Category Archives: Gene Medicine

The World Health Organization (WHO) recently declared an international public health emergency over the global outbreak of the novel coronavirus. One day later, the Wellcome Trust research charity called for researchers, journals and funders around the world to share research data and findings relevant to the coronavirus rapidly and openly, to inform the public and help save lives.

On the same day, the China National Knowledge Infrastructure launched a free website and called for scientists to publish research on the coronavirus with open access. Shortly after, the prominent scientific journal Nature issued an editorial urging all coronavirus researchers to keep sharing, stay open.

So while cities are locked down and borders are closed in response to the coronavirus outbreak, science is becoming more open. This openness is already making a difference to scientists response to the virus and has the potential to change the world.

But its not as simple as making every research finding available to anyone for any purpose. Without care and responsibility, there is a danger that open science can be misused or contribute to the spread of misinformation.

Open science can come in a variety of forms, including open data, open publications and open educational resources.

1. Open data

DNA sequencing is of great importance to developing specific diagnostic kits around the world. Yong-Zhen Zhang and his colleagues from Fudan University in Shanghai were the first to sequence the DNA of the novel coronavirus. They placed the gene sequence in GenBank, an open-access data repository. Researchers around the world immediately started analysing it to develop diagnostics.

As of February 19 2020, 81 different coronavirus gene sequences had been shared openly via GenBank and 189 via the China National Genomics Data Centre. They provide the data that will allow scientists to decode the mystery of the virus and hopefully find a treatment or vaccine.

The WHO and national organisations like the Chinese Center for Disease Control and Prevention also publish open statistical data, such as the number of patients. This can help researchers to map the spread of the virus and offer the public up-to-date and transparent information.

2. Open publications

Science publications are costly. One of the most expensive Elsevier journals, Tetrahedron Letters, costs 16,382 for an institutional annual subscription and 673 for a personal one. Even the University of Harvard cannot afford to subscribe to all journals. This means not all researchers have access to all subscription-based publications.

Authors can publish their articles free to access, which often means they need to pay the publishers an average 2,000 in article processing costs. In 2018, only 36.2% of science publications were open-access.

As of February 18 2020, there were 500 scientific articles about the novel coronavirus in the comprehensive scholarly database Dimensions. Only 160 (32%) of them were in open-access publications. This includes preprint servers such as bioRxiv and arXiv, which are widely used open-access archives to publish research before it goes through scientific peer review.

Normally, you would need to pay subscription fees to read any of the other 340 articles. However, articles published by the 100 companies who have signed the Wellcome Trusts statement on sharing coronavirus research have been made freely accessible by publishers.

Major publishers including Elsevier, Springer Nature, Wiley Online Library, Emerald, Oxford University Press and Wanfang have also set up featured open-access resources page. The Chinese database CQVIP has offered free access to all of its 14,000 journals during the coronavirus outbreak.

As it takes on average 160 days for a preprint to be published after peer review, sharing preprints can save time and save life. Free access to articles on the coronavirus can also accelerate global research on this subject.

3. Open educational resources

Due to the outbreak, universities in China have postponed their new semesters and switched to online learning. But alongside the 24,000 online courses open to students, universities (including the elite Peking University, Tsinghua University and Xian Jiaotong University) are offering free online courses to the public about the coronavirus. Such courses can offer the public reliable information grounded in academic research, helping them better understand and protect themselves against the virus.

While all these developments are positive, it is important to remember that open science doesnt mean science without limits. It must be used responsibly by researchers and the public.

To start, researchers need to have mutual respect for the integrity of their work. For example, there have reportedly already been disagreements over whether scientists need to request consent to reuse pre-publication data from shared coronavirus gene sequencing.

Assuming researchers act in good faith and not to simply further their own careers, it is still important for them to clarify the conditions with which they make their research available, and to carefully check and follow such conditions when using other peoples data. Responsible uses of pre-publication data are vital to fostering a scientific culture that encourages transparent and explicit cooperation.

There are also issues with making research available without peer review - as happens with preprint servers - as misinterpretations and mistakes can easily happen. One paper posted on bioRxiv on February 2 2020 claimed to show insertions in the coronaviruss DNA that showed an uncanny similarity to regions found in HIV DNA.

After criticism of the their work, the papers authors withdrew it stating they did not intend to feed into the conspiracy theories that the novel coronavirus had been deliberately engineered. Such conspiracy theories were recently condemned by 27 scientists from eight countries in their open statement to the leading medical journal The Lancet.

