science writing

PCSK9 Inhibitors Bring Good News to Nearly Half of Patients Currently at Risk for Heart Disease — If They Can Afford It

The strategy for cardiovascular disease prevention is currently changing in a big, expensive way. Many cardiologists are hopeful that PCSK9 inhibitors will soon bring an end to high cholesterol, effectively changing cardiology forever. Unfortunately, the pharmaceutical companies that developed these potentially miraculous drugs have priced them at a whopping $14-15K a year, more than fifty times the price of statins, the current standard of care[1]. This high price point will lead to the highest therapy cost the United States has ever seen[2] — a cost that will affect all Americans, especially lower income individuals.

Cardiovascular disease is the number one killer of Americans, causing around 610,000- or roughly one in every four- deaths each year[3]. One of the best indicators available for cardiovascular health is low density lipoprotein cholesterol (LDL-C), or  “the bad cholesterol”, levels. If you can get that magical number down below 70-130 milligrams per deciliter (mg/dL) depending on your risk category, then you are considered to have a low risk for cholesterol buildup in your blood vessels and a reduced risk of heart disease[4].

For some people, reaching that number simply requires switching to a “Mediterranean diet” and getting more exercise. However, for many people it requires medication[5]. Currently, statins are the drug category of choice for lowering LDL-C levels.

Unfortunately, statins simply do not work for everyone, leaving a patient care gap of 25-40%.

While there are some steps that can be taken to aid these patients, such as stacking the non-statin therapy ezetimbe with a statin for additional LDL reduction, these combination therapies often still don’t get the job done. For a disease that causes 610,000 deaths a year, a patient care gap of 40% is, simply put, a big, scary deal.

The good news: PCSK9 inhibitors may be just the therapy to close that gap.

PCSK9 inhibitors are antibodies that can help regulate the body’s metabolism of LDL-C. They latch onto a protein called proprotein convertase subtilisin/kexin type 9, or PCSK9, which binds to the LDL-receptors, tagging them for destruction in the liver and keeping cholesterol levels high. By binding to PCSK9, the PCSK9 inhibitors allow the LDL receptors to continue binding to LDL, resulting in a lowering of cholesterol.

More good news: PCSK9 inhibitors are particularly good at lowering LDL-C in the patients who need it most — the ones who currently have no other options. Since the invention of these inhibitors, several trials have shown PCSK9 inhibitors decrease LDL-C in patients with familial hypercholesterolemia (FH), a genetic condition that leads to high cholesterol unmanaged by statins.    

In light of these trials, the FDA approved the use of two PCSK9 inhibitors this past summer for use in patients with FH or clinical atherosclerotic cardiovascular disease (ASCVD).  These patients have already had heart attacks or strokes due to plaque buildup in their arteries and do not benefit from statin therapy [6]. It is estimated that 5-10M people have either FH or ASCVD[7]. At roughly $15K annual cost per person for either PCSK9 inhibitor, the price to insurance companies and the people they represent- and charge- will be astronomical.

But that’s just the beginning. Many cardiologists, pharmaceutical companies, and insurance companies alike expect that those 5-10M people are just a small sliver of the population for whom these drugs will eventually be prescribed[8].  If this is the case, it means that a huge number of people will potentially be prescribed PCSK9 inhibitors in the near future, at great expense. Estimates for the cost to the U.S. healthcare system of such an expansive prescription base for these expensive drugs are between $100-150B per year[9]. PCSK9 inhibitors are by no means the most expensive per-use medications on the market, but at their current price point they are the most expensive drugs that require a lifetime of continued use.

Many people wonder why drugs like the PCSK9 inhibitors and other “biologics” are so expensive. Part of the answer is the high cost for a continued cycle of research and development for newer and better drugs. The making of the antibodies is expensive. Drug trials done properly are also expensive and require a wide range of participants to demonstrate broad spectrum efficacy. In fact, the drug companies do not make money unless their drug works well[10]. In the end, it’s a balancing act between the economics of these high cost medications and the ethics of the inherent decreased access to care.

The United States government does not govern the price of drugs —  the market does. In places like Europe or Canada, the costs of these drugs would never be set so high because they are set by the government. In fact, the European version of the FDA, the European Medicines Agency, rejected PCSK9 inhibitors until their prices were halved[11].

