

The Vanderbilt investigators have developed what they believe to be a new metric for evaluating a compound’s effect on cell proliferation—called the DIP (drug-induced proliferation) rate—that overcomes the flawed bias in the traditional method.

The findings from this study were published recently in Nature Methods in an article entitled “An Unbiased Metric of Antiproliferative Drug Effect In Vitro.”

For more than three decades, researchers have evaluated the ability of a compound to kill cells by adding the compound in vitro and counting how many cells are alive after 72 hours. Yet, proliferation assays that measure cell number at a single time point don’t take into account the bias introduced by exponential cell proliferation, even in the presence of the drug.

“Cells are not uniform, they all proliferate exponentially, but at different rates,” Dr. Quaranta noted. “At 72 hours, some cells will have doubled three times and others will not have doubled at all.”

Dr. Quaranta added that drugs don’t all behave the same way on every cell line—for example, a drug might have an immediate effect on one cell line and a delayed effect on another.

The research team decided to take a systems biology approach, a mixture of experimentation and mathematical modeling, to demonstrate the time-dependent bias in static proliferation assays and to develop the time-independent DIP rate metric.

“Systems biology is what really makes the difference here,” Dr. Quaranta remarked. “It’s about understanding cells—and life—as dynamic systems.”This new study is of particular importance in light of recent international efforts to generate data sets that include the responses of thousands of cell lines to hundreds of compounds. Using the

• Cancer Cell Line Encyclopedia (CCLE) and
• Genomics of Drug Sensitivity in Cancer (GDSC) databases

will allow drug discovery scientists to include drug response data along with genomic and proteomic data that detail each cell line’s molecular makeup.

“The idea is to look for statistical correlations—these particular cell lines with this particular makeup are sensitive to these types of compounds—to use these large databases as discovery tools for new therapeutic targets in cancer,” Dr. Quaranta stated. “If the metric by which you’ve evaluated the drug sensitivity of the cells is wrong, your statistical correlations are basically no good.”

The Vanderbilt team evaluated the responses from four different melanoma cell lines to the drug vemurafenib, currently used to treat melanoma, with the standard metric—used for the CCLE and GDSC databases—and with the DIP rate. In one cell line, they found a glaring disagreement between the two metrics.

“The static metric says that the cell line is very sensitive to vemurafenib. However, our analysis shows this is not the case,” said co-lead study author Leonard Harris, Ph.D., a systems biology postdoctoral fellow at Vanderbilt. “A brief period of drug sensitivity, quickly followed by rebound, fools the static metric, but not the DIP rate.”

Dr. Quaranta added that the findings “suggest we should expect melanoma tumors treated with this drug to come back, and that’s what has happened, puzzling investigators. DIP rate analyses may help solve this conundrum, leading to better treatment strategies.”

The researchers noted that using the DIP rate is possible because of advances in automation, robotics, microscopy, and image processing. Moreover, the DIP rate metric offers another advantage—it can reveal which drugs are truly cytotoxic (cell killing), rather than merely cytostatic (cell growth inhibiting). Although cytostatic drugs may initially have promising therapeutic effects, they may leave tumor cells alive that then have the potential to cause the cancer to recur.

The Vanderbilt team is currently in the process of identifying commercial entities that can further refine the software and make it widely available to the research community to inform drug discovery.

 

An unbiased metric of antiproliferative drug effect in vitro

Leonard A Harris, Peter L Frick, Shawn P Garbett, Keisha N Hardeman, B Bishal Paudel, Carlos F Lopez, Vito Quaranta & Darren R Tyson
Nature Methods 2 May (2016)                 doi:10.1038/nmeth.3852

In vitro cell proliferation assays are widely used in pharmacology, molecular biology, and drug discovery. Using theoretical modeling and experimentation, we show that current metrics of antiproliferative small molecule effect suffer from time-dependent bias, leading to inaccurate assessments of parameters such as drug potency and efficacy. We propose the drug-induced proliferation (DIP) rate, the slope of the line on a plot of cell population doublings versus time, as an alternative, time-independent metric.

