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Cleanroom technology for the IVF industry – Cleanroom Technology

3-Dec-2019

Design and Build | Pharmaceuticals

In vitro fertilisation is a process that mimics nature and as such, the industry requires state-of-the-art facilities to control environmental conditions and prevent contamination of the product. Giles Palmer explains

From its humble beginnings in a small cottage hospital in Oldham (UK) to its acceptance in mainstream medicine and everyday life, the in vitro fertilisation (IVF) industry has evolved continuously, and is increasingly applicable not only with the treatment of a growing variety of fertility issues but also with challenges of todays society and lifestyle choices.

Globally, infertility affects seven million people: one in six couples have a problem in conceiving. Last year we celebrated the 40th anniversary of the first test-tube baby, Louise Brown, and in doing so the birth of clinical embryology as a profession.

Over the years, IVF success rates have increased. The introduction of hormonal stimulation produced more oocytes than the early natural cycle attempts leading to a more streamlined and controlled treatment cycle leading to a better choice of embryos to transfer, and the need to cryopreserve remaining embryos.

Originally designed for patients with tubal damagewhen the oocyte could not journey from the oviduct to the uterus to implantthe application of this science has been developed to include all forms of infertility, from hormonal disorders to severe male infertility. The shift has seen the opening of new possibilities that have been both morally, spiritual and socially questioned, such as the use of donor sperm and oocytes, sex selection, genetic screening and posthumous use.

These processes are manual manipulations in laminar flow hood with heated work surfaces, cultured in special low volume incubators

Embryologists working in the lab mimic nature, closely maintaining optimum conditions of temperature, pH and osmolarity; monitoring the development of embryos, and selecting the best embryo for transfer. These processes are manual manipulations in laminar flow hood with heated work surfaces, cultured in special low volume incubators.

Culturing outside the body close to physiological conditions has paved the way for new techniques, such as intracytoplasmic sperm injection (ICSI) and preimplantation diagnosis via embryo biopsy coupled with the ever-evolving science of molecular genetics.

Recent advances in cryobiology have also meant that frozen embryos have now succeeded in producing a viable pregnancy as fresh embryos (Thomson, 2019).

Embryos are routinely cultured now to five- or six-day post insemination before being transferred to the intended mother when the embryo has reached the blastocyst stage. This ready-to-implant embryonic stage (previously difficult to achieve with suboptimal culture media) now has a success rate of 54%, according to London Womens Clinic data.

Giles Palmer, Senior Embryologist

The IVF lab is almost always adjacent to an operating theatre where procedures such as egg collection (by follicle aspiration) under sedation and embryo transfer are performed. The eggs and embryos are transferred hand-to-hand, literally, by a hatch (a passthrough you might say in the cleanroom industry) that must remain open for lengths of time up to 30 minutes.

Positive pressure and HEPA filters are commonplace in IVF laboratories, but industry standards are somewhat elusive: there is no consensus on what constitutes an IVF laboratory, and guidelines may differ greatly from country to country.

Only about 15% of IVF clinics are housed within a hospital, and currently may be designed within a medical centre, doctors offices and general buildings.

The IVF process also requires auxiliary rooms. An andrology laboratory (preferably in a separate room but not globally mandatory) is used to process the non-aseptic semen. A cryobiology room is then used to store the frozen samples. Plus, a medical gas room is also required.

Apart from gases used by the anaesthetists, mixtures of medical-grade gasses are required to produce the correct environment within the incubators for the developing embryo; typically 6% CO2 with low O2 tension.

The IVF industry might not manufacture a product, as many industries using cleanrooms, but it seems appropriate to measure success by an endpoint of the birth of a healthy child. Development and normal growth, however, can be limited in adverse air conditions. The entire IVF process is governed by the biology of sperm, egg and embryo, and we must optimise conditions to protect the product against exposure to adverse external factors. The problem lies in the lack of agreement of these conditions.

The human embryo is sensitive to light, temperature and other environmental conditions. Pollutants can settle on workspaces, and although embryos bathed in their culture media overlaid with a layer of light paraffin oil, attention has to be paid to the risk of toxins infiltrating the barrier because embryos lack an immune system to stave off harmful environmental contaminants.

It should be noted that disposables and new equipment can introduce hazards in the laboratory, too

Urban air can contain high levels of pollutants, such as carbon monoxide, nitrous oxide, sulphur dioxide and heavy metals. Indoor construction materials, such as MDF, PVC flooring, paints and adhesives, constitute the major source of volatile organic compounds (VOCs).

Once only anecdotal in the early days of IVF, studies emerged, showing the negative effect of poor air quality and ultimately, pregnancy outcome (Cohen 1997, Hall 1998, Mayer 1999, Boone 1999). It was shown that compressed gases that fed the incubators had high levels of VOCs (namely benzene, isopropanol and pentane) and it was not uncommon for the laboratory environment to have higher VOC concentrations than indoor air.