In America, specialty drugs like cancer drugs and those for Hep-C are inherently in low demand, which allows for a higher price only as long as the consumer, which is the insurance company in the United States, is willing to pay for it. If these conditions are met, that price point remains.

This high price point does provide some overall benefits. By consumers paying more here than in other countries for drug use, the United States foots the majority of the bill for the entire world when it comes to research and development of new drugs[12]. Drugs like the PCSK9 inhibitors may be significantly more expensive in the United States than in Europe, but the revenue from prescription drug use in the United States has a global health impact. So the question becomes: is this a fair situation for Americans? Perhaps not — especially for those who cannot afford it. Yet, there is currently no other option if we support the continued development of novel medications.

The regulation of drug prices by the government has been in the national limelight lately, with people ranging from Martin Shkreli of Turing Pharmaceuticals, who raised the price of the AIDS-related drug Daraprim from $13.50 to $750 per pill overnight, to Bernie Sanders and Hillary Clinton who have been expressing a need for change on Twitter and in their campaign platforms[13].

Shkreli argues that his price increase for Daraprim was a consequence of this model: the economic necessity for research and development. In September, the BBC called Shkreli the “most hated man in America”[14] and his face was all over the news. Hillary Clinton tweeted her outrage at him. Is there any difference between Shkreli’s 5000% price hike and the insanely high prices of such important drugs like the PCSK9 inhibitors?

The difference is in the need for R&D. Daraprim was developed over 40 years ago, unlike the brand new PCSK9 inhibitors, and is sufficient, unlike statins. Although Daraprim does treat a rare condition  and has a low demand, the production cost to Turing Pharmaceuticals is very low, unlike the PCSK9 inhibitors.

So, what about PCSK9 inhibitors? Do the economic and ethical factors of such a novel and important pharmaceutical dictate and permit their extremely high ticket price? Only Amgen and Regeneron, the pharmaceutical companies selling them, seem to say yes[15]. Pharmacies that stock the drugs, government agencies that study drug prices, and cardiologists are in agreement that the price point of the PCSK9 inhibitors is simply too high, even for a drug that so greatly reduces LDL-C[16], especially considering the possibility that they will be used by so many millions before the end of the decade.

People like Martin Shkreli give “Big Pharma” a worse reputation than it deserves, but he’s not the only culprit. When considering the price of drugs, the price of research and development and the demand must be considered. If the United States accepts the lion’s share of the responsibility for worldwide medication research and development, the costs to consumers in the United States may become untenable in this age of costly pharmaceuticals.

The introduction of PCSK9 inhibitors to the drug market could truthfully bring an end to high cholesterol and dramatically reduce cardiovascular disease across the world. However, Americans simply cannot bear the economic weight when the drugs cost each user nearly $15K annually for the rest of his or her life. The price must be reduced, but only time will tell by what means such a change will occur.

 

Bibliography

Brendan M. Everett, M.D., M.P.H., Robert J. Smith, M.D., and William R. Hiatt, M.D.

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Cainzos-Achirica M, Martin SS, Cornell JE, Mulrow CD, Guallar E. PCSK9 Inhibitors: A New Era in Lipid-Lowering Treatment?. Ann Intern Med. 2015;163:64-65. doi:10.7326/M15-0920

Cassels A., Enthusiasm for PCSK9 inhibitors to lower LDL cholesterol is premature. Clinical Pharmacist, Vol 8, No 4, online | DOI: 10.1211/CP.2016.20200902 4/11/2016

Curfman G. PCSK9 inhibitors: a major advance in cholesterol-lowering drug therapy. Harvard Health Publications. 15 March 2015.

Dorey, E. “Cholesterol Busting PCSK9 drugs” The Pharmaceutical Journal, 18 April 2015, Vol 294, No 7858, online | DOI: 10.1211/PJ.2015.20068181

Express Scripts. The country’s first PCSK9 inhibitor. 29 July 2015.

Lee Joseph, Jennifer G. Robinson, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition and the Future of Lipid Lowering Therapy, Progress in Cardiovascular Diseases, Volume 58, Issue 1, July–August 2015, Pages 19-31, ISSN 0033-0620, http://dx.doi.org/10.1016/j.pcad.2015.04.004.

Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e29-322.