1. Zuber, J. et al. Nat. Biotechnol. 29, 79–83 (2011).
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Mapping Traits to Genes with CRISPR

Researchers develop a technique to direct chromosome recombination with CRISPR/Cas9, allowing high-resolution genetic mapping of phenotypic traits in yeast.

By Catherine Offord | May 5, 2016

http://www.the-scientist.com/?articles.view/articleNo/46029/title/Mapping-Traits-to-Genes-with-CRISPR

 

http://www.the-scientist.com/images/News/May2016/sciencefigure.jpg

Researchers used CRISPR/Cas9 to make a targeted double-strand break (DSB) in one arm of a yeast chromosome labeled with a green fluorescent protein (GFP) gene. A within-cell mechanism called homologous repair (HR) mends the broken arm using its homolog, resulting in a recombined region from the site of the break to the chromosome tip. When this cell divides by mitosis, each daughter cell will contain a homozygous section in an outcome known as “loss of heterozygosity” (LOH). One of the daughter cells is detectable because, due to complete loss of the GFP gene, it will no longer be fluorescent.REPRINTED WITH PERMISSION FROM M.J. SADHU ET AL., SCIENCE

When mapping phenotypic traits to specific loci, scientists typically rely on the natural recombination of chromosomes during meiotic cell division in order to infer the positions of responsible genes. But recombination events vary with species and chromosome region, giving researchers little control over which areas of the genome are shuffled. Now, a team at the University of California, Los Angeles (UCLA), has found a way around these problems by using CRISPR/Cas9 to direct targeted recombination events during mitotic cell division in yeast. The team described its technique today (May 5) in Science.

“Current methods rely on events that happen naturally during meiosis,” explained study coauthor Leonid Kruglyak of UCLA. “Whatever rate those events occur at, you’re kind of stuck with. Our idea was that using CRISPR, we can generate those events at will, exactly where we want them, in large numbers, and in a way that’s easy for us to pull out the cells in which they happened.”

Generally, researchers use coinheritance of a trait of interest with specific genetic markers—whose positions are known—to figure out what part of the genome is responsible for a given phenotype. But the procedure often requires impractically large numbers of progeny or generations to observe the few cases in which coinheritance happens to be disrupted informatively. What’s more, the resolution of mapping is limited by the length of the smallest sequence shuffled by recombination—and that sequence could include several genes or gene variants.

“Once you get down to that minimal region, you’re done,” said Kruglyak. “You need to switch to other methods to test every gene and every variant in that region, and that can be anywhere from challenging to impossible.”

But programmable, DNA-cutting champion CRISPR/Cas9 offered an alternative. During mitotic—rather than meiotic—cell division, rare, double-strand breaks in one arm of a chromosome preparing to split are sometimes repaired by a mechanism called homologous recombination. This mechanism uses the other chromosome in the homologous pair to replace the sequence from the break down to the end of the broken arm. Normally, such mitotic recombination happens so rarely as to be impractical for mapping purposes. With CRISPR/Cas9, however, the researchers found that they could direct double-strand breaks to any locus along a chromosome of interest (provided it was heterozygous—to ensure that only one of the chromosomes would be cut), thus controlling the sites of recombination.

Combining this technique with a signal of recombination success, such as a green fluorescent protein (GFP) gene at the tip of one chromosome in the pair, allowed the researchers to pick out cells in which recombination had occurred: if the technique failed, both daughter cells produced by mitotic division would be heterozygous, with one copy of the signal gene each. But if it succeeded, one cell would end up with two copies, and the other cell with none—an outcome called loss of heterozygosity.

“If we get loss of heterozygosity . . . half the cells derived after that loss of heterozygosity event won’t have GFP anymore,” study coauthor Meru Sadhu of UCLA explained. “We search for these cells that don’t have GFP out of the general population of cells.” If these non-fluorescent cells with loss of heterozygosity have the same phenotype as the parent for a trait of interest, then CRISPR/Cas9-targeted recombination missed the responsible gene. If the phenotype is affected, however, then the trait must be linked to a locus in the recombined, now-homozygous region, somewhere between the cut site and the GFP gene.