Particle monitors and VOC counters have also emerged in the IVF marketplace

The industry took notice and has produced ingenious ways to protect the embryos, from closed laminar flow hoods to improvements to filters systems with in-line gas filters and standalone portable air filtration units. Particle monitors and VOC counters have also emerged in the IVF marketplace (Forman, 2004).

It should be noted that disposables and new equipment can introduce hazards in the laboratory, too. Sterile plastic test tubes and dishes in packages need off-gassing. The polystyrene-based plastics can emit styrene (Sing, 2015), and it is good practice to open the consumables well before use and leave in a laminar flow hood. New equipment must also be burnt in (to release residual VOCs from the manufacturing process) in a separate room before use.

While health and safety authorities have safe limits for VOC exposure for humans, there is nothing documented for developing embryos. Industry guidelines were (and still are) vague, but both the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine recognise air quality is a key factor to success (ASRM 2014, ESHRE 2004) yet without specific details.

In 2004, the IVF landscape changed in Europe with the announcement of the European Union Tissue and Cell Directive, which specified precise quality and safety requirements for the donations, procurement, testing coding and storing. A key point in this policy was clean air (EUCTD, 2004). It was meant to bring cell and tissue use on par with blood and organ handling.

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The inclusion of the IVF was both unexpected and fiercely debated (Mortimer 2005, Saunders and Pope 2005) because the original specifications would have been detrimental to in vitro embryo development.

The Directive stated: Where tissues or cells are exposed to the environment (...) an air quality of Grade A, as defined in the current European Guide to Good Manufacturing Practice, is required. The background must be demonstrated to guarantee the maintenance of Grade A in the tissue/cell manipulation while in use and unmanned. The document highlighted areas of improvements; there was little or no air management before this draft.

Where tissues or cells are exposed to the environment (...) an air quality of Grade A, as defined in the current European Guide to Good Manufacturing Practice, is required

It was argued that risk of infection is low and that the product cannot be sterilised. Equally, the cooling effects of maintaining airflow of a Grade A environment would have been detrimental to embryo culture and introduce vibrations not conducive to fine accurate manipulation needed in many techniques.

A second draft of the Directive stated a less stringent environment if Grade A was either detrimental or technically impossible, but did not define a level of air quality other than close to A.

In the UK, the Human Fertilisation and Embryology Authority (HFEA), a government watchdog, supported a Grade C working environment with a background of Grade D. From 2007, all manipulations must be within a Class II laminar flow hood. This regulation meant IVF labs at the very least had to make some adjustments to facilities and standard operating procedure. In the design of a laboratory, great care should be placed on location and adjacent rooms, so to avoid proximity to laundry, canteen or pathology labs emitting possible air contaminants. In a hospital environment, however, limited available space is always a problem.

The same deal of attention should be paid during and after laboratory renovation or build. The wrong materials can be the difference between a triumphant inauguration with great IVF success rates or failure with long-lasting effects.

Construction should involve using furniture free of VOCs, preferably stainless steel and low VOC materials and adhesives.

Lab improvements can help increase IVF success by implementing cleanroom standards

In a study following the VOC measurements during a renovation of a laboratory, I was able to show key VOC emissions, such as ethyl alcohol, acetone, hexane and toluene, at various point of construction phases, and ways to alleviate and eliminate the VOCs upon completion of the work (Palmer, 2010). This may be common knowledge to the cleanroom aficionados, but was something quite new a decade or so ago.

Other papers on air quality improvements followed, illustrating how lab improvements can help increase IVF success by implementing cleanroom standards.

Heitmann et al. in 2015, for example, described how a former lab with an unreliable HVAC system was transformed. The project used the strategy of pre-filter, photocatalytic irradiation and chemical filtration, by means of activated carbon, potassium permanganate, and finally HEPA filters. Implantation rates were drastically increased, and clinical pregnancy rate increased by 10%.

Still, as IVF resides predominately in the private healthcare sector, a great variety of different types of facilities exist, from renovated listed buildings of grandeur to purpose-built installations.

There was a clear need for clarity within the existing guidelines on optimal laboratory conditions, but in a recently published article, a survey of 36 clinics using an IVF quality control app globally, little conformity could be found (Palmer, 2019).

Laboratory temperatures varied from 17oC to 35oC, and humidity from 5% to 80%; only four laboratories measured air quality; and only two measured VOCs.

The implementation of stricter guidelines is not always welcome. The mere mention of my talk on this subject at Cleanzone Middle East on social media raised a quiet storm doubting the merits of cleanroom technologies. Those raising an eyebrow pointed to costs, increase in staff required and questioned the necessity. Needless to say, the feedback was from old school scientists who had clearly not read or approved of the recent Cairo consensus published in 2018.

The Cairo meeting of experts was set out in the wake of growing evidence for recommending technical and operational requirements, control of particulates, aspirational benchmarks, and help in laboratory commissioning in the future.