O’Riordan, Michael. “PCSK9 Inhibitors: Good Early Responses With Pricey Drugs, but Doctors Still Waiting on Read Data.” tctmd.com. tctmd, 26 Jan. 2016. Web. 13 May 2016.

Peck, P. (2015, September 08). PCSK9 Inhibitors: Now That We Have Them, What Do We Do? Retrieved April 29, 2016, from http://www.medpagetoday.com/Cardiology/Dyslipidemia/53451

Phend C. Update: PCSK9 inhibitors hit the market. Medpage Today. 3 January 2016.

Qiu, L. (2015, September 24). Fact-checking Martin Shkreli's claim that Daraprim is 'underpriced, relative to its peers' Retrieved April 29, 2016, from http://www.politifact.com/punditfact/statements/2015/sep/24/martin-shkreli/fact-checking-martin-shkrelis-claim-daraprim-under/

Reuters. (2015, November 19). U.K. Cost Watchdog Nixes Repatha. Retrieved April 29, 2016, from http://www.medpagetoday.com/Cardiology/Dyslipidemia/54783

Riordan M. PCSK9 inhibitors not cost-effective at current price: ICER review. Medscape. 9 September 2015.

Rishi Puri, Steven E. Nissen, Ransi Somaratne, Leslie Cho, John J.P. Kastelein, Christie M. Ballantyne, Wolfgang Koenig, Todd J. Anderson, Jingyuan Yang, Helina Kassahun, Scott M. Wasserman, Robert Scott, Marilyn Borgman, Stephen J. Nicholls, Impact of PCSK9 inhibition on coronary atheroma progression: Rationale and design of Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV), American Heart Journal, Volume 176, June 2016, Pages 83-92, ISSN 0002-8703, http://dx.doi.org/10.1016/j.ahj.2016.01.019.

Taylor N. European Regulatory Roundup: UK’s NICE takes sides in PCSK9 market. 11 February 2016

Thomas, Z., & Smith, T. (2015, September 23). Who is Martin Shkreli - 'the most hated man in America'? Retrieved April 29, 2016, from http://www.bbc.com/news/world-us-canada-34331761

Tice JA, Kazi DS, Pearson SD. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors for Treatment of High Cholesterol Levels: Effectiveness and Value. JAMA Intern Med. 2016;176(1):107-108. doi:10.1001/jamainternmed.2015.7248.

Tirrel, M., & Mangan, D. (2015, September 21). Hillary calls Rx price 'outrageous,' vows action. Retrieved April 29, 2016, from http://www.cnbc.com/2015/09/21/clinton-calls-drug-price-hike-outrageous-vows-plan.html

Tirell, M., & Mangan, D. (2015, October 06). How Express Scripts plans to cover a $14,000 drug. Retrieved April 29, 2016, from http://www.cnbc.com/2015/10/06/pricey-new-cholesterol-rx-covered-by-big-drug-plan-but.html

Waters DD, Hsue PY, Bangalore S. PCSK9 Inhibitors for Statin Intolerance?. JAMA. 2016;315(15):1571-1572. doi:10.1001/jama.2016.3670.

Whalen, J. (2015, December 1). Why the U.S. Pays More Than Other Countries for Drugs. Retrieved April 29, 2016, from http://www.wsj.com/articles/why-the-u-s-pays-more-than-other-countries-for-drugs-1448939481

Whitman, E. (2015, September 02). Bernie Sanders Says Drug Prices Are Too High, And He's Introducing A Bill To Bring Them Down. Retrieved April 29, 2016, from http://www.ibtimes.com/bernie-sanders-says-drug-prices-are-too-high-hes-introducing-bill-bring-them-down-2079226?rel=rel2

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Sneaky Salmonella's ability to survive in dry foods challenges common perceptions of food risk

Salmonella. We’re all familiar with the bacterium that stops us from eating raw cookie dough and has us double- and triple-checking our meat thermometers. Common knowledge tells us that if we follow certain precautions, we can avoid a terrible bout of food poisoning. However, it is becoming increasingly evident that salmonella can also survive for several months in dry foods such as nuts, dry milk, crackers, and chocolate, revealing that it may be a greater threat to food safety than generally understood.

The public has been aware of the risks of salmonella for decades. Every year, salmonella is responsible for approximately one million cases of foodborne illness and three hundred eighty annual deaths in the United States, with risk of further complications in young children and the elderly. Usually, infected individuals experience symptoms such as fever, diarrhea, and abdominal cramps for four to seven days and recover without treatment.