Yet until February 19 2020, the withdrawn paper was the most discussed study in the world in online news and social media, according to the academic ranking site Altmetric. The paper may have been withdrawn but it wont have been forgotten.

Open science is vital to tackling the worlds big challenges. But when information can be misused, skewed or misinterpreted at global level so quickly, we also need scientists and the public to treat open science with great care and responsibility.

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The hunt for a coronavirus cure is showing how science can change for the better - The Conversation UK

Each week, The Dailys Science & Tech section produces a roundup of the most exciting and influential research happening on campus or otherwise related to Stanford. Heres our digest for the week of Feb. 16 Feb. 22.

Artificial intelligence decreases testing time for car batteries

An artificial intelligence (AI)-based method has decreased electric vehicle (EV) battery testing time from around two years to 16 days, a 98% reduction, according to a study published on Feb. 19 in Nature.

In battery testing, you have to try a massive number of things, because the performance you get will vary drastically, computer science assistant professor Stefano Ermon told Stanford News. With AI, were able to quickly identify the most promising approaches and cut out a lot of unnecessary experiments.

The researchers focused on finding the charging method for an EV battery that maximizes the batterys lifetime. The AI program efficiently tested battery protocols to figure out the best optimal protocols for charging.

It gave us this surprisingly simple charging protocol something we didnt expect, Ermon told Stanford News. Thats the difference between a human and a machine: The machine is not biased by human intuition, which is powerful but sometimes misleading.

Increased gene activity associated with fish embryo diapause

An increase in the activity of a specific gene has been identified in African killifish embryos that undergo a hibernation-like state, called diapause, during early development, found a study published on Feb. 21 in Science.

African killifish enter diapause to avoid the harsh conditions during the dry season, and exit diapause when conditions are optimal for development.

Diapause lasts around five months, about the same as an average African killifish lifespan, genetics professor Anne Brunet told Stanford Medicine News. But some killifish have stayed in diapause for 2.5 years. If you think about that in human terms, thats like if we were to exist, paused as an embryo, for some 400 years, only to resume natural development and live out a full life.

The findings suggested that during the diapause period, activity of the CBX7 gene increases. The gene is associated with regulating muscle maintenance, and African killifish embryos lacking CBX7 display muscle atrophy, which leads to exiting diapause too early.

As time passes, our organs progressively degenerate, especially in disease, Brunet told Stanford Medicine News. So identifying the general, fundamental mechanisms of organ preservation could be important to understanding how to counter the normal atrophy of organs over time or under disease conditions.

Extinctions of smaller ocean creatures throughout the past 485 million years

A fossil study indicated that the extinctions of smaller ocean organisms were more common than previously thought, according to a report published on Jan. 30 in Paleobiology.

Our findings suggest that the controls on extinction risk for marine animals across evolutionary time were quite different from those that are operating in the current extinction crisis, but were consistent across time and distantly related groups of animals, geological sciences Jonathan Payne told Stanford Earth News.

The researchers analyzed fossils related to the bivalve group Pectinida. The findings suggest that bivalve-related organisms, pancake-thin and smaller than a human palm, went extinct disproportionately more often than larger species. Larger bivalve-related organisms were more likely to survive.

The fossil record is our only archive of past extinction events, Payne told Stanford Earth News. This finding adds substantial urgency to our efforts to conserve species and ecosystems before extinction occurs.

Contact Derek Chen at derekc8 at stanford.edu.

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Research Roundup: Battery car testing, African killifish embryos and ocean organism extinctions - The Stanford Daily

Treatment for sickle cell disease has come a long way since the 1970s when the life expectancy of people living with it was less than 20 years.

People with sickle cell disease are not only living longer life expectancy is now 42 to 47 years of age but are enjoying a better quality of life, too.

"In the Philadelphia area, there has been great pediatric care for sickle cells disease and because of that people who have it are living very well," said Dr. Farzana Sayani, a hematologist at Penn Medicine.

Sayani is the director of a comprehensive sickle cell program focusing on adults living with the disease. Penn also has an active transition program for youth transitioning from a pediatric institution to adult care.

Sickle cell disease is an inherited red blood cell disorder that affects about 100,000 Americans.It is most often found in people of African or Hispanic descent.About 1 in 365 African-American babies are born with sickle cell disease, according to Sayani.