By systematically making cuts using CRISPR/Cas9 along chromosomes in a hybrid, diploid strain ofSaccharomyces cerevisiae yeast, picking out non-fluorescent cells, and then observing the phenotype, the UCLA team demonstrated that it could rapidly identify the phenotypic contribution of specific gene variants. “We can simply walk along the chromosome and at every [variant] position we can ask, does it matter for the trait we’re studying?” explained Kruglyak.

For example, the team showed that manganese sensitivity—a well-defined phenotypic trait in lab yeast—could be pinpointed using this method to a single nucleotide polymorphism (SNP) in a gene encoding the Pmr1 protein (a manganese transporter).

Jason Moffat, a molecular geneticist at the University of Toronto who was not involved in the work, toldThe Scientist that researchers had “dreamed about” exploiting these sorts of mechanisms for mapping purposes, but without CRISPR, such techniques were previously out of reach. Until now, “it hasn’t been so easy to actually make double-stranded breaks on one copy of a pair of chromosomes, and then follow loss of heterozygosity in mitosis,” he said, adding that he hopes to see the approach translated into human cell lines.

Applying the technique beyond yeast will be important, agreed cell and developmental biologist Ethan Bier of the University of California, San Diego, because chromosomal repair varies among organisms. “In yeast, they absolutely demonstrate the power of [this method],” he said. “We’ll just have to see how the technology develops in other systems that are going to be far less suited to the technology than yeast. . . . I would like to see it implemented in another system to show that they can get the same oomph out of it in, say, mammalian somatic cells.”

Kruglyak told The Scientist that work in higher organisms, though planned, is still in early stages; currently, his team is working to apply the technique to map loci responsible for trait differences between—rather than within—yeast species.

“We have a much poorer understanding of the differences across species,” Sadhu explained. “Except for a few specific examples, we’re pretty much in the dark there.”

M.J. Sadhu, “CRISPR-directed mitotic recombination enables genetic mapping without crosses,” Science, doi:10.1126/science.aaf5124, 2016.

 

CRISPR-directed mitotic recombination enables genetic mapping without crosses

Meru J Sadhu, Joshua S Bloom, Laura Day, Leonid Kruglyak

http://biorxiv.org/content/biorxiv/early/2016/02/19/040428.full.pdf     doi: http://dx.doi.org/10.1101/040428

Linkage and association studies have mapped thousands of genomic regions that contribute to phenotypic variation, but narrowing these regions to the underlying causal genes and variants has proven much more challenging. Resolution of genetic mapping is limited by the recombination rate. We developed a method that uses CRISPR to build mapping panels with targeted recombination events. We tested the method by generating a panel with recombination events spaced along a yeast chromosome arm, mapping trait variation, and then targeting a high density of recombination events to the region of interest. Using this approach, we fine-mapped manganese sensitivity to a single polymorphism in the transporter Pmr1. Targeting recombination events to regions of interest allows us to rapidly and systematically identify causal variants underlying trait differences.

The copyright holder for this preprint is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.

Meru Sadhu • 2 months ago

Thank you, David, for the kind words and comments. We agree that the most immediate applications of the CRISPR-based recombination mapping will be in unicellular organisms and cell culture. We also think the method holds a lot of promise for research in multicellular organisms, although we did not mean to imply that it “will be an efficient mapping method for all multicellular organisms”. Every organism will have its own set of constraints as well as experimental tools that will be relevant when adapting a new technique. To best help experts working on these organisms, here are our thoughts on your questions.

You asked about mutagenesis during recombination. We Sanger sequenced 72 of our LOH lines at the recombination site and did not observe any mutations, as described in the supplementary materials. We expect the absence of mutagenesis is because we targeted heterozygous sites where the untargeted allele did not have a usable PAM site; thus, following LOH, the targeted site is no longer present and cutting stops. In your experiments you targeted sites that were homozygous; thus, following recombination, the CRISPR target site persisted, and continued cutting ultimately led to repair by NHEJ and mutagenesis.