The mere mention of my talk on this subject at Cleanzone Middle East on social media raised a quiet storm doubting the merits of cleanroom technologies

The meeting listed the most common agents of contamination and compared a large number of older facilities with laboratories using cleanroom concepts:

In all, there were over 50 consensus points, and it was concluded that cleanroom design should be implemented in any new IVF laboratory builds.

The global fertility rate continues to decline. Main culprits of this trend are the increase in obesity, environmental factors and lifestyle as well as psychographic changes.

Based on 2019 figures, there are over 3,000 clinics worldwide, and the need for IVF is ever-growing. In the US, 1.5% of all children born are a result of assisted reproduction, while the number is 4% in Australia and Israel, and in Denmark 6.4%.

Several economic sources have valued the market to be approximately US$16 billion, with a compound annual growth rate (CAGR) of almost 10%. If this growth holds strong for the next five years, it would mean an industry worth nearly $40 billion by 2025.

Growth is similar in all areas of the globe and large corporations, backed by venture capitalists, are consolidating chains of clinics. Once a reserve of private consultants or small groups of doctors, IVF clinics have now gone big, resulting in chains of IVF clinics.

The success of freezing produces an ever-increasing inventory of cryo-stored embryos, and estimates from IVF research group TMR forecast 21 million people will have stored samples by 2025

The IVF industry has to invest in new facilities equipped with state-of-the-art technology to keep up with this demand and produce high and reproducible standards. The success of freezing produces an ever-increasing inventory of cryo-stored embryos, and estimates from IVF research group TMR forecast 21 million people will have stored samples by 2025. This is a huge capacity that will need significant infrastructure to back it up.

Driven by technological advances, especially in the field of fertility preservation, we will see IVF clinics even more widespread and frequently used than they are today.

Consulting on various projects, in the UK and abroad, I have seen a huge lack in understanding of what is required to construct and maintain a successful IVF facility. I welcome the introduction of cleanroom companies into the IVF industry, as many aspects of your work and products are applicable to our industry today.

The modular cleanroom initiatives, such as the Shellbe system, are particularly appealing for their capacity to produce a zero VOC laboratory customised to the clients needs.

I welcome the introduction of cleanroom companies into the IVF industry, as many aspects of your work and products are applicable to our industry today

Fickle and demanding, we embryologists may be about the conditions and the design of the IVF clinic, but I am often hampered by lack of local expertise (or material) in various places of the world. As real estate costs and availability become so prohibitive in many cities, the portable, adaptable modular lab can be designed, shipped and constructed like Lego and fit suitably in spaces that were previously unutilised.

With so much evidence and interest in our field, now is the time for the IVF industry to enter the biotechnology arena and be ready for cleanroom technology.

N.B. This article is featured in the December 2019 issue of Cleanroom Technology. Subscribe today and get your print copy!

The latest digital edition is available online.

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Big-think story: What does religious faith have to do with slumping global birth rates? – GetReligion

The End of Babies.

That was the arresting headline on a hefty and significant lead article in The New York Times Sunday Review section for Nov. 17 about spreading international reproductive malaise, a.k.a what some are now calling the Baby Bust.

This is big stuff. Yes, there are religious implications here.

The Guy is old enough to remember apocalyptic journalism about a lethal population explosion heading our way. Now social analysts are issuing the opposite warning for some countries. Among other ills, when average ages rise this causes labor shortages, lack of children to care for aged parents and deficits in public and private pension funds with fewer younger wage-earners to carry the oldsters.

Government interventions to skew population can cause trouble.

China feared increasing hordes and long forced couples to have only one child. Combined with open abortion and gender favoritism, that has produced a dire shortage of marriageable women. David French of thedispatch.com notes the National Bureau of Economic Research found that Californias paid family leave, which youd think would encourage more births, apparently reduced childbearing.

To keep the population from shrinking, a nation needs an average of 2.1 births per woman resident. Numbers fall well below that in e.g. Taiwan (1.13), Japan (1.42), Thailand (1.52), China (1.6), the United States (an all-time low of 1.7) and numerous well-off European nations like Denmark (also 1.7).

Denmark is a major puzzle in the Times piece by Anna Louie Sussman, working in partnership with the Pulitzer Center on Crisis Reporting. Affluent Danes are better able to cover the costs of child-rearing than parents in many countries. Denmarks welfare state makes it as easy as possible to have children, with 12 months of family leave after birth, government funding for in vitrofertilization, and heavily subsidized day care.

So what gives?

Better career opportunities for women are one factor. A culture in which legalized abortion is a given is another.

Reflecting the socio-political Left, Sussman thinks the climate crisis and income inequality make many couples reluctant to bring children into this world. She says capitalist economies are the big driver, providing wealth that makes many prefer recreation to bothering with kids, and turning employees into workaholics who feel they lack the time and energy for parenting.