People who have the disease inherit an abnormal type of hemoglobin in their red blood cells, called Hemoglobin S, from both their mother and father.When only one parent has the hemoglobin S gene, a child will have the sickle cell trait, but usually does not develop the disease. But they may pass it on to their children.

Hemoglobin is the protein in the blood responsible for carrying oxygen to the rest of the body. Hemoglobin S causes red blood cells to become stiff and sickle-shaped. Instead of being round in shape, they look like crescent moons.

Sickle cells are sticky and can bind together, blocking the flow of blood and preventing oxygen from getting where it needs to go in the body. This causes sudden attacks of pain referred to as a pain crisis.

There are severaldifferent types of sickle cell disease.Hemoglobin SS, also known as sickle cell anemia, is the most common and most severe type of sickle cell disease.

Anemia occurs when red blood cells die at a rate faster than the body can replace them. Normal red blood cells generally live for 90 to 120 days. Sickled cells only live for 10 to 20 days. This shorter life-to-death cycle is harder for the body to sustain.

Another form,Hemoglobin SC, is not as severe as sickle cell anemia, but it can still cause significant complications, Sayani said.Other forms include Hemoglobin S0 thalassemia, Hemoglobin S+ thalassemia, Hemoglobin SD and Hemoglobin SE.

Sickle cell disease screening is a mandatory part of newborn screenings in Pennsylvania.

If the screening is positive, the family is informed and plugged into the health care system in order to receive the proper care.

If the disease is not diagnosed at birth, a blood test can confirm it at any age in which symptoms start to surface.

The severity of sickle cell disease can vary.

Each individual is affected differently, making it difficult to predict who will get what complications, Sayani said. That is why a comprehensive sickle cell program is so important.

Early signs include a yellowish tint to the skin or jaundice, fatigue and a painful swelling of the hands and feet.

"Young children with sickle cell disease may be tired, not eat very well and have delayed growth," Sayani said. "They may also develop anemia, be at greater risk of infection and start to experience pain crises."

Acute pain crises, also known as vaso-occlusive crises, can lead to long stays in the hospital to manage the crippling pain. Children with sickle cell disease also tend to experience delayed growth and puberty.

As a person with sickle cell disease grows older, the sickled red blood cells start to affect various organs, bones and joints.

This can lead to acute chest syndrome, which occurs when damaged lung tissues makes it difficult to breathe. Brain complications, including stroke, are possible.People with sickle cell disease are also prone to heart damage, eye problems, and infections like chlamydia, salmonella and staphylococcus. Chronic and acute pain is common.

There are different types of medicine that can help manage sickle cell disease.

Last year, an oral medicine was approved that makes sickle cells less likely to sickle. So was an intravenous medicine that has been shown to reduce pain crises and hospitalizations by 50%. Some people living with sickle cell disease also may need regular blood transfusions.

Hydroxyurea has also been used successfully for many years to reduce pain crises and the need for blood transfusions and hospitalizations.

Currently, blood and bone marrow transplant is the only way to cure the disease. But it is not an option for everyone because of the difficulty of finding a well-matched stem cell donor.

A related donor is best but only about a third of sickle cell patients have a donor that is related and fully-matched, Sayani said.

While these transplants have a 85% or more success rate, they also are associated with significant risks, including organ dysfunction, infection and graft vs. host disease which can be quite debilitating.

Transplants completed in children have the best results, Sayani said. But because of the risks involved, doctors only suggest it for patients with severe forms of the disease.

Early clinical trials with gene therapy are also showing promise, she added.

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New sickle cell disease treatments are helping people live longer and giving them a higher quality of life - PhillyVoice.com

In pulmonary arterial hypertension (PAH), high blood pressure in the lungs arteries causes the heart to work extra hard to pump blood to the lungs and around the rest of the body. The condition is rare but deadly, and current treatments are expensive and have side effects and inconvenient modes of delivery. There is no cure.

With a goal of developing a more effective, convenient, and affordable therapy, research led by Henry Daniell of Penns School of Dental Medicine produced a protein drug in lettuce leaves to treat PAH. He worked with other scientists, including Steven M. Kawut of Penns Perelman School of Medicine; Tim Lahm from the Indiana University School of Medicine; Maria Arolfo and Hanna Ng of the Stanford Research Institute, on toxicology and pharmacokinetic studies; and Cindy McClintock and Diana Severynse-Stevens of RTI International, on regulatory studies.