Despite the associated threats, salmonella is not considered one of the more dangerous bacteria. Salmonella awareness literature, such as that presented by popular outlets such as foodsafety.net and webmd.com, commonly state that it is only a risk in raw meat and dairy, and so long as one cooks the food and cleans contacted surfaces, the risk is minimal.  In the past, it was often assumed that these precautions against salmonella were sufficient.

However, scientists studying salmonella have found that it can actually survive in a wide variety of host environments, including in the dry foods that sit on shelves. Most recently, Wonderful brand pistachios have been recalled due to salmonella outbreaks in several states, including Minnesota. These nuts are sold in many grocery stores and sit on shelves in countless households, thus demonstrating the need for greater awareness of salmonella in dry foods. Although it is not known exactly how these dry foods become contaminated, it is likely that salmonella capitalizes on the close quarters in industrial processing plants to travel from animal feces, to animal meat and dairy products, and eventually to dry foods.

Several recent studies have examined the extent to which salmonella can survive in a variety of dry environments; it was previously believed that a wet environment was required for survival. A current study from the lab of Dr. Irene Hanning at the Department of Food Science and Technology at the University of Tennessee examined the how different conditions- including acidity, temperature, and water content- affect salmonella survival.

Their primary finding was that salmonella is incredibly versatile and can adapt to a wide variety of environments, which explains how it can travel from a cow’s intestines, to soil, to a factory, to packaged food, and finally into humans. The study also found that not only could salmonella survive for long periods of time in dry foods, which was a relatively new discovery, but also that living in dryer environments actually makes the bacteria more resistant to the heat inactivation typically used to make foods safe during processing.[5] It is likely that this variable ability to survive at higher temperatures, which depends on the moistness of the environment, contributes to processing plants’ inability to fully eradicate salmonella from drier foods.

A second study done by the team of Dr. Larry Beuchat at the Center for Food Science and Technology at the University of Georgia looked into the ability of salmonella to survive in dry snack foods. Researchers in Beuchat’s lab exposed different varieties of peanut butter and cheese based cream-filled crackers to salmonella.  They found that the bacteria was able to colonize and survive in all of the food products, living the longest in cheese-filled crackers, likely due to the dryer environment. These studies show that salmonella is no longer something that we can combat with thorough baking and cleaning practices alone.

Since the beginning of 2016, two salmonella outbreaks have spread across the United States in dry food products, both reaching Minnesota. The first contamination discovered was in RAW Meal Organic Shake and Meal Products, causing illness for thirty-three people in twenty-three states. The second was in Wonderful pistachios, causing illness for eleven people in nine states.

This widespread contamination of dry food products is concerning for a number of reasons. First, unlike meat, consumers often buy products like nuts and consume them without heating to temperatures that would kill the bacteria. As a result, if a dry food product is contaminated, illness is significantly more likely.

Second, salmonella can live for up to six months in dried foods, many of which have a long shelf life. Consequently, even if there are recalls on contaminated foods, many people will have the tainted product in their homes for weeks or months, extending the window in which salmonella could cause illness from the damaged foods if consumers are not made aware of the recalls.

Third, and perhaps most importantly, these outbreaks raise questions about whether sanitation standards in food processing plants are taking salmonella’s presence and increased temperature resistance in dry food products into account. According to Dr. Linda Harris, the Associate Director at the Western Institute for Food Safety and Security at the University of California, Davis, it only takes the ingestion of ten salmonella cells to make a person sick. So perhaps the standards for food products like chicken and eggs, which will be cooked by consumers thus eliminating any remaining salmonella, are not high enough for products such as pistachios, which will be eaten without any additional preparation.

This may be a moment for major food processing companies to reexamine their food safety practices. Enforcing more stringent inactivation measures for dry food products could be a step toward avoiding future outbreaks. However, perhaps a more immediate first step is to change household knowledge about salmonella. Greater public awareness of the potential dangers of salmonella in dry foods could be instrumental in preventing unpleasant, and potentially deadly, food poisoning for families across the nation.