Journalists will consider that theres a major religious angle to focus on, as usually with societal trends. Couples without children feel less incentive to be active in religious congregations, which dwindle as a result. On the other hand, Sussman observes, declining religiosity generally means fewer births. Secularism fosters materialism fosters childlessness.

Some faiths are notably invested in producing children, for instance the Amish, Hasidic Jews and Latter-day Saints. Healthy birth rates are a major reason some demographers predict Islam will surpass Christianity as the worlds largest religion later this century. Growing religious flocks tend to make converts, retain their young people and encourage families with multiple children. Do the math.

Fortunately for religion writers, the Times feature appears simultaneously with a vigorous pro-reproduction religious proclamation titled The Gift of Children. It was issued by 24 American thinkers in the Evangelicals and Catholics Together (ECT) project, which has produced a series of joint statements since 1994 expressing traditional Christian teachings on cultural and religious issues.

Some journalists will want to report how these Catholics and Protestants jointly treat news topics like birth control, abortion, same-sex marriage and artificial methods of human reproduction. But here The Guy will note only their slant on the birth dearth.

In the Bibles view, the statement notes, God says to be fruitful and multiply (Genesis 1:28), Moses admonishes Israelites to choose life that you and your descendants may live (Deuteronomy 30:19), and children are a heritage from the Lord and a reward (Psalm 127:3). ECT says that to have a child is to have a future through committing ourselves to renewing and caring for the forward-flowing stream of life.

ECT asserts that being a parent is natural and an act of faith even for non-believers, and fundamental to what it means to be human. For believers, it is nothing less than a divine commandment where possible. Deliberately to refuse the gift of children implicates us in a turn away from the living God, so much so that were told clergy should not perform weddings of couples that intend to be childless.

Yes, Christianity does uphold those who are single or who enter celibate church vocations. But for ECT that does not endorse the sterility of the present age. The chaste single life does not refuse the gift of children for the sake of present pleasures or out of anxieties about a future we cannot control. Singles can function as parents for the children in their families, churches and communities.

Much generation-shaping material here for writers and their sources to examine.

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Big-think story: What does religious faith have to do with slumping global birth rates? - GetReligion

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Chinas CRISPR babies: Read exclusive excerpts from the unseen original research – MIT Technology Review

Earlier this year a source sent us a copy of an unpublished manuscript describing the creation of the first gene-edited babies, born last year in China. Today, we are making excerpts of that manuscript public for the first time.

Titled Birth of Twins After Genome Editing for HIV Resistance, and 4,699 words long, the still unpublished paper was authored by He Jiankui, the Chinese biophysicist who created the edited twin girls. A second manuscript we also received discusses laboratory research on human and animal embryos.

The metadata in the files we were sent indicate that the two draft papers were edited by He in late November 2018 and appear to be what he initially submitted for publication. A combined manuscript may also exist. After consideration by at least two prestigious journals, Nature and JAMA, his research remains unpublished.

The text of the twins paper is replete with expansive claims of a medical breakthrough that can control the HIV epidemic. It claims successa word used more than oncein using a novel therapy to render the girls resistant to HIV. Yet surprisingly, it makes little attempt to prove that the twins really are resistant to the virus. And the text largely ignores data elsewhere in the paper suggesting that the editing went wrong.

We shared the unpublished manuscripts with four expertsa legal scholar, an IVF doctor, an embryologist, and a gene-editing specialistand asked them for their reactions. Their views were damning. Among them: key claims that He and his team made are not supported by the data; the babies parents may have been under pressure to agree to join the experiment; the supposed medical benefits are dubious at best; and the researchers moved forward with creating living human beings before they fully understood the effects of the edits they had made.

Because these documents relate to one of the most important public interest issues of all timethe ability to change human heredity using technologywe here present excerpts from the twins manuscript, together with some of the experts comments, and explain the questions they raise. The excerpts are in the order in which they appear in the paper.

To understand why the manuscripts have remained unpublished up to now, read the accompanying article on He's attempts to get them into scientific journals. For the case for making their content public, read the op-ed by Kiran Musunuru, a gene-editing specialist at the University of Pennsylvania, who argues the Chinese data shows that gene-editing for reproduction is unsafe and premature.

1. Why arent the doctors among the papers authors?

The manuscript begins with a list of the authors10 of them, mostly from He Jiankuis lab at the Southern University of Science and Technology, but also including Hua Bai, director of an AIDS support network, who helped recruit couples, and Michael Deem, an American biophysicist whose role is under review by Rice University.

Its a small number of people for such a significant project, and one reason is that some names are missingnotably, the fertility doctors who treated the patients and the obstetrician who delivered the babies. Concealing them may be an attempt to obscure the identities of the patients. However, it also leaves unclear whether or not these doctors understood they were helping to create the first gene-edited babies.