The protein drug, composed of the enzyme angiotensin converting enzyme-2 (ACE2) and its protein product angiotensin (1-7), can be taken orally and, in an animal model of PAH, reduced pulmonary artery pressure and remodeling. In addition, rigorous toxicology and dose-response studies suggested the drugs safety in animals. Further work will be necessary to develop this novel treatment approach for patients with PAH. The teams findings appear in the March issue of the journal Biomaterials.

We completed extensive investigations to highly express these proteins in lettuce plants and to ensure the product is safe and effective, says Daniell. Were ready to progress with further work to move this to the clinic.

Daniell has employed his innovative platform to grow biomedically important proteins of many kinds in the leaves of plants. The system works by physically bombarding plant tissue with the genes of interest, prompting chloroplasts into taking up genes and then stably expressing that protein. Propagating those plants then creates a kind of pharmaceutical farm from which the researchers can harvest, dry, and process the leaves, resulting in a powder that can be placed in a capsule or suspended in a liquid for use as an oral medication.

A 2014 publication in the journal Hypertension, on which the current study was based, earned Daniell a prize from the American Heart Association, and support from the National Institutes of Health through its Science Moving TowArds Research Translation and Therapy (SMARTT) program, which aims to efficiently translate promising basic science discoveries into therapies that can make a difference in peoples lives.

That earlier publication had shown that ACE2 and angiotensin (1-7) could be expressed in tobacco leaves and, when fed to rats with a condition that models pulmonary arterial hypertension, could significantly reduce the animals pulmonary artery pressure while also improving cardiac function.

To create a drug that humans could safely ingest, however, required moving from a tobacco to a lettuce-based platform. The new work takes advantage of other advancements the Daniell lab has made during the last several years. He and colleagues have successfully devised methods to enhance expression of human genes in the plants and to remove the antibiotic resistance gene that is used to select for angiotensin-producing plants. Theyve also worked with a partner to produce genetically engineered plants in a production facility that adheres to FDA standards.

In the current work, the researchers demonstrated that they could accurately evaluate the dose of the ACE2 and angiotensin (1-7) proteins in lettuce, and that the products could be dried and kept shelf stable for as long as two years.

Funding from the SMARTT program enabled animal studies evaluating toxicology, pharmacodynamic, and pharmacokinetic studies, which evaluate the safety of the drug, where it goes in the body, and how long it persists in the body at different doses, in work done at Stanford University.

And to confirm that the lettuce formulation of the product had a positive impact on experimental PAH, the team fed rats a solution containing the drug for four weeks. Their lung pressures went down 30-50%, and the structure of their arteries also improved.

This is an innovative approach to targeting the renin-angiotensin-aldosterone system in pulmonary arterial hypertension, says Penn Medicines Kawut, which may hold promise in this and other diseases.

We are very excited about this work that shows efficacy of bioencapsulated ACE2 and angiotensin (1-7) in our animal model of pulmonary arterial hypertension, says Indiana Universitys Lahm. We now need to confirm that the intervention also works in other animal models and when given later in the disease. Ultimately, our goal is to move this to the clinic for trials in patients, but we need to make sure we learn as much as possible from animal studies and from studies in healthy human subjects to make sure this intervention is safe and efficacious in patients.

In other future work, Daniell hopes to continue evaluating the effects of ACE2 and angiotensin (1-7) in treating different types of cardiovascular disease, such as heart failure.

There are some potentially broad applications of this drug that were hoping to investigate, says Daniell.

Daniell, Kawut, and Lahms coauthors on the paper were Penn Dental Medicines Venkata Mangu, Jiyoung Park, Peyman Habibi, Yao Shi, and Patricia A. Gonnella; and Indiana Universitys Bakhtiyor Yakubov, Amanda Fisher, Todd Cook, and Lily Zeng.

Henry Daniell is vice chair and W.D. Miller Professor in the Department of Basic & Translational Sciences in the University of Pennsylvania School of Dental Medicine.

Steven M. Kawut is professor of medicine and director of the Pulmonary Vascular Disease Program at the University of Pennsylvania Perelman School of Medicine.

Funding for the study came from the National Institutes of Health (NIH) (grants HL107904, HL109442, and HL133191) and through the NIHs Science Moving TowArds Research Translation and Therapy (SMARTT) program (contracts HHSN268201600011C and HHSN268201600014C).