 

Bibliography

Andino, A., & Hanning, I. (2015). Salmonella enterica: Survival, Colonization, and Virulence Differences among Serovars. The Scientific World Journal, 2015, 520179. http://doi.org/10.1155/2015/520179

Center for Disease Control. (2016). Retrieved from http://www.cdc.gov/salmonella/montevideo-03-16/index.html

Diez-Gonzalez, F. (Speaker). (2016, March 15). “Exploring the Secrets to Salmonella’s Success” MPR News. Retrieved from http://www.mprnews.org/story/2016/03/14/salmonella

Harris, L. (2009). Building a Better Understanding of Salmonella in Pistachios. Retrieved from http://www.foodhaccp.com/1news/050109o.html

 Mann, D. (2015). Survival of Salmonella in Cookie and Cracker Sandwiches Containing Inoculated, Low-Water Activity Fillings. International Association for Food Protection. Retrieved from https://iafp.confex.com/iafp/2015/webprogram/

HIV Evades Previously Successful Gene Editing Treatment, Causing Disease Resistance

On March 4th, a research team from Temple University successfully removed latent human immunodeficiency virus (HIV) from infected human cells using an emerging gene editing technology called CRISPR-Cas9 (2), a promising treatment that could improve the quality of life for millions (1). By April 19th, a competing team demonstrated that HIV could mutate to escape CRISPR-Cas9. Rather than discrediting Temple University’s findings, the competing research demonstrates process as a core tenet of science and underscores the importance of collaboration.

More than 35 million people in the world are infected with HIV and that number continues to grow (1).  Once HIV enters the body, it targets key immune cells, such as T-cells, and incorporates HIV genetic information into the host genome. At this stage, HIV can remain latent- the viral DNA exists in the host genome but is not being used to produce more HIV (4). In its active form, HIV replicates using the host cell’s own mechanisms and destroys T-cells.

HIV targets a specific subset of T-cells, called T-helper cells (TH cells), that are responsible for fighting infection.  Acquired Immunodeficiency Syndrome (AIDS), HIV’s deadly successor, occurs when HIV has drastically reduced the TH cell population to the point that the body’s immune system is ineffective (5).

Currently, HIV is managed through antiretroviral treatment that prevents viral replication within the body6. This prevents HIV from spreading to other cells and can aid in restoring the TH cell population. While antiretroviral therapy has been effective in prolonging and improving the quality of life, the drugs are expensive and must be taken vigilantly for the remainder of one’s life. Antiretroviral treatment does not eradicate HIV in its latent stage and some strains of HIV have developed resistance to the treatments6. At this point in time, HIV is impossible to cure.

CRISPR offers the unique opportunity to remove HIV in its latent stage from the genome of cells, effectively curing cells of infection and preventing reinfection by the virus. 

The advent of CRISPR-Cas gene editing technology marked a huge advance in modern science.  Clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR associated proteins (Cas) provide immune protection to bacteria, but have recently been harnessed as a potent gene editing technology (3). CRISPR-Cas systems are capable of modifing DNA in cells, including human cells. CRISPR has the potential to edit out genes responsible for detrimental human diseases as well as making genetic modifications that prevent mushrooms from browning on the shelf of a grocery store. The applications of CRISPR are seemingly limitless.

Upon CRISPR’s release, researchers at Temple University were immediately interested in using CRISPR-Cas9 to treat and possibly cure HIV.  The Cas9 protein can be “programmed” to target removal of specific segments of a genome using a genetic template created by researchers (3).

At Temple University, Rafal Kaminski and his team used CRISPR-Cas9 to effectively remove HIV from the genome of human TH cells in a petri dish, the first step to making modifications in a living organism. The CRISPR-Cas9 treatment prevented HIV infection of treated human THcells and inhibited viral replication in peripheral blood cells from HIV+ samples. Kaminski  and his team had not only cured cells of latent HIV infection, they had prevented other cells from being infected by the virus.

The possibility of curing HIV using CRISPR-Cas9 was within reach. However, scientific breakthroughs rarely happen in one fell swoop and it was not long before a different research team found flaws in Rafal Kaminski’s model.

Six weeks later, Zhen Wang of McGill University published evidence that HIV develops evasion resistance to CRISPR-Cas9 technology. The introduction of Cas9, while fostering deletion of HIV in some THcells, caused mutations in others that promoted HIV resistance and increased viral infectivity. These mutations occurred exactly where Cas9 bound to the DNA targeted for removal, indicating that Cas9 is responsible for the mutations. The mutated HIV replicated more quickly than control HIV, increasing the potency of the virus and the potential for infection (2).