As to the more general question of the optimal mapping strategies in different organisms, they will depend on the ease of generating and screening for editing events, the cost and logistics of maintaining and typing many lines, and generation time, among other factors. It sounds like in Drosophila today, your related approach of generating markers with CRISPR, and then enriching for natural recombination events that separate them, is preferable. In yeast, we’ve found the opposite to be the case. As you note, even in Drosophila, our approach may be preferable for regions with low or highly non-uniform recombination rates.

Finally, mapping in sterile interspecies hybrids should be straightforward for unicellular hybrids (of which there are many examples) and for cells cultured from hybrid animals or plants. For studies in hybrid multicellular organisms, we agree that driving mitotic recombination in the early embryo may be the most promising approach. Chimeric individuals with mitotic clones will be sufficient for many traits. Depending on the system, it may in fact be possible to generate diploid individuals with uniform LOH genotype, but this is certainly beyond the scope of our paper. The calculation of the number of lines assumes that the mapping is done in a single step; as you note in your earlier comment, mapping sequentially can reduce this number dramatically.

David Stern 3 months ago

This is a lovely method and should find wide applicability in many settings, especially for microorganisms and cell lines. However, it is not clear that this approach will be, as implied by the discussion, an efficient mapping method for all multicellular organisms. I have performed similar experiments in Drosophila, focused on meiotic recombination, on a much smaller scale, and found that CRISPR-Cas9 can indeed generate targeted recombination at gRNA target sites. In every case I tested, I found that the recombination event was associated with a deletion at the gRNA site, which is probably unimportant for most mapping efforts, but may be a concern in some specific cases, for example for clinical applications. It would be interesting to know how often mutations occurred at the targeted gRNA site in this study.

The wider issue, however, is whether CRISPR-mediated recombination will be more efficient than other methods of mapping. After careful consideration of all the costs and the time involved in each of the steps for Drosophila, we have decided that targeted meiotic recombination using flanking visible markers will be, in most cases, considerably more efficient than CRISPR-mediated recombination. This is mainly due to the large expense of injecting embryos and the extensive effort and time required to screen injected animals for appropriate events. It is both cheaper and faster to generate markers (with CRISPR) and then perform a large meiotic recombination mapping experiment than it would be to generate the lines required for CRISPR-mediated recombination mapping. It is possible to dramatically reduce costs by, for example, mapping sequentially at finer resolution. But this approach would require much more time than marker-assisted mapping. If someone develops a rapid and cheap method of reliably introducing DNA into Drosophila embryos, then this calculus might change.

However, it is possible to imagine situations where CRISPR-mediated mapping would be preferable, even for Drosophila. For example, some genomic regions display extremely low or highly non-uniform recombination rates. It is possible that CRISPR-mediated mapping could provide a reasonable approach to fine mapping genes in these regions.

The authors also propose the exciting possibility that CRISPR-mediated loss of heterozygosity could be used to map traits in sterile species hybrids. It is not entirely obvious to me how this experiment would proceed and I hope the authors can illuminate me. If we imagine driving a recombination event in the early embryo (with maternal Cas9 from one parent and gRNA from a second parent), then at best we would end up with chimeric individuals carrying mitotic clones. I don’t think one could generate diploid animals where all cells carried the same loss of heterozygosity event. Even if we could, this experiment would require construction of a substantial number of stable transgenic lines expressing gRNAs. Mapping an ~20Mbp chromosome arm to ~10kb would require on the order of two-thousand transgenic lines. Not an undertaking to be taken lightly. It is already possible to perform similar tests (hemizygosity tests) using D. melanogaster deficiency lines in crosses with D. simulans, so perhaps CRISPR-mediated LOH could complement these deficiency screens for fine mapping efforts. But, at the moment, it is not clear to me how to do the experiment.

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