To some, the question of whether the manuscript is trustworthy arises immediately.

Hank Greely, professor of law, Stanford University: We have no, or almost no, independent evidence for anything reported in this paper. Although I believe that the babies probably were DNA-edited and were born, theres very little evidence for that. Given the circumstances of this case, I am not willing to grant He Jiankui the usual presumption of honesty.

2. The researchers own data dont support their main claims

The abstract, or summary, lays out the aim of the projectto generate humans resistant to HIVand the main results. It states that the team was successfully able to reproduce a known mutation in a gene called CCR5. The small percentage of people born naturally with this mutation, known as CCR5 delta 32, can be immune to infection by HIV.

But the summary goes well beyond what the data in the paper can back up. Specifically, as well see later, the team didnt actually reproduce the known mutation. Rather, they created new mutations, which might lead to HIV resistance but might not. They never checked to see, according to the paper.

Fyodor Urnov, genome-editing scientist, Innovative Genomics Institute, University of California, Berkeley: The claim they have reproduced the prevalent CCR5 variant is a blatant misrepresentation of the actual data and can only be described by one term: a deliberate falsehood. The study shows that the research team instead failed to reproduce the prevalent CCR5 variant. The statement that embryo editing will help millions is equal parts delusional and outrageous, and is akin to saying that the 1969 moonwalk brings hopes to millions of human beings seeking to live on the moon.

Rita Vassena, scientific director, Eugin Group: Approaching this document, I was hoping to see a reflective and mindful approach to gene editing in human embryos. Unfortunately, it reads more like an experiment in search of a purpose, an attempt to find a defensible reason to use CRISPR/Cas9 technology in human embryos at all costs, rather than a conscientious, carefully thought through, stepwise approach to editing the human genome for generations to come. As the current scientific consensus indicates, the use of CRISPR/Cas9 in human embryos destined to give rise to a pregnancy is, at this stage, unjustified and unnecessary, and should not be pursued.

3. Gene-editing embryos wont bring HIV under control, especially in the worst-affected countries

The end of the abstract and beginning of the main text is where the authors justify their research. They suggest that gene-editing babies could save millions of people from HIV infection. Our commenters call this claim preposterous and ludicrous, and point out that even if the CRISPR method works to create people who are HIV resistant, its unlikely to be practical in places where HIV is rampant, such as in the southern part of Africa.

Rita Vassena: This work offers little justification for the editing and subsequent transfer of human embryos to generate a pregnancy. The idea that editing-derived embryos may one day be able to control the HIV epidemic, as the authors claim, is preposterous. Public health initiatives, education, and widespread access to antiviral drugs have been shown to control the HIV epidemic.

Hank Greely: That this is a plausible way to control the HIV epidemic seems ludicrous. If every baby in the world were given this variation (beyond unlikely), it would begin to affect HIV infection substantially in 20 to 30 years, by which time we should have much better methods of stemming the epidemicas well as existing methods that have substantially, if not yet sufficiently, slowed it. The 64% increase in infections in China (if true) is from a very low base. China has a substantially lower rate of HIV infection than Western countries. The situation in some developing countries remains more serious. But that this high-tech response is likely to be helpful in those countries is not plausible.

4. The parents might have wanted to take part for the wrong reasons

Contrary to some interpretations, the point of using CRISPR on the babies DNA wasnt to prevent them from catching HIV from their father, who was infected. As the paper describes, this was achieved by sperm washing, a well-established technique. Instead, the purpose of the editing was to give the children immunity to HIV later in life. Thus, the experiment didnt provide clear, immediate medical benefits to either the parents or the children. Why did the couple agree? One reason may have been to access fertility treatment at all.

Rita Vassena: I find it worrying that the husband in the couple offered this experimental genome editing was positive to HIV infection, as one can imagine the unnecessary emotional pressure on the couple to consent to a procedure offering no improvement to the patient and their childrens health, but carrying a potential risk of negative consequences. It is worth remembering that HIV infection is not passed on through generations like a genetic disease; the embryo needs to catch the infection. For this reason, preventive measures such as controlling the viral load of the patient with appropriate drugs, and careful handling of the gametes during IVF, can avoid contagion very efficiently. Current assisted reproductive techniques ensure safe procreation for HIV-positive men and women, avoiding both horizontal (between partners) and vertical (between parent and embryo/fetus) transmission, making the editing of embryos in these cases unnecessary. In fact, the couple in the experiment did undergo such ART procedures, consisting in this case of an extended wash of semen to remove all seminal fluid, which may harbor HIV. Extended sperm washing has been used for almost two decades in IVF laboratories worldwide and in thousands of patients; in ours and others experience, it is safe for both parents and their future children and does not entail invasive manipulation of embryos.