Collectively, this research suggests that CRISPR-Cas9 technology requires some fine tuning before it will be successful for treating HIV. Several labs have confirmed the findings of Kaminski, including Wang, but there is no doubt that the CRISPR treatment must undergo revision. Wang suggested that targeting multiple sites within the HIV genome with a variety of templates may prevent the dangerous mutations that currently occur.

A room full of scientists will earnestly declare that science is a process, not simply a collection of facts. Science is driven by the kind of discussion demonstrated by Rafal Kaminski and Zhen Wang; no one is expected to have the answer right on the first try. Wang’s findings do not invalidate CRISPR-Cas use in HIV treatment, but advise caution. As is true with most things in science, harnessing CRISPR-Cas technology to treat HIV will be a process.

 

References

1.     Kaminski, R., Chen, Y., Fischer, T., Tedaldi, E., Napoli, A., Zhang, Y., Karn, J., Hu, W., and Kahili, K. (2016). Elimination of HIV-1 Genomes from Human T-lymphoid Cells by CRISPR/Cas9 Gene Editing. Scientific Reports. 6.

2.     Wang, Z., Pan, Q., Gendron, P., Cen, S., Wainberg, M., and Liang, C. (2016). CRISPR/Cas9-Derived Mutations Both Inhibit HIV-1 Replication and Accelerate Viral Escape. Cell Reports. 15. 481-489.

3.     Jink, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J., and Charpentier, E. (2012). A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity. Science. 333. 816-821.

4.     Douek, D. C., Roederer, M., and Koup, R. (2009). Emerging Concepts in the Immunopathogenesis of AIDS. Annu Rev Med. 60. 471-484

5.     Okoye, A.A., and Picker, L.J. (2013). CD4+ T cell Depletion in HIV Infection: Mechanisms of Immunological Failure. Immunolo Rev. 254. 54-64.

6.   National Institute of Health AIDSinfo. (2016). HIV Treatment: The Basics.

Showdown Between Two Groundbreaking Scientists Determines the Future of Genome Editing Technology

The United States Patent and Trademark Office (USPTO) currently has to resolve a billion dollar patent battle over a genome editing tool called CRISPR/Cas9. Jennifer Doudna of University of California, Berkley and Feng Zhang of the Broad Institute both claimed they made the major discoveries to the CRISPR system. With the potential to edit human genomes and cure genetic diseases at stake, the patent battle over CRISPR has become the center of attention for scientists worldwide.

CRISPR- or clustered regularly interspaced short palindromic repeats- is a genome editing technology that allows biologists and medical researchers to precisely edit parts of the genome along with a protein called Cas9, which acts as molecular scissors to cut DNA at specified locations [1]. Other genetic editing techniques such as transcription activator-like effector nuclease (TALEN) and zinc finger nuclease (ZNF) have been around since the early 2000s, but the simplicity and efficiency of CRISPR has led it to become the superior genome editing technology.

CRISPR’s genomic editing capability has a wide range of potential functions. One major application is genetically modifying foods and crops; CRISPR can be used to genetically modify the common white button mushroom to gain resistance to browning [2]. Additionally, CRISPR has the potential to cure genetic diseases and be used as a cancer treatment. While much research must be done before this is possible, many scientists think CRISPR can revolutionize therapeutics.

The CRISPR legal battle arose when the Broad Institute paid extra to expedite the patent process, giving them several patents that cover the use of CRISPR in eukaryotic organisms. This would allow them to use the technology in all multicellular organisms, ranging from mice to humans. Dr. Doudna and UC Berkeley filed an earlier patent application, but the Broad Institute argued that the application of CRISPR in eukaryotes was strictly speculation in Dr. Doudna’s work.

While the Broad Institute was the first to receive the patent, lawyers from UC Berkeley argued that Dr. Zhang and the Broad Institute overstated their discoveries in the patent application and never demonstrated or documented such genetic capabilities, specifically the use of tracrRNA- an RNA molecule that activates the DNA cutting segment of the CRISPR/Cas9 system. In addition, UC Berkeley lawyers pointed out that Dr. Zhang omitted several co-inventors from the patent application, which they argue was “deceitful intent”.