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Advancing an oral drug for pulmonary arterial hypertension - Penn: Office of University Communications

San Francisco, California (UroToday.com)Approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC) cannot be assessed for a response using RECIST 1.1 criteria and there is a need to develop a dynamic endpoint that provides an early indication of clinical benefit. Circulating tumor cells (CTCs) are easily accessible, reflect tumor biology, and could be a marker of anti-tumor activity beyond PSA and conventional imaging. CTC0 and CTC conversion to <5 CTCs/7.5 mL blood may occur very early on treatment and were highly correlated with OS across 5 large phase III trials of mCRPC therapies in a recent landmark paper by Heller et al.1 Niraparib, a highly potent and selective poly (ADP-ribose) polymerase (PARP) inhibitor received breakthrough designation by US FDA for treatment of patients withBRCA1,2mutant mCRPC who progressed on taxane and androgen receptor-targeted therapy. CTC detection associates with poor outcomes, with declining counts consistent with improved survival. At todays prostate cancer session at GU ASCO 2020, Matthew Smith presented results of their CTC correlative data assessing CTC0 as an endpoint in mCRPC.

The GALAHAD study assessed niraparib (300 mg daily) in patients with mCRPC plus DRD. Patients with non-measurable soft tissue disease by RECIST 1.1 were required to have a baseline CTC count 1 cell/7.5 mL blood. CTC response was defined as CTC conversion to <5 for patients with baseline CTC5 and CTC drop to 0 post-baseline for patients with 1 baseline CTC.

There were 204 patients included in this study. For the primary efficacy population of patients withBRCA1/2mutations, the objective response rate (ORR) by RECIST 1.1 criteria was 41.4%. CTC response rates for this population were as high as ORR regardless of measurability:

CTC0 and CTC conversion were early indicators of response and are associated with longer time on therapy in patients with measurable and non-measurable disease. Furthermore, CTC0 and CTC conversion are associated with longer OS:

Additionally, CTC0 was associated with improved rPFS in the overall population, and CTC0 and CTC conversion were also associated with PSA reduction among these BRCA patients.

Dr. Smith concluded with several take home messages:

Clinical trial information:NCT02854436

Presented by: Matthew R. Smith, MD, Ph.D., Professor of Medicine, Harvard Medical School, Assistant in Medicine, Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Written by: Zachary Klaassen, MD, MSc Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_mdat the 2020 Genitourinary Cancers Symposium, ASCO GU#GU20, February 13-15, 2020, San Francisco, California

References:

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ASCO GU 2020: Niraparib in Patients with mCRPC and Biallelic DNA-Repair Gene Defects: Correlative Measures of Tumor Response in Phase II GALAHAD Study...

In August of 2011, Carl June and his team published a landmark paper showing their CART treatment had cleared a patient of cancer. A year-to-the-month later, Jennifer Doudna made an even bigger splash when she published the first major CRISPR paper, setting off a decade of intense research and sometimes even more intense public debate over the ethics of what the gene-editing tool could do.

Last week, June, whose CART work was eventually developed by Novartis into Kymriah, published in Sciencethe first US paper showing how the two could be brought together. It was not only one of the first time scientists have combined the groundbreaking tools, but the first peer-reviewed American paper showing how CRISPR could be used in patients.

June used CRISPR to edit the cells of three patients with advanced blood cancer, deleting the traditional T cell receptor and then erasing the PD1 gene, a move designed to unleash the immune cells. The therapy didnt cure the patients, but the cells remained in the body for a median of 9 months, a major hurdle for the therapy.

Endpoints caught up with June about the long road both he and the field took to get here, if the treatment will ever scale up, and where CRISPR and other advancements can lead it.

The interview has been condensed and edited.

Youve spoken in the past about howyou started working in this field in the mid-90s after your wife passed away from cancer. What were some of those early efforts? How did you start?

Well, I graduated from high school and had a low draft number [for the Vietnam War] and was going to go to study engineering at Stanford, but I was drafted and went into the Naval Academy in 1971, and I did that so I wouldnt have to go to the rice fields.

The war ended in 73, 74, so when I graduated in 1975, I was allowed to go to medical school, and then I had a long term commitment to the Navy because they paid for the Acadamy and Medical school. And I was interested in research and at the time, what the Navy cared about was a small scale nuclear disaster like in a submarine, and like what happened at Chernobyl and Fukushima. So they sent me to the Fred Hutchinson Cancer Center where I got trained in cancer, as a medical oncologist. I was going to open a bone marrow transplant center in Bethesda because the Navy wanted one in the event of a nuclear catastrophe.