Jeanne OBrien, reproductive endocrinologist, Shady Grove Fertility: Being HIV-positive in China carries a significant social stigma. In spite of intense familial and societal obligations to have a child, HIV-positive patients have no access to treatment for infertility. The social context in which the clinical study was carried out is problematic and it targeted a vulnerable patient group. Did the study provide a genetic treatment for a social problem? Was this couple free from undue coercion?

5. The gene edits werent the same as the mutations that confer natural HIV resistance

Here, the researchers describe the changes CRISPR actually made to the twins. They removed a few cells from the IVF embryos to look at their DNA, and found that edits intended to disable the CCR5 gene had indeed taken hold.

But while they expect these edits to confer HIV resistance by nullifying the activity of the gene, they cant know for sure, because the edits are similar but not identical to CCR5 delta 32, the mutation that occurs in nature. Moreover, only one of the embryos had edits to both copies of the CCR5 gene (one from each parent); the other had only one edited, giving partial HIV resistance at best.

Hank Greely: Successfully is iffy here. None of the embryos got the 32-base-pair deletion to CCR5 that is known in millions of humans. Instead, the embryos/eventual babies got novel variations, whose effects are not clear. As well, what does partial resistance to HIV mean? How partial? And was that enough to justify transferring the embryo, with a CCR5 gene never before seen in humans, to a uterus for possible birth?

6. There could have been other, unwanted CRISPR edits

CRISPR isnt a perfect tool. Trying to edit one gene can sometimes create other, unintended changes elsewhere in the genome. Here the team discusses their search for such unwanted edits, called off-target mutations, and say they found just one.

The search was incomplete, however, and the manuscript also glosses over a key point: any cells the researchers took from the early-stage embryos to test didnt, therefore, actually contribute to the twins bodies. The remaining cells, the ones that would multiply and grow to become the twins, could have harbored off-target effects too, but there would have been no way to know that in advance of starting the pregnancy.

Fyodor Urnov: An egregious misrepresentation of the actual data that can, again, only be described as a blatant falsehood. It is technically impossible to determine whether an edited embryo did not show any off-target mutations without destroying that embryo by inspecting every one of its cells. This is a key problem for the entirety of the embryo-editing field, one that the authors sweep under the rug here.

7. The doctors treating the couple may not have known what was going on

Reporting by a variety of news outlets, including the Wall Street Journal, has charged that Hes team tricked doctors by switching blood samples and that not all of them knew they were involved in creating gene-edited children. If true, thats a problem, since its the duty of doctors to do what is in the best interest of the patient.

Jeanne OBrien: The IVF procedure described follows the same steps and time line whether or not CRISPR is used for genome editing. The Chinese physicians who performed the IVF may have been unaware of the fathers HIV status or that the embryos were genetically modified. He Jiankui would have only needed a willing embryologist to inject CRISPR at the time of insemination. Hes comments make it appear as if the physicians who performed the IVF were not involved in the subsequent decision regarding which embryos to select for transfer. This is a wake-up call to physicians involved in IVF: the science and technology will continue to progress, and desperate couples with infertility may overlook the unknowns or believe the technology is proven safe. Once we, the infertility physicians, knowingly transfer an embryo with germline editing, we are in essence confirming the safety of the modification to the parents and the future child. Is it ever possible to know that?

8. The manuscript misrepresents when the babies were born

By now, several media reports and people familiar with the research have established that the twins were born in October, not November. Why did Hes team include a false date? It may have been to protect the anonymity of the patients and their twins. In a country the size of China, there could be more than ten thousand sets of twins born each month. The falsified date may have been an attempt to make their reidentification even more difficult.

9. Its not clear if there was a proper ethics review

The paper includes an exceptionally brief discussion of ethics. It says the research plan was registered with the China Clinical Trial Registry, but in fact the public registration occurred only after the twins were born.

Hank Greely: Registered when? The answer is on November 8, 2018, after the births and very shortly before they were announced, and probably in order to increase publication potential. This was not a normal registration. Maybe there was an ethics approvalthough that hospital has denied it. Who is telling the truth? Not sure well ever know. The phrase we were told about a comprehensive ethics review is not very powerful evidence. The article also does not discuss the Chinese ban on assisted reproductive services for HIV-positive parents. It has been reported that He had other men pretend to be the intended fathers for purpose of the required HIV tests. The article doesnt say this. It seems to me likely to be trueand damning. If true, it means He defrauded the Chinese regulatory process.

10. The researchers didnt test whether the HIV immunity worked before creating living human beings

Here the Chinese team outlines their plan to collect blood from the twins to see if their edited cells really resist HIV. That is something they could have tried to learn ahead of time, before creating the girls. Before transferring the embryos, they could have kept them frozen while they made identical edits in laboratory cells and tested the effects of HIV on those cells.