Both Dr. Doudna and Dr. Zhang were groundbreaking scientists even before the CRISPR discovery. Dr Doudna was awarded the prestigious Alan T. Waterman Award for her work in RNA crystallization and function while working at Yale University. Comparatively, Feng Zhang was featured in 35 Innovators Under 35 in 2013 for his work with optogenetics- a technique which uses light intensities to control light-sensitive cells- to cure psychiatric diseases in mouse models.

Despite their accolades, the influence of money cannot be overlooked, especially in a case this monumental. A 2015 report from the renowned global market research firm MarketsandMarkets projected the global genome editing market to be worth $3.5B by 2019 [3], a $2.7B increase from 2014. Additionally, the report stated, “By technology, the market is divided into CRISPR, TALEN, ZNF, antisense technology, and other technologies. Of these, CRISPR will account for the largest and the fastest-growing segment of the global genome editing market by 2019.”

Due to the financial potential, many scientists are investing in CRISPR-focused biotechnology companies. Dr. Doudna and Dr. Zhang, along with leading geneticist George Church, cofounded a biotechnology startup called Editas, which plans to use the CRISPR system to create personalized human therapeutics. The patent battle led to Dr. Doudna leaving this company and starting a rival biotech startup called Caribou Biosciences, Inc.

While the financial implications of the CRISPR breakthrough are immense, many people around the world are more concerned about the ethics behind the new technology. Since her CRISPR paper was published, Dr. Doudna has traveled all around the country discussing the issues of human modification with fellow scientists, congressmen and women, and even White House Officials. The major concerns are the implications of editing human eggs, sperm, and embryos.

 The Napa Bioethics Forum, a small consortium of scientists including Dr. Doudna, met in the spring of 2015 and have since urged researchers to avoid using CRISPR in human research until the precision and capabilities of the technology have been further explored [4].

Despite the recommendation by Dr. Doudna and the Napa Bioethics Forum, Chinese researchers led by Junjiu Huang, a genomic engineer at Sun Yat-sen University, have studied the use of CRISPR in nonviable embryos, or embryos that cannot result in live births. Only a fraction of the embryos maintained the genetic manipulation, while others showed incorrect cuts within the DNA[5]. These results point to the serious challenges with CRISPR and demonstrate that more research must be done before it is applied to human therapeutics.

The potential of CRISPR is promising, but no one knows how far the technology will progress. With the potential to make billions of dollars in human therapeutics on the line, the patent battle over CRISPR will only become more heated.

 

Bibliography:

Baltimore, D. et al. (2015). A prudent path forward for genomic engineering and germline gene modification. Science Perspective. http://science.sciencemag.org/content/348/6230/36.full

Begley, S. (2016). Clash of scientific titans: CRISPR hits the courts, with money and prestige at stake. STAT. https://www.statnews.com/2016/03/08/crispr-patent-fight/

Begley, S. (2016). In the CRISPR patent fight, the Broad Institute gains edge in early rulings. STAT. https://www.statnews.com/2016/03/18/crispr-patent-dispute/

Doudna, J. (2015). Genome-editing revolution: My whirlwind year with CRISPR. Nature Comment. http://www.nature.com/news/genome-editing-revolution-my-whirlwind-year-with-crispr-1.19063

Gill C. (2016). Gene-edited mushroom created by Penn State researcher is changing GMO dialogue. Penn State News. http://news.psu.edu/story/405406/2016/04/19/research/gene-edited-mushroom-created-penn-state-researcher-changing-gmo

Jinek, M., et al. (2012). A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity. Science 337, 816-820.

Liang, P. et al. (2015). CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein & Cell 6. 363-372.

Marketsandmarkets.com (2015). Genome Editing / Genome Engineering Market by Application (Cell Line Engineering, Animal & Plant Genetic Engineering), Technology (CRISPR, Antisense, TALEN, Zinc Finger Nuclease) & End User (Biotechnology & Pharmaceutical, CRO) - Global Forecast to 2019.