And then in 1989, the Berlin Wall came down and there was no more Cold War. I had gone back to the Navy in 86 for the transplant center, which never happened, so then I had to work in the lab full time. But in the Navy, all the research has to be about combat and casualty. They care about HIV, so my first papers were on malaria and infectious disease. And the first CAR-T trials were on HIV in the mid-90s.

In 96, my wife got diagnosed with ovarian cancer and she was in remission for 3-4 years. I moved to the University of Pennsylvania in 1999 and started working on cancer because I wasnt allowed to do that with the Navy. My wife was obviously a lot of motivation to do that. She passed away in 2001. Then I started working with David Porter on adoptive transfer T cells.

I got my first grant to do CAR-T cells on HIV in 2004, and I learned a whole lot. I was lucky to have worked on HIV because we did the first trials using lentiviruses, which is an engineered HIV virus.

I was trained in oncology, and then because of the Navy forced to work on HIV. It was actually a blessing in disguise.

So if you hadnt been drafted, you wouldve become an engineer?

Yes. Thats what I was fully intending. My dad was a chemical engineer, my brother is an engineer. Thats what I thought I was going to do. No one in my family was ever a physician. Its one of those many quirks of fate.

Back then, we didnt have these aptitude tests. It was just haphazard. I applied to three schools Berkeley, Stanford and Caltech and I got into all three. It was just luck, fate.

And it turned out when I went to the Naval Academy, they had added a pre-med thing onto the curriculum the year before, so thats what I did when I started, I did chemistry.

I wouldve [otherwise] been in nuclear submarines. The most interesting thing in the Navy then was the nuclear sub technology.

You talked about doing the first CAR-T trials on HIV patients because thats where the funding was. Was it always in your head that this was eventually going to be something for cancer?

So I got out of the Navy in 99 and moved to Penn. I started in 98 working on treating leukemia, and then once I got to Penn, I continued working one day a week on HIV.

Its kind of a Back-to-the-Future thing because now cancer has paved out a path to show that CART cells can work and put down the manufacturing and its going to be a lot cheaper making it for HIV. I still think thats going to happen.

Jim Riley, who used to be a postdoc in my lab, has some spectacular results in monkeys with HIV models. They have a large NIH and NIAID research program.

So were going to see more and more of that. The CAR technology is going to move outside of cancer, and into autoimmune and chronic infections.

I want to jump over to cytotoxic release syndrome (CRS)because a big part of the CRISPR study was that it didnt provoke this potentially deadly adverse effect. When did you first become aware that CRS was going to be a problem?

I mean we saw it in the very first patient we treated but in all honesty, we missed it. Im an MD, but I dont see the patient and David Porter tookcare of the first three patients and our first pediatric patient,Emily Whitehead.

In our first patients, 2 out of 3, had complete remission and there were fevers and it was CRS but we thought it was just an infection, and we treated with antibiotics for 3 weeks and[eventually] it went away. And sort of miraculously he was in remission and is still in remission, 9 years later.

And then when we treated Emily. She was at a 106-degree fever over three days, and there was no infection.

Ive told this story before. My daughter has rheumatoid arthritis, and I had been president of the Clinical Immunologists Society from 2009 to 2010, and the first good drug for juvenile rheumatoid arthritisthat came out. I was invited to give the Japanese scientist Tadamitsu Kishimoto the presidential award for inventing the drug.

Then in 2012, Emily Whitehead was literally dying from CRS, she had multiple organ failures. And her labs came back and IL-6 levels were 1000x normal. It turns out the drug I was looking at for my daughter, it blocks IL-6 levels. I called the physician and I said, listen theres something actionable here, since its in your formulary to give it to her off-label.

And she gave her the appropriate dose for rheumatoid arthritis. It was miraculous. She woke up very rapidly.

Now its co-labeled. When the FDA approvedKymriah, it was co-labeled. It kind of saved the field.

How were you feeling during this time? Did you have any idea what was happening to her?

No, not until we got the cytokine levels, and then it was really clear. The cytokine levels go up and it exactly coincided. Then we retroactively checked out adults and they had adverse reactions and it easy to see. We hadnt been on the lookout because it wasnt in our mouse models.

And it appeared with those who got cured. Its one of the first on-target toxicities seen in cancer, a toxicity that happens when you get better. All the toxicities from chemotherapy are off-target: like leukopenia or hair loss.