Fyodor Urnov: This statement proves that the research team placed their interests above those of the couple who donated the embryos and of their prospective children. There is zero evidence in the manuscript supporting the essential expectation that the new forms of CCR5 would be HIV-protective. It was essential to have determined that before the embryos were implanted. They could have done so using a known assay: introduce the same edits into immune system cells in the laboratory and then infect them with HIV. Only the cells that have HIV-protective variants of CCR5 survive. The research team chose not to do that assay. Instead, they made children out of embryos that had forms of CCR5 of entirely uncertain functional impact. Were the researchers in a rush? Did they simply not care? Whatever the explanation, this egregious violation of elementary norms of ethics and of research borders on the criminal.

11. An American Nobelist may have helped He justify his experiment

The articles conclusion contains an unexpected digression that puts forth an entirely new justification for the research, one that connects the project to the heart of the HIV epidemic in Africa. Its that many uninfected children of African mothers with HIV suffer a syndrome called HEU that makes them more susceptible to a variety of childhood illnesses. The authors say genome editing could be a novel strategy against HEU.

There isnt any evidence for this idea, but there are some clues about where He got it. In an email he sent on November 22 to Craig Mello, a biologist at the University of Massachusetts who at the time was an advisor to one of his companies, He thanked Mello for suggestions on the topic and enclosed in his email the same paragraph above.

Does that mean Mello, a winner of the 2006 Nobel Prize for medicine, contributed a key idea to the paper? Mello was told about the twins project early on but, through a spokesman, says he never gave He advice on how to write the paper. According to Hes email, however, any such interaction was meant to remain unacknowledged. Again, I wont tell people you know what is happening here, he wrote to Mello.

12. The project had other supporters, but some key information is missing

The manuscript concludes by thanking a list of people who, according to He, gave him direct feedback on draft versions of the text or other advice. In an acknowledgement for editing the text, he names Mark Dewitt, a researcher at the University of California. Dewitt didnt reply to emails but earlier gave a description of his role, saying he had warned against the project. William Hurlbut, an ethicist at Stanford, says he gave ethics advice to He but didnt know that the Chinese scientist had created children.

He also thanks W.R. Twink Allen, an equine reproduction specialist in the United Kingdom, and Allens onetime student Jin Zhang, also known as John Zhang, who is now head of New Hope Fertility Center in New York, one of the largest in the US. According to reports, Zhang was planning with He late last year to open a medical tourism business for gene-edited babies.

Of these names, only Allens has not previously been cited in connection with the CRISPR-baby research. Allen did not reply to attempts to contact him by email. Zhang, who has not been forthcoming about his role, told us he was not familiar with the manuscript. I have never seen it, he told us in October.

The version of the twins manuscript we have is missing two critically important disclosures usually present in scientific papers. First, it gives no information about who funded the project or what financial interests the authors have in the outcome. Also missing is a section in which each authors scientific contribution is detailed. This means the text does not explicitly describe the role of the single non-Chinese author, Michael Deem of Rice University in Texas. The nature of Deems roleparticularly any hands-on involvement with the patientscould determine penalties that Deem, or his university, could face. Deems lawyers did not answer questions, including a request for copies of his past statements, which sought to minimize his role in the research. Rice says its investigation is ongoing.

13. The researchers ignored evidence that the gene edits werent uniform

In data attached to the paper, in the so-called supplementary material, are tables that He previously showed publicly. It shows chromatograms, or the readout of the DNA sequences found in the embryos and birth tissues of the twins (the umbilical cord and placenta) when his team tried to measure what editing had happened to the CCR5 gene.

Some observers, including Musunuru in our accompanying op-ed, say these data show clearly that the embryos are mosaic, meaning that different cells in the embryo were edited differently. He says presence of multiple edits is visible in the chromatograms, where several distinct readings are registered in overlapping signals at a given DNA position.

The implication of the data is that the twins bodies could be composites of cells edited in different ways, or not at all. That, Musunuru points out, means only some of their cells might have the HIV-resistant gene edit; it also means some might have undetected "off-target" edits, which could potentially cause health problems. The problem of mosaicism was well known to He from his experiments on animal embryos. One of the mysteries of the research project is why He chose to proceed with embryos if they were flawed in this way.

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In his manuscript, He doesnt resolve the mystery. It says only, The CCR5 gene was deep sequenced for all samples to examine the mosaicism of gene editing. Theres no interpretation of what was found, and no acknowledgement that the data seem to show mosaicism or that its a problem.

Fyodor Urnov: They should have worked and worked and worked until they reduced mosaicism to as close to zero as possible. This failed completely. They forged ahead anyway.

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This Irresponsible Sex Ed Curriculum Is Being Taught in Texas School Districts – Friendly Atheist – Patheos

In case youre wondering what bad sex education looks like in some school districts, look no further than than Texas where eight school districts, including the Leander Independent School District (LISD), outsources its sex ed curriculum to a group called Austin LifeGuard (ALG).