Regalado, A. (2015). CRISPR Patent Fight Now A Winner-Take-All Match. MIT Technology Review. https://www.technologyreview.com/s/536736/crispr-patent-fight-now-a-winner-take-all-match/

Servick, K. (2016). Accusation of errors and deception fly in CRISPR patent fight. Science Community.

http://www.sciencemag.org/news/2016/03/accusations-errors-and-deception-fly-crispr-patent-fight

Yeadon, J., (2014). Pros and Cons of ZNFS,TALENS and CRISPR/CAS. The Jackson Laboratory Blog Post.  https://www.jax.org/news-and-insights/jax-blog/2014/march/pros-and-cons-of-znfs-talens-and-crispr-cas

Exploring the Ethics of Fecal Microbiota Transplant (FMT) in Pediatric Patients

On March 8th, Dr. Stacy Kahn from the University of Chicago spoke regarding the ethics of Fecal Microbiota Transplant (FMT) in pediatric patients during a three-part lecture series hosted by the University of Minnesota Consortium of Law and Values.

Kahn opens up her case study

Assume you are a physician. You have a 13-year-old female patient with ulcerative colitis. There is discomfort and blood streaks in the stool, signs of early ulcerative colitis.  The patient's mother put her on a dairy and gluten-free diet along with various vitamins and natural supplements to aid in easing the condition.

Mom wants to do an at home FMT and is convinced, based on videos and books, that she can treat her child. After much deliberation about the risks the mother says, “Thanks doctor, but I’m going to do FMT anyway.” 

As a physician, what do you do? Do you call child protection services? Do you give information about FMT and stool banks despite the treatment not being FDA approved and still in clinical trials with not enough data to support or invalidate its efficacy? Do you let the parent go on with the decision? These are all ethical questions around FMT and the field of pediatrics.

What is FMT?

FMT stands for Fecal Microbiota Transfer where bacteria from the gut in the form of feces is transplanted into a patient to recolonize the damaged tissue. FMT is often performed via colonoscopy, nasal tube, or orally in a pill.  The process is currently a treatment for GI conditions like irritable bowel disease, ulcerative colitis, and Crohn's Disease.  FMT also has the potential to treat other diseases associated with non-GI microflora including: psoriasis, acne, asthma, diabetes, and obesity. Despite the recent media attention, FMT is not new. The first FMT in the states was conducted in the 1950s for a disease similar to recurrent ulcerative colitis, although there are historical accounts dating back to 4th Century Chinese “dragon soup”.  FMT is FDA allowed but not approved and lacks many of the typical clinical and animal studies. There are also concerns about intellectual property, regulations, and safe practices among other things.

FMT and pediatrics

Now it’s important to consider the ethical pillars of medicine:

Beneficence: duty to do good.

Non-Maleficence: duty to not do bad/cause harm.

Autonomy: respect for patient's individual rights and self determination.

Justice: to treat all equally and equitably.

But when it comes children the pillars don’t quite fit. Children don’t have autonomy; they have a legal guardian or parent to advocate and speak on their behalf. Doctors need consent from a guardian and assent, approval, and understanding of the procedure from the patient.

Also children’s metabolism of drugs and foods are different due to differences in blood volume, hormone secretion, and activity levels. So dosing matters. The problem is that most drugs being studied and two-thirds of drugs sold on the market don’t use clinical studies involving children or have never been tested for children. We don’t know the efficacy of the drugs prescribed nor the safe and effective dosage, which is very concerning for both parents and physicians.

Perceptions and concerns of the treatment

But the concerns are not felt in the same way across the parties involved. Patients are frustrated with the slow rate of drug development, physicians, and pain.  The constant effort for effective treatments is exhausting. Patients are desperate for any type of relief. FMT, in the patient’s perspective, is believed to be natural and therefore safer than western medicine practices and pharmaceuticals. The books and articles out on the market give patients a false sense of security by restoring autonomy over their own health. There is a general lack of data regarding the efficacy of the treatment and a risk that at home treatments will worsen the condition.

Doctors, on the other hand, are concerned about the ethics and efficacy of the treatment. There’s no data to support the benefits or assess the risks, making it difficult to prescribe despite patient requests. Being able to reconcile all these concerns starts with open conversation about FMT and the concerns.

Moving forward

More research needs to be conducted about FMT and its effects. International Review Boards and local research institutions need to coordinate with larger research institutions to effectively disseminate information and document findings. This keeps physicians up-to-date with treatment research to better serve their patients.

But most importantly, patients need to be involved in the conversation. The risk of adversarial conversations is likely to inspire patients to go rogue with high risk and poorly informed self treatment.