I had a physician who had a fever of 106, I saw him on a fever when he was starting to get CRS. When the nurse came in and it said 106, they thought the thermometer must be broken. On Monday, I saw him, and said how are you feeling and he said fine. And I looked at the thermometer and histemperature was still 102.

People will willingly tolerate on-target toxicity thats very different from chemotherapy if they know it helps get them better. Thats a new principle in cancer therapy.

You had these early CART results almost at the same time that Doudna publishes the first CRISPR papers, then still in bacteria. When did you first start thinking about combining the two?

Yeah, it was published inSciencein 2012 and thats when Emily Whitehead got treated. Its an amazing thing.

Thats something so orthogonal. You think how in the heck can that ever benefit CART cells? but my lab had done the first edited cells in patients, published in 2012. And we used zinc-fingered nucleases, which were the predecessors to CRISPR. It knocked out one gene at a time, but we showed it was safe.

I was already into gene editing because it could make T cells resistant to HIV. So it was pretty obvious that there were candidates in T cells that you can knock out. And almost every lab started working on some with CRISPR, cause it was much easier.

We were the first to get full approval by the FDA, so we worked on it from 2012, had all the preclinical data by 2016, and then it takes a while to develop a lot of new assays for this as we were very cautious to optimize safety and it took longer than we wanted, but in the end, we learned a tremendous amount.

So what did we learn?

First of all our patients had advanced metastatic cancer and had had a lot of chemotherapy. The first patient had had 3 bone marrow transplants.

One thing is feasibility: could you really do all the complex engineering? So we found out we could. feasibility was passed.

Another was the fact that cas9 came out of bacteria, forms of strep and staph. Everyone has pre-existing immunity to Cas9 and we had experience from the first trial with Sangamo[with zinc-finger nucleases] where some patients had a very high fever. In that case, we had used adenoviruses, and it turned out our patients had very high levels of baseline immune response to adenoviruses, so we were worried that would happen with CRISPR, and it did not happen.

It did not have any toxicity. If it had, it would have really set the field back. If there was animmune response to cas9 and CRISPR, there couldve been a real barrier to the field.

And then, the cells survived in the patients. The furthest on, it was 9 months. The cells had a very high level of survival. In the previous trials, the cells survived less than 7 days. In our case, the half-life was 85 days. We dont know the mechanism yet.

And we found very big precision in the molecular scissors, and that was a good thing for the field. You could cut 3 different genes on 3 different chromosomes and have such high fidelity.

It [CRISPR] is living up to the hype. Its going to fix all these diseases.

Whats the potential in CAR-T, specifically?

Well theres many many genes that you can add. There are many genes that knocking outwill make the cells work better. We started with the cell receptor. There are many, I think, academics and biotechs doing this now and it should make the cells more potent and less toxic.

And more broadly, what else are you looking at for the future of CART? The week before your paper, there were the results from MD Anderson on natural killer cells.

Different cell types, natural killer cells, stem cells putting CAR molecules into stem cells, macrophages. One of my graduate students started a company to do CAR macrophages and macrophages actually eat tumor cells, as opposed to T cells that punch holes in them.

There will be different cell types and there will be many more ways to edit cells. The prime editing and base editing. All different new variations.

Youve talked about how people used to think the immuno-oncology, if it ever worked, would nevertheless be a boutique treatment. Despite all the advancements, Novartis and Gilead still have not met the sales they once hoped to grab from their CART treatments. Are you confident CART will ever be widely accessible?

Oh yeah, Novartis sales are going up. They had a hiccup launching.

Back in 96 or 97, when Genentech launched Herceptin, their commercial antibody, they couldnt meet the demand either and then they scaled up and learned how to do better cultures. So right now Novartis is using tech invented in my lab in the 1990s culture tech thats complex and requires a lot of labor, so the most expensive part is human labor. A lot can be made robotic. The scale problem will be much easier.

Thats an engineering problem that will become a thing of the past. The manufacturing problem will get a lot cheaper. Here in the US, we have a huge problem with how drugs are priced. We have a problem with pricing. Thats a political issue.

But in cell therapy, its just kind of the growth things you see in a new industry. Itll get worked out.

This article has been updated to reflect that Jim Riley conducted work on CAR in HIV.

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Carl June on CRISPR, CART and how the Vietnam War dropped him into medicine - Endpoints News