ALG is run by Austin LifeCare now using the more deceptive name The Source a self-described anti-abortion crisis pregnancy center with Christian connections. Naturally, theyre less interested in educating students about making safe decisions when having sex, choosing instead to scare them away from sex altogether. That option never works. Which means students are left to fend for themselves when they finally choose to do anything physical.

April S. Kelley writes about the problem for the Hill Country News.

In the 7th grade curriculum, an activity involving Skittles is used to demonstrate how easily sexually transmitted infections are spread from person to person.

The Houston Chronicle published an article in September, and quoted a former LISD student. She shared how the Skittles activity gave her the insinuation of the more people you have sex with, the dirtier you are.

The course packet said each student would be given one Skittle. Students with yellow Skittles would be told to keep their Skittles, while anyone with any other color would trade with as many classmates as possible. After doing so, the students would be asked if they would eat those Skittles. The yellow Skittles represent abstinence.

The executive director of ALG didnt deny they promoted this activity. He just said the focus wasnt about whos dirty. It was meant to teach kids about exposure to sexually transmitted diseases. But the implication in the activity is obvious.

They also mislead students about the effective of condoms. ALG tells students that condoms are only 87% effective, which is a number that includes people who misuse them. Rather than teach kids how to use them properly, though something that the government says has a 98% success rate they would rather mislead kids into thinking condoms are less effective than they really are.

It gets worse.

The 7th grade curriculum also shows a lack of balance between male and female sexuality. The curriculum, which is taught co-ed, shows a diagram of both male and female anatomy to explain human reproduction. In the female anatomy, however, there was one part missing the clitoris.

in the female curriculum, there is no mention of arousal, sexual feelings or of those things being a normal part of female puberty.

Then there are the commercials. Like this one promoting a I Heart Pants campaign because if youre wearing pants, youll never have sex. (These people have clearly never met teenagers)

Another commercial suggests that sexually active teens are not capable of getting good grades or acceptance into top colleges.

Maybe the most disturbing thing about all this is that the LISD has been working with this sex negative group for 13 years; the most recent three-year contract was signed in 2018 at a cost of $35,000 (a year, presumably).

Its yet another example of a conservative Christian organization sneaking its way into public schools with the goal of making students less informed, more at risk, and more in need of outside help down the road. Theyre hurting kids. And that wont change unless students and parents pressure the school board into making decisions that benefit kids instead of appeasing right-wing Christian groups.

(Thanks to @smileysatanist for the link)

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Don’t Know Much Biology – The Reality-Based Community

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Apparently, Republican state legislators in Pennsylvania are attempting to rise to the level of ignorance of biology displayed by their counterparts in Ohio. Specifically, they have introduced House Bill 1890 that requires health care facilities that possess fetal remains to cremate or inter the fetal remains.

The proposed statute defines fetal remains to mean a fetus expelled or extracted in the case of a fetal death. The term fetus is not defined. Rather, the proposed statute defines fetal death to be the expulsion or extraction from its mother of a product of conception which shows no evidence of life after the expulsion or extraction. Thus, the statute ignores the difference between an embryo and a fetus. According to the Merck Manual, an embryo is not considered a fetus until the end of the 8th week after fertilization (10 weeks of pregnancy).

At least one study has calculated that 15% of the documented pregnancies ended in first trimester miscarriages per pregnancy. Further, current research showing about 50% to 60% of miscarriages are the result of random fetal chromosomal abnormalities incompatible with life. (Endnotes omitted.) Somewhat different statistics are presented by the National Institutes of Health which finds that [i]t is estimated that as many as26% of all pregnancies end in miscarriage and up to 10% of clinically recognized pregnancies. Moreover, 80% of early pregnancy loss occurs in the first trimester. (Endnotes omitted.)

Pennsylvania House Bill 1890 is nothing more than a ham-handed attempt to impose specific religious beliefs. It simply ignores the biology of human reproduction. As this paper finds:

A synthesis of many large-scale studies from the last 15 years unambiguously confirms the Wood-Boklage-Holman hypothesis that abortion is an intrinsic and overarching component of human reproduction. It is the most common outcome of conception across a womans lifetime and the predominant factor controlling age-specific variation in human female fertility. To reproduce, a human female cannot forgo a high risk of abortion, and to have a large family it is virtually impossible to avoid multiple abortions. Modern birth control with access to elective abortions, markedly reduces rather than increases the lifetime number of abortions a woman produces.

Oh, yeah, one other thing. The proposed bill is unlikely to raise GOP support among women.

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Column: Alas, the era of the Chicago gangway is coming to an end – Chicago Tribune

Despite those perils, gangways provided a detour around street-gang conflicts. Or, in my case, religious disputes. My afternoon passage from grade school to Hebrew school came perilously close to a Catholic school. On the sidewalks, I was more than once confronted by boys who wanted to debate theology with their fists. Then I discovered a gangway route, and sidestepped further confrontations.

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Column: Alas, the era of the Chicago gangway is coming to an end - Chicago Tribune

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